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Background and purposeIntracarotid arterial infusion of nonionic, low-osmolal iohexol contrast medium has been associated with increased intracranial hemorrhage in a rat middle cerebral artery occlusion model compared with saline infusion. Iso-osmolal iodixanol (290 mOsm/kg H2O) infusion demonstrated smaller infarcts and less intracranial hemorrhage compared with low-osmolal iopamidol and saline. No studies comparing iodinated radiographic contrast media in human stroke have been performed, to our knowledge. We hypothesized that low-osmolal contrast media may be associated with worse outcomes compared with iodixanol in the Interventional Management of Stroke III Trial (IMS III).Materials and methodsWe reviewed prospective iodinated radiographic contrast media data for 133 M1 occlusions treated with endovascular therapy. We compared 5 prespecified efficacy and safety end points (mRS 0-2 outcome, modified TICI 2b-3 reperfusion, asymptomatic and symptomatic intracranial hemorrhage, and mortality) between those receiving iodixanol (n = 31) or low-osmolal contrast media (n = 102). Variables imbalanced between iodinated radiographic contrast media types or associated with outcome were considered potential covariates for the adjusted models. In addition to the iodinated radiographic contrast media type, final covariates were those selected by using the stepwise method in a logistic regression model. Adjusted relative risks were then estimated by using a log-link regression model.ResultsOf baseline or endovascular therapy variables potentially linked to outcome, prior antiplatelet agent use was more common and microcatheter iodinated radiographic contrast media injections were fewer with iodixanol. Relative risk point estimates are in favor of iodixanol for the 5 prespecified end points with M1 occlusion. The percentage of risk differences are numerically greater for microcatheter injections with iodixanol.ConclusionsWhile data favoring the use of iso-osmolal iodixanol for reperfusion of M1 occlusion following IV rtPA are inconclusive, potential pathophysiologic mechanisms suggesting clinical benefit warrant further investigation.

Objectives: To determine the optimal cooling duration for children after out-of-hospital cardiac arrest (OHCA) using an adaptive Bayesian trial design., Design: The Pediatric Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (P-ICECAP) trial is a randomized, response-adaptive duration/dose-finding clinical trial with blinded outcome assessment. Participants are randomized to one of several cooling durations (0, 12, 18, 24, 36, 48, 60, 72, 84, or 96 hr). The first 150 participants are randomized 1:1:1 to 24-, 48-, and 72-hour durations. Response-adaptive randomization is used thereafter to allocate participants based on emerging duration-response data., Setting: PICUs., Patients: Up to 900 pediatric patients 2 days to younger than 18 years old who have survived OHCA and been admitted to an ICU., Interventions: Duration of targeted temperature management using a surface temperature control device., Measurements and Main Results: The primary outcome is the Vineland Adaptive Behavior Scales-Third Edition mortality composite score, assessed at 12 months. Secondary outcomes include changes in the Pediatric Cerebral Performance Category and Pediatric Resuscitation after Cardiac Arrest scores, as well as survival at 12 months. Bayesian modeling is employed to evaluate the duration-response curve and determine the optimal cooling duration. The trial is designed to adaptively update randomization probabilities every 10 weeks, maximizing the allocation of participants to potentially optimal cooling durations. Over 90% power is achieved for the hypothesized scenarios., Conclusions: The P-ICECAP trial aims to identify the shortest cooling duration that provides the maximum treatment effect for pediatric OHCA patients. The adaptive design allows for flexibility and efficiency in handling various clinical scenarios, potentially transforming pediatric cardiac arrest care by optimizing hypothermia treatment protocols., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: The usual antithrombotic treatment for symptomatic intracranial atherosclerotic stenosis (ICAS) consists of dual treatment with clopidogrel and aspirin for 90 days followed by aspirin alone but the risk of recurrent stroke remains high up to 12 months. The Comparison of Anticoagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) trial was designed to determine whether other combinations of dual antithrombotic therapy are superior to clopidogrel and aspirin., Methods: CAPTIVA is an ongoing, prospective, double-blinded, three-arm clinical trial at over 100 sites in the United States and Canada that will randomize 1683 high-risk subjects with a symptomatic infarct attributed to 70-99% stenosis of a major intracranial artery to 12 months of treatment with (1) ticagrelor (180 mg loading dose, then 90 mg twice daily), (2) low-dose rivaroxaban (2.5 mg twice daily), or (3) clopidogrel (600 mg loading dose, then 75 mg daily). All subjects receive aspirin (81 mg daily), intensive risk factor management, and will undergo blinded CYP2C19 genotype analysis. The primary goal of the trial is to determine whether rivaroxaban or ticagrelor or both are superior to clopidogrel for lowering the primary endpoint (ischemic stroke, intracerebral hemorrhage (ICH), or vascular death) within 12 months. A prespecified interim safety analysis will be conducted when the first 450 randomized subjects have been followed for 12 months to evaluate the risk of major hemorrhage in the rivaroxaban and ticagrelor arms., Results: Enrollment began in August 2022 and, as of 26 June 2024, the 450th subject was randomized into the study., Conclusion: CAPTIVA is evaluating two alternative dual antithrombotic therapies to clopidogrel and aspirin to maximize the chance of establishing more effective antithrombotic therapy for symptomatic ICAS, one of the most common and high-risk cerebrovascular diseases worldwide., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:B.L.H., MD, MBA:Relevant: NIH, AstraZeneca is supplying ticagrelor and Janssen Pharmaceutical is supplying rivaroxaban for the CAPTIVA trial.Not relevant: University of Florida, NIH, and research support from the Brain Aneurysm Foundation and The Aneurysm and AVM Foundation. B.L.H. is an investor in FastWave, Galaxy Therapeutics, Kandu, Progressive Neuro, ProprioVision, and Solenic.M. I. C., MBChB:Relevant: NIH. Salary support as a multiple principal investigator for the ongoing NIH-funded CAPTIVA trial. AstraZeneca is supplying ticagrelor and Janssen Pharmaceutical is supplying rivaroxaban for the CAPTIVA trial.Not relevant: Medtronic (DSMB for subdural hemorrhage trial), Boehringer Ingelheim (stroke adjudicator for steatohepatitis clinical trial)S.D.Y., PhD:Relevant: NIHNot Relevant: journal Stroke (Statistical Editor)T.N.T., MD:Relevant: NIH, AstraZeneca (clinical event adjudication committee member)Not relevant: clinical event adjudication committee member for Novo Nordisk, Gore Inc., Occlutech, Horizon Therapeutics, LG Chem, Sanofi, and Areteia Therapeutics; and royalties from UpToDateK.R.P., MD:Relevant: NIHNonrelevant: Department of Defense. Industry-funded research through Toshiba America Medical Systems, Canon, and Banyan Biomarkers.L.H.C., PharmD:Relevant: NIHNonrelevant: NIH, Werfen (research support)J.P.B., MD:Relevant: NIHNonrelevant: Novo Nordisk (research support); Genentech (support for University of Cincinnati Department of Neurology and Rehabilitation Medicine); Roche, BrainsGate Ltd., Basking Biosciences, and the Pharmacy and Therapeutics Committee of Kroger Prescriptions Plans, Inc.R.H.M., R.M.B., S.M., L.B., J.S., A.M.W., N.S., C.U., and J.S.F.:Relevant: NIHNot relevant: none

Purpose: Perceived poor prognosis can lead to withdrawal of life-sustaining therapies (WLST) in patients who might otherwise recover. We characterized clinicians' approach to post-arrest prognostication in a multicenter clinical trial., Methods: Semi-structured interviews were conducted with clinicians who treated a comatose post-cardiac arrest patient enrolled in the Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP) trial (NCT04217551). Two authors independently analyzed each interview using inductive and deductive coding. The clinician reported how they arrived at a prognosis for the specific patient. We summarized the frequency with which clinicians reported using objective diagnostics to formulate their prognosis, and compared the reported approaches to established guidelines. Each respondent provided demographic information and described local neuroprognostication practices., Results: We interviewed 30 clinicians at 19 US hospitals. Most claimed adherence to local hospital neuroprognostication protocols (n = 19). Prognostication led to WLST for perceived poor neurological prognosis in 15/30 patients, of whom most showed inconsistencies with guidelines or trial recommendations, respectively. In 10/15 WLST cases, clinicians reported relying on multimodal testing. A prevalent theme was the use of "clinical gestalt," defined as prognosticating based on a patient's overall appearance or a subjective impression in the absence of objective data. Many clinicians (21/30) reported using clinical gestalt for initial prognostication, with 9/21 expressing high confidence initially., Conclusion: Clinicians in our study state they follow neuroprognostication guidelines in general but often do not do so in actual practice. They reported clinical gestalt frequently informed early, highly confident prognostic judgments, and few objective tests changed initial impressions. Subjective prognostication may undermine well-designed trials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The impact of intracerebral hemorrhage (ICH) on cognition and the determinants of cognitive recovery early after ICH remain elusive. In this post hoc analysis of the intracerebral hemorrhage deferoxamine (iDEF) trial, we examined the trajectories of cognitive impairment and the determinants of early cognitive recovery after ICH., Methods: We examined baseline factors associated with a 90-day cognitive outcome and constructed generalized linear mixed models to examine the trajectory of cognitive function over time among iDEF participants. Cognition was measured by the Montreal Cognitive Assessment (MoCA) scores on days 7, 30, and 90., Results: 291 were available for analysis under the trial's modified intention-to-treat definition (38% female, mean age 60.3 ± 12.0 years, median NIHSS 13, IQR 8-18). The median baseline ICH volume was 12.9 IQR (6.4-26.0) mL; 59 (20%) of the ICH cases were lobar, 120 (41%) had intraventricular extension. There was an overall significant increase in total MOCA score with time (p < 0.0001). Total MOCA score increased by an estimated 3.9 points (95% CI: 3.1, 4.7) between the day 7 and day 30 assessments and by an additional 2.9 points (95% CI: 2.2, 3.6) between the day 30 and day 90 assessments. Despite the overall improvement, 134 of 205 (65%) patients with an available 90-day MoCA score remained cognitively impaired with a score <26 on day 90. Older age, higher NIHSS score, baseline ICH volume, intraventricular hemorrhage, and perihematoma edema had an adjusted negative impact on cognitive recovery., Conclusions: Although ICH survivors exhibit significant improvement of cognitive status over the first 3 months, cognitive performance remains impaired in the majority of patients. Among factors independently associated with worse cognitive recovery, higher baseline ICH, intraventricular blood and perihematomal edema volumes, are potential therapeutic targets that merit further exploration., (© 2024 S. Karger AG, Basel.)

Introduction: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life., Methods: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE., Conclusion: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins., (S. Karger AG, Basel.)

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction., (© 2023 John Wiley & Sons Ltd.)

Introduction: During the COVID-19 pandemic, research organizations accelerated adoption of technologies that enable remote participation. Now, there's a pressing need to evaluate current decentralization practices and develop appropriate research, education, and operations infrastructure. The purpose of this study was to examine current adoption of decentralization technologies in a sample of clinical research studies conducted by academic research organizations (AROs)., Methods: The setting was three data coordinating centers in the U.S. These centers initiated coordination of 44 clinical research studies during or after 2020, with national recruitment and enrollment, and entailing coordination between one and one hundred sites. We determined the decentralization technologies used in these studies., Results: We obtained data for 44/44 (100%) trials coordinated by the three centers. Three technologies have been adopted across nearly all studies (98-100%): eIRB, eSource, and Clinical Trial Management Systems. Commonly used technologies included e-Signature (32/44, 73%), Online Payments Portals (26/44, 59%), ePROs (23/44, 53%), Interactive Response Technology (22/44, 50%), Telemedicine (19/44, 43%), and eConsent (18/44, 41%). Wearables (7/44,16%) and Online Recruitment Portals (5/44,11%) were less common. Rarely utilized technologies included Direct-to-Patient Portals (1/44, 2%) and Home Health Nurse Portals (1/44, 2%)., Conclusions: All studies incorporated some type of decentralization technology, with more extensive adoption than found in previous research. However, adoption may be strongly influenced by institution-specific IT and informatics infrastructure and support. There are inherent needs, responsibilities, and challenges when incorporating decentralization technology into a research study, and AROs must ensure that infrastructure and informatics staff are adequate., Competing Interests: MC and BB are employees of Doxy.me, LLC, a commercial telemedicine company. The other authors have no relevant competing interests., (© The Author(s) 2023.)

Importance: The effects of moderate systolic blood pressure (SBP) lowering after successful recanalization with endovascular therapy for acute ischemic stroke are uncertain., Objective: To determine the futility of lower SBP targets after endovascular therapy (<140 mm Hg or 160 mm Hg) compared with a higher target (≤180 mm Hg)., Design, Setting, and Participants: Randomized, open-label, blinded end point, phase 2, futility clinical trial that enrolled 120 patients with acute ischemic stroke who had undergone successful endovascular therapy at 3 US comprehensive stroke centers from January 2020 to March 2022 (final follow-up, June 2022)., Intervention: After undergoing endovascular therapy, participants were randomized to 1 of 3 SBP targets: 40 to less than 140 mm Hg, 40 to less than 160 mm Hg, and 40 to 180 mm Hg or less (guideline recommended) group, initiated within 60 minutes of recanalization and maintained for 24 hours., Main Outcomes and Measures: Prespecified multiple primary outcomes for the primary futility analysis were follow-up infarct volume measured at 36 (±12) hours and utility-weighted modified Rankin Scale (mRS) score (range, 0 [worst] to 1 [best]) at 90 (±14) days. Linear regression models were used to test the harm-futility boundaries of a 10-mL increase (slope of 0.5) in the follow-up infarct volume or a 0.10 decrease (slope of -0.005) in the utility-weighted mRS score with each 20-mm Hg SBP target reduction after endovascular therapy (1-sided α = .05). Additional prespecified futility criterion was a less than 25% predicted probability of success for a future 2-group, superiority trial comparing SBP targets of the low- and mid-thresholds with the high-threshold (maximum sample size, 1500 with respect to the utility-weighted mRS score outcome)., Results: Among 120 patients randomized (mean [SD] age, 69.6 [14.5] years; 69 females [58%]), 113 (94.2%) completed the trial. The mean follow-up infarct volume was 32.4 mL (95% CI, 18.0 to 46.7 mL) for the less than 140-mm Hg group, 50.7 mL (95% CI, 33.7 to 67.7 mL), for the less than 160-mm Hg group, and 46.4 mL (95% CI, 24.5 to 68.2 mL) for the 180-mm Hg or less group. The mean utility-weighted mRS score was 0.51 (95% CI, 0.38 to 0.63) for the less than 140-mm Hg group, 0.47 (95% CI, 0.35 to 0.60) for the less than 160-mm Hg group, and 0.58 (95% CI, 0.46 to 0.71) for the high-target group. The slope of the follow-up infarct volume for each mm Hg decrease in the SBP target, adjusted for the baseline Alberta Stroke Program Early CT score, was -0.29 (95% CI, -0.81 to ∞; futility P = .99). The slope of the utility-weighted mRS score for each mm Hg decrease in the SBP target after endovascular therapy, adjusted for baseline utility-weighted mRS score, was -0.0019 (95% CI, -∞ to 0.0017; futility P = .93). Comparing the high-target SBP group with the lower-target groups, the predicted probability of success for a future trial was 25% for the less than 140-mm Hg group and 14% for the 160-mm Hg group., Conclusions and Relevance: Among patients with acute ischemic stroke, lower SBP targets less than either 140 mm Hg or 160 mm Hg after successful endovascular therapy did not meet prespecified criteria for futility compared with an SBP target of 180 mm Hg or less. However, the findings suggested a low probability of benefit from lower SBP targets after endovascular therapy if tested in a future larger trial., Trial Registration: ClinicalTrials.gov Identifier: NCT04116112.

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Early triage and treatment after TBI have been shown to improve outcome. Identifying patients at risk for increased intracranial pressure (ICP) via baseline computed tomography (CT) , however, has not been validated previously in a prospective dataset. We hypothesized that acute CT findings of elevated ICP, combined with direct ICP measurement, hold prognostic value in terms of six-month patient outcome after TBI. Data were obtained from the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECTIII) multi-center clinical trial. Baseline CT scans for 881 participants were individually reviewed by a blinded central neuroradiologist. Five signs of elevated ICP were measured (sulcal obliteration, lateral ventricle compression, third ventricle compression, midline shift, and herniation). Associations between signs of increased ICP and outcomes (six-month functional outcome and death) were assessed. Secondary analyses of 354 patients with recorded ICP monitoring data available explored the relationships between hemorrhage phenotype/anatomic location, sustained ICP ≥20 mm Hg, and surgical intervention(s). Univariate and multi-variate logistic/linear regressions were performed; p  < 0.05 is defined as statistically significant. Imaging characteristics associated with ICP in this cohort include sulcal obliteration ( p  = 0.029) and third ventricular compression ( p  = 0.039). Univariate regression analyses indicated that increasing combinations of the five defined signs of elevated ICP were associated with death, poor functional outcome, and time to death. There was also an increased likelihood of death if patients required craniotomy (odds ratio [OR] = 4.318, 95% confidence interval [1.330-16.030]) or hemicraniectomy (OR = 2.993 [1.109-8.482]). On multi-variate regression analyses, hemorrhage location was associated with death (posterior fossa, OR = 3.208 [1.120-9.188] and basal ganglia, OR = 3.079 [1.178-8.077]). Volume of hemorrhage >30 cc was also associated with increased death, OR = 3.702 [1.575-8.956]). The proportion of patient hours with sustained ICP ≥20 mm Hg, and maximum ICP ≥20 mm Hg were also directly correlated with increased death (OR = 6 4.99 [7.731-635.51]; and OR = 1.025 [1.004-1.047]), but not with functional outcome. Poor functional outcome was predicted by concurrent presence of all five radiographic signs of elevated ICP (OR = 4.44 [1.514-14.183]) and presence of frontal lobe (OR = 2.951 [1.265-7.067]), subarachnoid (OR = 2.231 [1.067-4.717]), or intraventricular (OR = 2.249 [1.159-4.508]) hemorrhage. Time to death was modulated by total patient days of elevated ICP ≥20 mm Hg (effect size = 3.424 [1.500, 5.439]) in the first two weeks of hospitalization. Sulcal obliteration and third ventricular compression, radiographic signs of elevated ICP, were significantly associated with measurements of ICP ≥20 mm Hg. These radiographic biomarkers were significantly associated with patient outcome. There is potential utility of ICP-related imaging variables in triage and prognostication for patients after moderate-severe TBI.

From 2016 to 2021, the National Institutes of Health Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke initiated ten multicenter randomized controlled clinical trials. Optimal subject randomization designs are demanded with 4 critical properties: (1) protection of treatment assignment randomness, (2) achievement of the desired treatment allocation ratio, (3) balancing of baseline covariates, and (4) ease of implementation. For acute stroke trials, it is necessary to minimize the time between eligibility assessment and treatment initiation. This article reviews the randomization designs for 3 trials currently enrolling in Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke, the SATURN (Statins in Intracerebral Hemorrhage Trial), the MOST (Multiarm Optimization of Stroke Thrombolysis Trial), and the FASTEST (Recombinant Factor VIIa for Hemorrhagic Stroke Trial). Randomization methods utilized in these trials include minimal sufficient balance, block urn design, big stick design, and step-forward randomization. Their advantages and limitations are reviewed and compared with traditional stratified permuted block design and minimization., Competing Interests: Disclosures Dr Zhao reports grants from National Institutes of Health. Dr Yeatts reports other intellectual property licensed to American Stroke Association; compensation from C.R. Bard, Inc & Subsidiaries for data and safety monitoring services; employment by Medical University of South Carolina; grants from National Heart, Lung, and Blood Institute; grants from National Institute of Neurological Disorders and Stroke; and compensation from Emory University for data and safety monitoring services. Dr Selim reports grants from NIH/NIA; compensation from MedRhythms, Inc for consultant services; and grants from NIH/NINDS. Dr Adeoye reports service as Chief Medical Officer for sense diagnostics and compensation from NICO Corporation for data and safety monitoring services. Dr Durkalski-Mauldin reports grants from National Institutes of Health. Dr Elm reports grants from National Institutes of Health.

Multiple randomized, controlled clinical trials have yielded discordant results regarding the efficacy of convalescent plasma in outpatients, with some showing an approximately 2-fold reduction in risk and others showing no effect. We quantified binding and neutralizing antibody levels in 492 of the 511 participants from the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) of a single unit of COVID-19 convalescent plasma (CCP) versus saline infusion. In a subset of 70 participants, peripheral blood mononuclear cells were obtained to define the evolution of B and T cell responses through day 30. Binding and neutralizing antibody responses were approximately 2-fold higher 1 hour after infusion in recipients of CCP compared with saline plus multivitamin, but levels achieved by the native immune system by day 15 were almost 10-fold higher than those seen immediately after CCP administration. Infusion of CCP did not block generation of the host antibody response or skew B or T cell phenotype or maturation. Activated CD4+ and CD8+ T cells were associated with more severe disease outcome. These data show that CCP leads to a measurable boost in anti-SARS-CoV-2 antibodies but that the boost is modest and may not be sufficient to alter disease course.

Background/aims: Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy., Methods: We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios., Results: Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis., Conclusion: The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Background: Transcranial Doppler ultrasonography (TCD) is a portable, bedside, noninvasive diagnostic tool used for the real-time assessment of cerebral hemodynamics. Despite the evident utility of TCD and the ability of this technique to function as a stethoscope to the brain, its use has been limited to specialized centers because of the dearth of technical and clinical expertise required to acquire and interpret the cerebrovascular parameters. Additionally, the conventional pragmatic episodic TCD monitoring protocols lack dynamic real-time feedback to guide time-critical clinical interventions. Fortunately, with the recent advent of automated robotic TCD technology in conjunction with the automated software for TCD data processing, we now have the technology to automatically acquire TCD data and obtain clinically relevant information in real-time. By obviating the need for highly trained clinical personnel, this technology shows great promise toward a future of widespread noninvasive monitoring to guide clinical care in patients with acute brain injury., Methods: Here, we describe a proposal for a prospective observational multicenter clinical trial to evaluate the safety and feasibility of prolonged automated robotic TCD monitoring in patients with severe acute traumatic brain injury (TBI). We will enroll patients with severe non-penetrating TBI with concomitant invasive multimodal monitoring including, intracranial pressure, brain tissue oxygenation, and brain temperature monitoring as part of standard of care in centers with varying degrees of TCD availability and experience. Additionally, we propose to evaluate the correlation of pertinent TCD-based cerebral autoregulation indices such as the critical closing pressure, and the pressure reactivity index with the brain tissue oxygenation values obtained invasively., Conclusions: The overarching goal of this study is to establish safety and feasibility of prolonged automated TCD monitoring for patients with TBI in the intensive care unit and identify clinically meaningful and pragmatic noninvasive targets for future interventions., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: There are limited data on the trajectory of recovery and long-term functional outcomes after intracerebral hemorrhage (ICH). Most ICH trials have conventionally assessed outcomes at 3 months following the footsteps of ischemic stroke. The i-DEF trial (Intracerebral Hemorrhage Deferoxamine Trial) assessed modified Rankin Scale (mRS) longitudinally at prespecified time points from day 7 through the end of the 6-month follow-up period. We evaluated the trajectory of mRS among trial participants and examined the effect of deferoxamine on this trajectory., Methods: We performed a post hoc analysis of the i-DEF trial, a multicenter, randomized, placebo-controlled, double-blind, futility-design, phase 2 clinical trial, based on the actual treatment received. Favorable outcome was defined as mRS score of 0-2. A generalized linear mixed model was used to evaluate the outcome trajectory over time, as well as whether the trajectory was altered by deferoxamine, after adjustments for randomization variables, presence of intraventricular hemorrhage, and ICH location., Results: A total of 291 subjects were included in analysis (145 placebo and 146 deferoxamine). The proportion of patients with mRS score of 0-2 continually increased from day 7 to 180 in both groups (interaction P <0.0001 for time in main effects model), but treatment with deferoxamine favorably altered the trajectory (interaction P =0.0010). Between day 90 and 180, the deferoxamine group improved ( P =0.0001), whereas there was not significant improvement in the placebo arm ( P =0.3005)., Conclusions: A large proportion of patients continue to improve up to 6 months after ICH. Future ICH trials should assess outcomes past 90 days for a minimum of 6 months. In i-DEF, treatment with deferoxamine seemed to accelerate and alter the trajectory of recovery as assessed by mRS., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02175225.

Background: White matter hyperintensity (WMH) on brain MRI is associated with developing dementia or mild cognitive impairment (MCI), but WMH progression over time has not been fully investigated as an independent risk factor., Methods: We performed a post hoc analysis of the Systolic Blood Pressure Intervention Trial - Memory and Cognition in Decreased Hypertension (SPRINT MIND) trial. The primary outcome was incident probable dementia or MCI (dementia/MCI) before the follow-up MRI at 48 months from enrolment. The primary predictor was WMH progression, defined as the Z score difference between the follow-up and baseline WMH volumes. The secondary predictor was a binary WMH progression threshold (≥1.4 mL vs <1.4 mL)., Results: Among the 433 included patients, 33 (7.6%) developed dementia/MCI. There were 156 (36.0%) patients who met the WMH progression threshold of ≥1.4 mL, in whom the rate of dementia/MCI was 12.8% (20/156) vs 4.7% (13/277) of patients with <1.4 mL WMH progression (p=0.002). In multivariable logistic regression, the Z score of WMH progression was associated with dementia/MCI (OR 1.51, 95% CI 1.12 to 2.04, p=0.007) as was the WMH progression threshold of ≥1.4 mL (OR 2.89, 95% CI 1.23 to 6.81, p=0.015)., Conclusions: In this post hoc analysis of SPRINT MIND, WMH progression over 48 months was associated with the development of probable dementia or MCI., Competing Interests: Competing interests: AdH has investigator-initiated research support from Regeneron, AMGEN and AMAG pharmaceuticals; KNS reports funding from Biogen, Novartis, Bard, Hyperfine, Astrocyte and Alva Health., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

National Institutes of Health Stroke Scale (NIHSS), measured a few hours to days after stroke onset, is an attractive outcome measure for stroke research. NIHSS at the time of presentation (baseline NIHSS) strongly predicts the follow-up NIHSS. Because of the need to account for the baseline NIHSS in the analysis of follow-up NIHSS as an outcome measure, a common and intuitive approach is to define study outcome as the change in NIHSS from baseline to follow-up (ΔNIHSS). However, this approach has important limitations. Analyzing ΔNIHSS implies a very strong assumption about the relationship between baseline and follow-up NIHSS that is unlikely to be satisfied, drawing into question the validity of the resulting statistical analysis. This reduces the precision of the estimates of treatment effects and the power of clinical trials that use this approach to analysis. ANCOVA allows for the analysis of follow-up NIHSS as the dependent variable while adjusting for baseline NIHSS as a covariate in the model and addresses several challenges of using ΔNIHSS outcome using simple bivariate comparisons (eg, a t test, Wilcoxon rank-sum, linear regression without adjustment for baseline) for stroke research. In this article, we use clinical trial simulations to illustrate that variability in NIHSS outcome is less when follow-up NIHSS is adjusted for baseline compared to ΔNIHSS and how a reduction in this variability improves the power. We outline additional, important clinical and statistical arguments to support the superiority of ANCOVA using the final measurement of the NIHSS adjusted for baseline over, and caution against using, the simple bivariate comparison of absolute NIHSS change (ie, delta).

Background: Hematoma volume (HV) is a powerful determinant of outcome after intracerebral hemorrhage. We examined whether the effect of the iron chelator, deferoxamine, on functional outcome varied depending on HV in the i-DEF trial (Intracerebral Hemorrhage Deferoxamine)., Methods: A post hoc analysis of the i-DEF trial; participants were classified according to baseline HV (small <10 mL, moderate 10-30 mL, and large >30 mL). Favorable outcome was defined as a modified Rankin Scale score of 0-2 at day-180; secondarily at day-90. Logistic regression was used to evaluate the differential treatment effect according to HV., Results: Two hundred ninety-one subjects were included in the as-treated analysis; 121 with small, 114 moderate, and 56 large HV. Day-180 modified Rankin Scale scores were available for 270/291 subjects (111 with small, 105 moderate, and 54 large HV). There was a differential effect of treatment according to HV on day-180 outcomes ( P -for-interaction =0.0077); 50% (27/54) of deferoxamine-treated patients with moderate HV had favorable outcome compared with 25.5% (13/51) of placebo-treated subjects (adjusted odds ratio, 2.7 [95% CI, 1.13-6.27]; P =0.0258). Treatment effect was not significant for small (adjusted odds ratio, 1.37 [95% CI, 0.62-3.02]) or large (adjusted odds ratio, 0.12 [95% CI, 0.01-1.05]) HV. Results for day-90 outcomes were comparable ( P -for-interaction =0.0617). Sensitivity analyses yielded similar results., Conclusions: Among patients with moderate HV, a greater proportion of deferoxamine- than placebo-treated patients achieved modified Rankin Scale score 0-2. The treatment effect was not significant for small or large HVs. These findings have important trial design and therapeutic implications., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02175225.

Objectives: Severe acute brain injury (SABI) from cardiac arrest and traumatic brain injury happens suddenly and unexpectedly, carrying high potential for lifelong disability with substantial prognostic uncertainty. Comprehensive assessments of family experiences and support needs after SABI are lacking. Our objective is to elicit "on-the-ground" perspectives about the experiences and needs of families of patients with SABI., Design: Two-phase qualitative study of families and multidisciplinary U.S. healthcare professionals (mHCPs) with expertise in SABI: Phase 1 included semistructured interviews to generate formative findings; phase 2 entailed facilitated discussions to confirm and expand initial findings., Setting: Phase 1: academic medical center; phase 2: virtual workshop., Subjects: Phase 1 included seven family members and 12 mHCPs. Phase 2 included nationally recruited stakeholders (17 family members and 12 mHCPs)., Intervention: None., Measurements and Results: We explored: 1) what are families' needs in the first 48 hours? 2) How are these needs addressed? and 3) How can hospitals better meet these needs? Qualitative analysis included inductive and deductive approaches guided by a conceptual ecological model. Four major needs were identified: 1) challenges in coping with uncertainty in early prognostication, 2) inattention to physical needs of family, 3) deficits in compassionate and consistent communication, and 4) need for engagement with families as stakeholders in improving future practices. Participants' recommendations included: 1) ways to communicate more clearly and consistently, 2) better assistance with navigating resources and access to places for families to care for themselves, and 3) opportunities for families to remain connected with their loved ones, social support networks, and the clinical team., Conclusions: Stakeholders identified novel insights regarding families' experiences during the hospitalization of comatose SABI patients and factors that can contribute to improved decision-making and physical/emotional outcomes. Interventions to address these unmet needs are promising targets to improve outcomes., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19., Methods: In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause., Results: A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups., Conclusions: The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.)., (Copyright © 2021 Massachusetts Medical Society.)

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from pre-clinical studies of progesterone in TBI. To understand the reasons for the negative clinical trial, we investigated whether progesterone treatment has the desired biological effect of decreasing brain cell death. We quantified brain cell death using serum levels of biomarkers of glial and neuronal cell death (glial fibrillary acidic protein [GFAP], ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], and Alpha II Spectrin Breakdown Product 150 [SBDP]) in the Biomarkers of Injury and Outcome-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (BIO-ProTECT) study. Serum levels of GFAP, UCHL1, S100B, and SBDP were measured at baseline (≤4 h post-injury and before administration of study drug) and at 24 and 48 h post-injury. Serum progesterone levels were measured at 24 and 48 h post-injury. The primary outcome of ProTECT was based on the Glasgow Outcome Scale-Extended assessed at 6 months post-randomization. We found that at baseline, there were no differences in biomarker levels between subjects randomized to progesterone treatment and those randomized to placebo ( p  > 0.10). Similarly, at 24 and 48 h post-injury, there were no differences in biomarker levels in the progesterone versus placebo groups ( p  > 0.15). There was no statistically significant correlation between serum progesterone concentrations and biomarker values obtained at 24 and 48 h. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurological outcome ( p of interaction term >0.39 for all biomarkers). We conclude that progesterone treatment does not decrease levels of biomarkers of glial and neuronal cell death during the first 48 h post-injury.

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) randomized patients to a goal systolic blood pressure (SBP) <120 mm Hg vs. <140 mm Hg. In a subset of participants, the SPRINT MIND ancillary study performed a baseline MRI and measured white matter hyperintensity volume (WMHv). In this secondary analysis, we evaluated the association between baseline WMHv and cardiovascular events during follow-up in the overall sample., Methods: The primary outcome was the same as SPRINT, a composite of stroke, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, or cardiovascular death. We fit Cox models to the primary outcome and report adjusted hazard ratios (HR) for log-transformed WMHv and quartiles of WMHv., Results: Among 717 participants, the median (IQR) baseline WMHv was 1.62 (0.66-3.98) mL. The primary outcome occurred in 51/719 (7.1%). The median WMHv was higher in patients with the primary outcome (3.40 mL versus 1.56 mL, p < 0.001). In adjusted models, WMHv as a log-transformed continuous variable was associated with the primary outcome (HR 1.44, 95% CI 1.15-1.80). The highest quartile of WMHv, compared to the lowest, was also independently associated with the primary outcome (HR 3.21, 95% CI 1.27-8.13)., Conclusions: We found that the baseline volume of WMH was associated with future CVD risk in SPRINT MIND. Prospective clinical trials with larger sample sizes than the current study are needed to determine whether intensive BP lowering can reduce the high cardiovascular risk in patients with WMH., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hemorrhage volume is an important variable in emergently assessing traumatic brain injury (TBI). The most widely used method for rapid volume estimation is ABC/2, a simple algorithm that approximates lesion geometry as perfectly ellipsoid. The relative prognostic value of volume measurement based on more precise hematoma topology remains unknown. In this study, we compare volume measurements obtained using ABC/2 versus computer-assisted volumetry (CAV) for both intra- and extra-axial traumatic hemorrhages, and then quantify the association of measurements using both methods with patient outcome following moderate to severe TBI. A total of 517 computer tomography (CT) scans acquired during the Progesterone for Traumatic Brain Injury Experimental Clinical Treatment Phase-III (ProTECTIII) multi-center trial were retrospectively reviewed. Lesion volumes were measured using ABC/2 and CAV. Agreement between methods was tested using Bland-Altman analysis. Relationship of volume measurements with 6-month mortality, Extended Glasgow Outcome Scale (GOS-E), and Disability Rating Scale (DRS) were assessed using linear regression and area under the curve (AUC) analysis. In subdural hematoma (SDH) >50cm 3 , ABC/2 and CAV produce significantly different volume measurements ( p  < 0.0001), although the difference was not significant for smaller SDH or intra-axial lesions. The disparity between ABC/2 and CAV measurements varied significantly with hematoma size for both intra- and extra-axial lesions ( p  < 0.0001). Across all lesions, volume was significantly associated with outcome using either method ( p  < 0.001), but CAV measurement was a significantly better predictor of outcome than ABC/2 estimation for SDH. Among large traumatic SDH, ABC/2 significantly overestimates lesion volume compared with measurement based on precise bleed topology. CAV also offers significantly better prediction of patient functional outcofme and mortality.

Background and Purpose: Fewer women than men tend to be enrolled in clinical trials of intracerebral hemorrhage. It is unclear whether this reflects lower prevalence of intracerebral hemorrhage in women, selection bias, or poor recruitment efforts. We undertook this study to examine differences between men and women in the reasons for exclusion from the iDEF trial (Intracerebral Hemorrhage Deferoxamine)., Methods: The screen failure log included 29 different reasons for exclusion. Chi-square statistics were used to evaluate the differences in reasons for exclusion between men and women., Results: A total of 38.2% of participants in iDEF were women. Three thousand nine hundred eighty-two women (45.7%) and 4736 men (54.3%) were screen failures ( P <0.0001). Similar proportions of women (1.28%) and men (1.73%) were excluded due to inability to obtain consent ( P =0.1). Patients or families declined participation in 1.26% of women versus 1.31% of men ( P =0.9). More women than men failed screening because of age>80 (22.40% versus 12.61%; adjusted P =0.0007) and preexisting do-not-resuscitate/do-not-intubate (3.69% versus 2.83%; adjusted P =0.067)., Conclusions: Lower rates of women enrollment in the iDEF trial may be attributed to older age. Inability to obtain consent or declining participation was similar between women and men, arguing against selection bias. Our findings should be confirmed in other intracerebral hemorrhage trials to determine best strategies to improve women's representation in future trials.

The Glasgow Outcome Scale-Extended (GOS-E), an ordinal scale measuring global outcome, is used commonly as the primary outcome measure in clinical trials of traumatic brain injury. Analysis is often based on a dichotomization and thus has inherent statistical limitations, including loss of information related to the collapse of adjacent categories. A fixed dichotomization defines favorable outcome consistently for all subjects, whereas a sliding dichotomy tailors the definition of favorable outcome according to baseline prognosis/severity. Literature indicates that the sliding dichotomy is more statistically efficient than the fixed dichotomy; however, the sliding dichotomy still collapses categories and therefore discards information. We propose an alternative, a sliding scoring system for the GOS-E, intended to address the limitations of the sliding dichotomy. The score is assigned based on the number of levels between the achieved score and the favorable cut-point. The proposed scoring system reflects the magnitude of change, where change is defined according to each subject's baseline prognosis. Because the score is approximately continuous, statistical methods can rely on the normal distribution, both for analysis and study design. Two examples show the corresponding potential for improved power. A sliding score approach allows for quantification of the magnitude of change while still accounting for prognosis. Scientific advantages include increased power and an intuitive interpretation.

Background and Purpose: In patients with symptomatic vertebrobasilar intracranial atherosclerotic disease (ICAD), impaired distal flow predicts recurrent stroke, but limited data exist on the association between perfusion status and recurrent stroke in anterior circulation ICAD., Methods: This is a retrospective study of patients hospitalized for symptomatic ICAD with 50-99% stenosis of the intracranial carotid or middle cerebral artery. The primary outcome is recurrent symptomatic ischemic stroke in the territory of the artery with ≥50% stenosis within 90 days. The primary predictor is distal hypoperfusion on magnetic resonance (MR) or computed tomography (CT) perfusion, defined as a ≥15 mL volume of territory of the symptomatic artery with Tmax >6 seconds., Results: Fifty patients met inclusion criteria, including 15 (30%) with recurrent stroke and 15 (30%) with distal hypoperfusion. Distal hypoperfusion was present in 10 of 15 (66.7%) with recurrent stroke versus 5 of 35 (14.3%) without recurrent stroke (P < .001). The hazard ratio for recurrent stroke in patients with distal hypoperfusion was 6.80 (95% confidence interval [CI] 2.31-20.0)., Conclusion: Distal hypoperfusion in acutely symptomatic ICAD with 50-99% stenosis is associated with stroke recurrence. Distal hypoperfusion could be used to enrich future trials of secondary stroke prevention in ICAD patients., (© 2020 American Society of Neuroimaging.)

Background and Purpose- The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods- We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results- In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22-2.32) to respectively 1.36 (95% CI, 0.97-1.91) and 1.24 (95% CI, 0.87-1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions- The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1-4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E ( p  < 0.001). Compared with a model containing baseline patient variables/characteristics, inclusion of S100B and GFAP significantly improved prognostic capacity ( p  ≤ 0.05 both comparisons); conversely, UCH-L1 and SBDP did not. A final predictive model incorporating baseline patient variables/characteristics and biomarker data (S100B and GFAP) had the best prognostic capability (area under the curve [AUC] = 0.85, 95% confidence interval [CI]: CI 0.81-0.89). Very early measurements of brain-specific biomarkers are independently associated with 6-month outcome after moderate-to-severe TBI and enhance outcome prediction.

Background and Purpose: Studies have shown an association between infarct patterns and recurrent stroke in patients with symptomatic intracranial stenosis (sICAS) but there are limited data on associations with perfusion imaging mismatch profile. We aim to determine the association between infarct pattern, optimal mismatch profile definition, and recurrent cerebrovascular events (RCVE) in patients with anterior circulation sICAS., Methods: This is a retrospective study of consecutive patients with acutely sICAS admitted to a comprehensive stroke center over 18 month's period. Patients with sICAS underwent magnetic resonance perfusion (MRP) imaging within 24 hours from admission. Infarct patterns (internal BZ [IBZ], cortical BZ [CBZ], and core/perforator [C/P]) and RCVE within 90 days, were independently adjudicated by two reviewers. We compared mismatch profiles and recurrent event rates across infarct patterns., Results: Twenty-five patients met inclusion criteria; 28% had IBZ infarcts and overall RCVE rate was 32.0%. When compared to patients without IBZ infarcts, those with IBZ infarcts were more likely to have a target mismatch profile using T max > 6 seconds (60% vs. 6.7%, P = .007) and RCVE (62.5% vs. 11.8%, P = .01). There were no associations between CBZ and C/P infarcts and target mismatch profiles and RCVE., Conclusion: IBZ infarcts may be a surrogate marker of distal perfusion status and RCVE risk. Larger multicenter, prospective, core-lab blindly adjudicated studies are needed to confirm our findings., (© 2019 by the American Society of Neuroimaging.)

Background: Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial., Methods: We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed., Findings: We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related., Interpretation: Deferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile., Funding: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To estimate the impact of goal-directed therapy on outcome after traumatic brain injury, our team applied goal-directed therapy to standardize care in patients with moderate to severe traumatic brain injury, who were enrolled in a large multicenter clinical trial., Design: Planned secondary analysis of data from Progesterone for the Treatment of Traumatic Brain Injury III, a large, prospective, multicenter clinical trial., Setting: Forty-two trauma centers within the Neurologic Emergencies Treatment Trials network., Patients: Eight-hundred eighty-two patients were enrolled within 4 hours of injury after nonpenetrating traumatic brain injury characterized by Glasgow Coma Scale score of 4-12., Measurements and Main Results: Physiologic goals were defined a priori in order to standardize care across 42 sites participating in Progesterone for the Treatment of Traumatic Brain Injury III. Physiologic data collection occurred hourly; laboratory data were collected according to local ICU protocols and at a minimum of once per day. Physiologic transgressions were predefined as substantial deviations from the normal range of goal-directed therapy. Each hour where goal-directed therapy was not achieved was classified as a "transgression." Data were adjudicated electronically and via expert review. Six-month outcomes included mortality and the stratified dichotomy of the Glasgow Outcome Scale-Extended. For each variable, the association between outcome and either: 1) the occurrence of a transgression or 2) the proportion of time spent in transgression was estimated via logistic regression model., Results: For the 882 patients enrolled in Progesterone for the Treatment of Traumatic Brain Injury III, mortality was 12.5%. Prolonged time spent in transgression was associated with increased mortality in the full cohort for hemoglobin less than 8 gm/dL (p = 0.0006), international normalized ratio greater than 1.4 (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0003), and systolic blood pressure less than 90 mm Hg (p < 0.0001). In the patient subgroup with intracranial pressure monitoring, prolonged time spent in transgression was associated with increased mortality for intracranial pressure greater than or equal to 20 mm Hg (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0293), hemoglobin less than 8 gm/dL (p = 0.0220), or systolic blood pressure less than 90 mm Hg (p = 0.0114). Covariates inversely related to mortality included: a single occurrence of mean arterial pressure less than 65 mm Hg (p = 0.0051) or systolic blood pressure greater than 180 mm Hg (p = 0.0002)., Conclusions: The Progesterone for the Treatment of Traumatic Brain Injury III clinical trial rigorously monitored compliance with goal-directed therapy after traumatic brain injury. Multiple significant associations between physiologic transgressions, morbidity, and mortality were observed. These data suggest that effective goal-directed therapy in traumatic brain injury may provide an opportunity to improve patient outcomes.

Importance: The DEFUSE 3 randomized clinical trial previously demonstrated benefit of endovascular thrombectomy for acute ischemic stroke in the 6- to 16-hour time window. For treatment recommendations, it is important to know if the treatment benefit was universal., Objective: To determine the outcomes among patients who may have a reduced effect of thrombectomy, including those who are older, have milder symptoms, or present late., Design, Setting, and Participants: DEFUSE 3 was a randomized, open-label, blinded end point trial conducted from May 2016 to May 2017. This multicenter study included 38 sites in the United States. Of 296 patients who were enrolled in DEFUSE 3, 182 patients met all inclusion criteria and were randomized and included in the intention-to-treat analysis, which was conducted in August 2017. These patients had acute ischemic strokes due to an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion computed tomography or magnetic resonance imaging. The study was stopped early for efficacy., Interventions: Endovascular thrombectomy plus medical management vs medical management alone., Main Outcomes and Measures: Functional outcome at day 90, assessed on the modified Rankin Scale. Multivariate ordinal logistic regression was used to calculate the adjusted proportional association between endovascular treatment and clinical outcome (shift in the distribution of modified Rankin Scale scores expressed as a common odds ratio) among patients of different ages, baseline stroke severities, onset-to-treatment times, locations of the arterial occlusion, and imaging modalities used to document the presence of salvageable tissue (computed tomography vs magnetic resonance imaging)., Results: This study included 182 patients (median [interquartile range] age, 70 [59-80] years; median [interquartile range] National Institutes of Health Stroke Scale score, 16 [11-21], and 92 women [51%]). In the overall cohort, independent predictors of better functional outcome were younger age, lower baseline National Institutes of Health Stroke Scale score, and lower serum glucose level. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1 (95% CI, 1.8-5.4). There was no significant interaction between this treatment effect and age (P = .93), National Institutes of Health Stroke Scale score (P = .87), time to randomization (P = .56), imaging modality (P = .49), or location of the arterial occlusion (P = .54)., Conclusions and Relevance: Endovascular thrombectomy, initiated up to 16 hours after last known well time in patients with salvageable tissue on perfusion imaging, benefits patients with a broad range of clinical features. Owing to the small sample size of this study, a pooled analysis of late time window endovascular stroke trials is needed to confirm these results., Trial Registration: ClinicalTrials.gov identifier: NCT02586415.

Background and Purpose: Impaired distal perfusion predicts neurological deterioration in large artery atherosclerosis. We aim to determine the optimal threshold of Tmax delay on perfusion imaging that is associated with neurological deterioration in patients with symptomatic proximal anterior circulation large artery stenosis., Methods: Data were abstracted from a prospective ischemic stroke database of consecutively enrolled patients with symptomatic proximal intracranial stenosis (internal carotid artery or M1 segment of the middle cerebral artery) who underwent magnetic resonance perfusion imaging within 24 hours of symptom onset during a 15-month period. Tissue volumes of perfusion delay Tmax 0-4 seconds, Tmax > 4 seconds, Tmax > 6 seconds, and Tmax > 8 seconds were calculated using an automated approach. A target mismatch (penumbra-core) was defined as ≥15mL of brain tissue using each of the Tmax threshold categories. The outcome was neurological deterioration at 30 days defined as new or worsening neurological deficits that are not attributed to a nonvascular etiology., Results: Among 52 patients with symptomatic intracranial stenosis, 26 patients met inclusion criteria. Neurological deterioration was associated with target mismatch profile defined according to Tmax > 6 seconds (66.7% [6/9] vs. 5.9% [1/17], P < .01) and Tmax >8 seconds (57.1% [4/7] vs. 15.8% [3/19], P = .05] but not according to Tmax > 4 seconds (27.3% [6/17] vs. 11.1% [1/9], P = .35]., Conclusions: A target mismatch profile using Tmax > 6 seconds may define tissue at risk in patients with acute symptomatic proximal anterior circulation intracranial stenosis. More studies are needed to confirm our findings., (© 2018 by the American Society of Neuroimaging.)

Although obesity and diabetes mellitus, or diabetes, are independently associated with mortality-related events ( e.g., all-cause mortality and cardiovascular-related mortality) following an ischemic stroke, little is known about the joint effect of obesity and diabetes on mortality-related events following an ischemic stroke. The aim of this study is to evaluate the joint effect of obesity and diabetes on mortality-related events in subjects with a recent ischemic stroke. Data from the multicenter Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial was analyzed for this study. The joint effect of obesity and diabetes on mortality-related events was estimated via Cox proportional hazards regression models. No difference in the hazard of all-cause mortality following an ischemic stroke was observed between obese subjects with diabetes and underweight/normal-weight subjects without diabetes. In contrast, obese subjects with diabetes had an increased hazard of cardiovascular-related mortality following an ischemic stroke compared with underweight/normal-weight subjects without diabetes. Additionally, there was evidence of an attributable proportion due to interaction as well as evidence of a highly statistically significant interaction on the multiplicative scale for cardiovascular-related mortality. In this clinical trial cohort of ischemic stroke survivors, obesity and diabetes synergistically interacted to increase the hazard of cardiovascular-related mortality.

Background and Purpose- Endovascular therapy in an extended time window has been shown to be beneficial in selected patients. This study correlated angiographic outcomes of patients randomized to endovascular therapy with clinical and imaging outcomes in the DEFUSE 3 study (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3). Methods- Angiograms were assessed for the primary arterial occlusive lesion and the modified Thrombolysis in Cerebral Infarction (TICI) score at baseline and the final modified TICI score. Clinical outcomes were assessed using an ordinal analysis of 90-day modified Rankin Scale and a dichotomous analysis for functional independence (modified Rankin Scale score of 0-2). TICI scores were correlated with outcome, types of device used for thrombectomy, and 24-hour follow-up imaging. Results- TICI 2B-3 reperfusion was achieved in 70 of 92 patients (76%). TICI 2B-3 reperfusion showed a more favorable distribution of Rankin scores compared with TICI 0-2A; odds ratio, 2.77; 95% confidence interval, 1.17-6.56; P=0.019. Good functional outcome (90-day modified Rankin Scale score of 0-2) increased with better TICI scores ( P=0.0028). There was less disability comparing TICI 3 patients to TICI 2B patients ( P=0.037). Successful reperfusion (TICI 2B-3) was independent of the device used, the site of occlusion (internal carotid artery or M1) or adjunctive use of carotid angioplasty and stenting. Significantly less infarct growth at 24 hours was seen in TICI 3 patients compared with TICI 0-2A ( P=0.0015) and TICI 2B ( P=0.0002) patients. Conclusions- Thrombectomy in an extended time window demonstrates similar rates of TICI 2B-3 reperfusion to earlier time window studies. Successful reperfusion was independent of the device used, the site of occlusion or adjunctive use of carotid angioplasty and stenting. TICI 3 reperfusion was more likely to result in low rates of infarct growth at 24 hours and good functional outcome at 90 days. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02586415.

Rationale Over half of acute ischemic stroke patients have a low National Institutes of Health Stroke Scale of 0-5 and up to two-thirds may not appear clearly disabled at presentation. The efficacy of intravenous alteplase for the latter group is not known. Aim Potential of rtPA for Ischemic Strokes with Mild Symptoms (PRISMS) was designed to evaluate the safety and efficacy of intravenous alteplase for the treatment of acute ischemic stroke with National Institutes of Health Stroke Scale 0-5 and without clearly disabling deficits. Sample size estimates A maximum of 948 subjects were required to test the superiority hypothesis with 80% power, according to a one-sided 0.025 level of significance. Methods and design PRISMS was a multicenter, randomized, double-blind, placebo-controlled phase 3b clinical trial. Patients were randomized to the active arm (intravenous alteplase standard dose of 0.9 mg/kg, up to a maximum of 90 mg, plus oral aspirin placebo) or the control arm (intravenous alteplase placebo plus active oral aspirin dose of 325 mg). Study outcome The primary efficacy endpoint was favorable functional outcome, defined as a modified Rankin Scale score 0 or 1 assessed at 90-day postrandomization.

Importance: More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled., Objective: To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling., Design, Setting, and Participants: The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017., Interventions: Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157)., Main Outcomes and Measures: The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment., Results: Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, -1.1%; 95% CI, -9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%)., Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT02072226.

Background: Obesity and diabetes mellitus, or diabetes, are independently associated with post-ischemic stroke outcomes (e.g., functional disability and all-cause mortality). Although obesity and diabetes are also associated with post-ischemic stroke outcomes, the joint effect of obesity and diabetes on these post-ischemic stroke outcomes has not been explored previously. The purpose of the current study was to explore whether the effect of obesity on post-ischemic stroke outcomes differed by diabetes status in a cohort of acute ischemic stroke subjects with at least a moderate stroke severity., Methods: Data from the Interventional Management of Stroke (IMS) III clinical trial was analyzed for this post-hoc analysis. A total of 656 subjects were enrolled in IMS III and were followed for one year. The joint effects of obesity and diabetes on functional disability at 3-months and all-cause mortality at 1-year were examined., Results: Of 645 subjects with complete obesity and diabetes information, few were obese (25.74%) or had diabetes (22.64%). Obese subjects with diabetes and non-obese subjects without diabetes had similar odds of functional disability at 3-months following an ischemic stroke (adjusted common odds ratio, 1.038, 95% CI: 0.631, 1.706). For all-cause mortality at 1-year following an ischemic stroke, obese subjects with diabetes had a similar hazard compared with non-obese subjects without diabetes (adjusted hazard ratio, 1.005, 95% CI: 0.559, 1.808). There was insufficient evidence to declare a joint effect between obesity and diabetes on either the multiplicative scale or the additive scale for both outcomes., Conclusions: In this post-hoc analysis of data from the IMS III clinical trial of acute ischemic stroke patients with at least a moderate stroke severity, there was not sufficient evidence to determine that the effect of obesity differed by diabetes status on post-ischemic stroke outcomes. Additionally, there was not sufficient evidence to determine that either factor was independently associated with all-cause mortality. Future studies could differentiate between metabolically healthy and metabolically unhealthy patients within BMI categories to determine if the effect of obesity on post-stroke outcomes differs by diabetes status.

Background: Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms., Methods: We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90., Results: The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18)., Conclusions: Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).

Under covariate adaptive randomization, the covariate is tied to both randomization and analysis. Misclassification of such covariate will impact the intended treatment assignment; further, it is unclear what the appropriate analysis strategy should be. We explore the impact of such misclassification on the trial's statistical operating characteristics. Simulation scenarios were created based on the misclassification rate and the covariate effect on the outcome. Models including unadjusted, adjusted for the misclassified, or adjusted for the corrected covariate were compared using logistic regression for a binary outcome and Poisson regression for a count outcome. For the binary outcome using logistic regression, type I error can be maintained in the adjusted model, but the test is conservative using an unadjusted model. Power decreased with both increasing covariate effect on the outcome as well as the misclassification rate. Treatment effect estimates were biased towards the null for both the misclassified and unadjusted models. For the count outcome using a Poisson model, covariate misclassification led to inflated type I error probabilities and reduced power in the misclassified and the unadjusted model. The impact of covariate misclassification under covariate-adaptive randomization differs depending on the underlying distribution of the outcome.

Rationale Early reperfusion in patients experiencing acute ischemic stroke is effective in patients with large vessel occlusion. No randomized data are available regarding the safety and efficacy of endovascular therapy beyond 6 h from symptom onset. Aim The aim of the study is to demonstrate that, among patients with large vessel anterior circulation occlusion who have a favorable imaging profile on computed tomography perfusion or magnetic resonance imaging, endovascular therapy with a Food and Drug Administration 510 K-cleared mechanical thrombectomy device reduces the degree of disability three months post stroke. Design The study is a prospective, randomized, multicenter, phase III, adaptive, blinded endpoint, controlled trial. A maximum of 476 patients will be randomized and treated between 6 and 16 h of symptom onset. Procedures Patients undergo imaging with computed tomography perfusion or magnetic resonance diffusion/perfusion, and automated software (RAPID) determines if the Target Mismatch Profile is present. Patients who meet both clinical and imaging selection criteria are randomized 1:1 to endovascular therapy plus medical management or medical management alone. The individual endovascular therapist chooses the specific device (or devices) employed. Study outcomes The primary endpoint is the distribution of scores on the modified Rankin Scale at day 90. The secondary endpoint is the proportion of patients with modified Rankin Scale 0-2 at day 90 (indicating functional independence). Analysis Statistical analysis for the primary endpoint will be conducted using a normal approximation of the Wilcoxon-Mann-Whitney test (the generalized likelihood ratio test).