Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

Golden Hour Intravenous Thrombolysis for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

OBJECTIVES: The benefits of intravenous thrombolysis are time-dependent, with maximum efficacy when administered within the first "golden" hour after onset. Nevertheless, the impact of golden hour thrombolysis has not been well quantified. METHODS: Medline, Embase, and Web of Science databases were systematically searched from inception to August 27, 2023. We included studies that reported safety and efficacy outcomes of ischemic stroke patients treated with intravenous thrombolysis in the golden hour versus later treatment window. The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale score of 0-1 at 90 days. The secondary efficacy outcome was a good functional outcome (defined as modified Rankin Scale score of 0-2). The main safety outcome was symptomatic intracerebral hemorrhage. RESULTS: Seven studies involving 78,826 patients met the selection criteria. Golden hour thrombolysis was associated with higher odds of 90-day excellent functional outcomes (OR 1.40, 95% CI 1.16-1.67) and 90-day good functional outcomes (OR 1.38, 95% CI 1.13-1.69) compared with thrombolysis outside the golden hour. The number needed to treat to benefit for golden hour thrombolysis to reduce disability by at least 1 level on the modified Rankin Scale per patient was 2.6. Rates of symptomatic intracerebral hemorrhage and mortality were similar between groups. INTERPRETATION: Golden hour thrombolysis significantly improved acute ischemic stroke outcomes. The findings provide rationale for intensive efforts aimed at expediting thrombolytic therapy within the golden hour window following the onset of acute ischemic stroke. ANN NEUROL 2024;96:582-590.

Strokes Averted by Intravenous Thrombolysis: A Secondary Analysis of a Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

OBJECTIVE: This study was undertaken to examine averted stroke in optimized stroke systems. METHODS: This secondary analysis of a multicenter trial from 2014 to 2020 compared patients treated by mobile stroke unit (MSU) versus standard management. The analytical cohort consisted of participants with suspected stroke treated with intravenous thrombolysis. The main outcome was a tissue-defined averted stroke, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis and no acute infarction/hemorrhage on imaging. An additional outcome was stroke with early symptom resolution, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis. RESULTS: Among 1,009 patients with a median last known well to thrombolysis time of 87 minutes, 159 (16%) had tissue-defined averted stroke and 276 (27%) had stroke with early symptom resolution. Compared with standard management, MSU care was associated with more tissue-defined averted stroke (18% vs 11%, adjusted odds ratio [aOR] = 1.82, 95% confidence interval [CI] = 1.13-2.98) and stroke with early symptom resolution (31% vs 21%, aOR = 1.74, 95% CI = 1.12-2.61). The relationships between thrombolysis treatment time and averted/early recovered stroke appeared nonlinear. Most models indicated increased odds for stroke with early symptom resolution but not tissue-defined averted stroke with earlier treatment. Additionally, younger age, female gender, hyperlipidemia, lower National Institutes of Health Stroke Scale, lower blood pressure, and no large vessel occlusion were associated with both tissue-defined averted stroke and stroke with early symptom resolution. INTERPRETATION: In optimized stroke systems, 1 in 4 patients treated with thrombolysis recovered within 24 hours and 1 in 6 had no demonstrable brain injury on imaging. ANN NEUROL 2024;95:347-361.

Anticoagulation Use and Endovascular Thrombectomy in Patients with Large Core Stroke: A Secondary Analysis of the SELECT2 Trial.

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4-6] vs MM 5 [4-6], adjusted generalized odds ratio 0.89 [0.53-1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3-6] vs MM 5 [4-6], adjusted generalized odds ratio 1.87 [1.45-2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024;96:887-894.

Dynamic Imaging of Blood Coagulation Within the Hematoma of Patients With Acute Hemorrhagic Stroke.

BACKGROUND: The dynamics of blood clot (combination of Hb [hemoglobin], fibrin, and a higher concentration of aggregated red blood cells) formation within the hematoma of an intracerebral hemorrhage is not well understood. A quantitative neuroimaging method of localized coagulated blood volume/distribution within the hematoma might improve clinical decision-making. METHODS: The deoxyhemoglobin of aggregated red blood cells within extravasated blood exhibits a higher magnetic susceptibility due to unpaired heme iron electrons. We propose that coagulated blood, with higher aggregated red blood cell content, will exhibit (1) a higher positive susceptibility than noncoagulated blood and (2) increase in fibrin polymerization-restricted localized diffusion, which can be measured noninvasively using quantitative susceptibility mapping and diffusion tensor imaging. In this serial magnetic resonance imaging study, we enrolled 24 patients with acute intracerebral hemorrhage between October 2021 to May 2022 at a stroke center. Patients were 30 to 70 years of age and had a hematoma volume >15 cm3 and National Institutes of Health Stroke Scale score >1. The patients underwent imaging 3×: within 12 to 24 (T1), 36 to 48 (T2), and 60 to 72 (T3) hours of last seen well on a 3T magnetic resonance imaging system. Three-dimensional anatomic, multigradient echo and 2-dimensional diffusion tensor images were obtained. Hematoma and edema volumes were calculated, and the distribution of coagulation was measured by dynamic changes in the susceptibilities and fractional anisotropy within the hematoma. RESULTS: Using a coagulated blood phantom, we demonstrated a linear relationship between the percentage coagulation and susceptibility (R2=0.91) with a positive red blood cell stain of the clot. The quantitative susceptibility maps showed a significant increase in hematoma susceptibility (T1, 0.29±0.04 parts per millions; T2, 0.36±0.04 parts per millions; T3, 0.45±0.04 parts per millions; P<0.0001). A concomitant increase in fractional anisotropy was also observed with time (T1, 0.40±0.02; T2, 0.45±0.02; T3, 0.47±0.02; P<0.05). CONCLUSIONS: This quantitative neuroimaging study of coagulation within the hematoma has the potential to improve patient management, such as safe resumption of anticoagulants, the need for reversal agents, the administration of alteplase to resolve the clot, and the need for surgery.

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

BACKGROUND: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied. METHODS: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients. RESULTS: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group. CONCLUSIONS: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).

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

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

Recruitment in Acute Stroke Trials: Challenges and Potential Solutions.

Randomized clinical trials of acute stroke have led to major advances in acute stroke therapy over the past decade. Despite these successes, recruitment in acute trials is often difficult. We outline challenges in recruitment for acute stroke trials and present potential solutions, which can increase the speed and decrease the cost of identifying new treatments for acute stroke. One of the largest opportunities to increase the speed of enrollment and make trials more generalizable is expansion of inclusion criteria whose impact on expected recruitment can be assessed by epidemiologic and registry databases. Another barrier to recruitment besides the number of eligible patients is availability of study investigators limited to business hours, which may be helped by financial support for after-hours call. The wider use of telemedicine has accelerated quicker stroke treatment at many hospitals and has the potential to accelerate research enrollment but requires training of clinical investigators who are often inexperienced with this approach. Other potential solutions to enhance recruitment include rapid prehospital notification of clinical investigators of potential patients, use of mobile stroke units, advances in the process of emergency informed consent, storage of study medication in the emergency department, simplification of study treatments and data collection, education of physicians to improve equipoise and enthusiasm for randomization of patients within a trial, and clear recruitment plans, and even potentially coenrollment, when there are competing trials at sites. Without successful recruitment, scientific advances and clinical benefit for acute stroke patients will lag.

Golden Hour Treatment With tPA (Tissue-Type Plasminogen Activator) in the BEST-MSU Study.

BACKGROUND: Treatment of patients with acute ischemic stroke on mobile stroke units (MSUs) improves outcomes compared with management by standard emergency medical services ambulances and is associated with more patients treated with intravenous tPA (tissue-type plasminogen activator) in the first golden hour after last known normal. We explored the predictors and outcomes of first-hour treatment (FHT) compared with later treatment in an alternating-week cluster-controlled trial of MSUs. METHODS: We analyzed all patients treated with intravenous tPA in the BEST-MSU Study (Benefits of Stroke Treatment Delivered by a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services). After stratifying by treatment timeframe, we identified factors associated with FHT. We performed adjusted analyses of the association between FHT and clinical outcome and modeled the shape of the relationship between last known normal-to-treatment time and excellent outcome. RESULTS: Among 941 tPA-treated patients, 206 (21.8%) had lytic started within 60 minutes. Treatment on the MSU, older age, male sex, alert by 911, faster arrival on-scene and imaging, more severe stroke, atrial fibrillation, and absence of heart failure and pretreatment antihypertensive treatment were associated with FHT. Compared with later treatment, FHT was associated with higher adjusted odds ratio for 90-day modified Rankin Scale score of 0 to 1 (odds ratio, 1.87 [95% CI, 1.25-2.84]; P=0.003). Among FHT patients, 68% achieved a 90-day modified Rankin Scale of 0 or 1 or returned to their baseline status. FHT was not associated with higher risk of hemorrhage and was associated with reduced risk of treating neurovascular mimics. CONCLUSIONS: FHT almost doubles the odds of excellent clinical outcome without increased risk compared with later treatment, which supports the use of MSUs.

Rapid Activation of Neuroinflammation in Stroke: Plasma and Extracellular Vesicles Obtained on a Mobile Stroke Unit.

BACKGROUND: Neuroinflammation is ubiquitous in acute stroke and worsens outcome. However, the precise timing of the inflammatory response is unknown, hindering the design of acute anti-inflammatory therapeutic interventions. We sought to identify the onset of the neuroinflammatory cascade using a mobile stroke unit. METHODS: The study is a proof-of-concept, cohort investigation of ultra-early blood- and extracellular vesicle-derived markers of neuroinflammation and outcome in acute stroke. Blood was obtained, prehospital, on an mobile stroke unit. Outcomes were biomarker concentrations, modified Rankin Scale score, and National Institutes of Health Stroke Scale score. RESULTS: Forty-one adults were analyzed, including 15 patients treated on the mobile stroke unit between August 2021 and April 2022, and 26 healthy controls to establish biomarker reference levels. Median patient age was 74 (range, 36-97) years, 60% were female, and 80% White. Ten (67%) were diagnosed as stroke, with 8 (53%) confirmed and 2 likely transient ischemic attack or stroke averted by thrombolysis; 5 were stroke mimics. For strokes, median initial National Institutes of Health Stroke Scale score was 11 (range, 4-19) and 6 (75%) received tPA (tissue-type plasminogen activator). Blood was obtained a median of 58 (range, 36-133) minutes after symptom onset. Within 36 minutes after stroke, plasma IL-6 (interleukin-6), neurofilament light chain, UCH-L1 (ubiquitin C-terminal hydrolase L1), and GFAP (glial fibrillary acidic protein) were elevated by as much as 10 times normal. In EVs, MMP-9 (matrix metalloproteinase-9), CXCL4 (chemokine (C-X-C motif) ligand 4), CRP (C-reactive protein), IL-6, OPN (osteopontin), and PECAM1 (platelet and endothelial cell adhesion molecule 1) were elevated. Inflammatory markers increased rapidly in the first 2 hours and continued rising for 24 hours. CONCLUSIONS: The neuroinflammatory cascade was found to be activated within 36 to 133 minutes after stroke and progresses rapidly. This is earlier than observed previously in humans and suggests injury from neuroinflammation occurs faster than had been surmised. These findings could inform development of acute immunomodulatory stroke therapies and lead to new diagnostic tools and improved outcomes.

Thrombectomy versus Medical Management in Mild Strokes due to Large Vessel Occlusion: Exploratory Analysis from the EXTEND-IA Trials and a Pooled International Cohort.

OBJECTIVE: This study was undertaken to evaluate functional and safety outcomes for endovascular thrombectomy (EVT) versus medical management (MM) in patients with large vessel occlusion (LVO) and mild neurological deficits, stratified by perfusion imaging mismatch. METHODS: The pooled cohort consisted of patients with National Institutes of Health Stroke Scale (NIHSS) < 6 and internal carotid artery (ICA), M1, or M2 occlusions from the Extending the Time for Thrombolysis in Emergecy Neurological Deficits - Intra-Arterial (EXTEND-IA) Trial,  Tenecteplase vs Alteplase before Endovascular Thrombectomy in Ischemic Stroke (EXTEND-IA TNK) trials Part I/II and prospective data from 15 EVT centers from October 2010 to April 2020. RAPID software estimated ischemic core and mismatch. Patients receiving primary EVT (EVTpri ) were compared to those who received primary MM (MMpri ), including those who deteriorated and received rescue EVT, in overall and propensity score (PS)-matched cohorts. Patients were stratified by target mismatch (mismatch ratio ≥ 1.8 and mismatch volume ≥ 15ml). Primary outcome was functional independence (90-day modified Rankin Scale = 0-2). Secondary outcomes included safety (symptomatic intracerebral hemorrhage [sICH], neurological worsening, and mortality). RESULTS: Of 540 patients, 286 (53%) received EVTpri and demonstrated larger critically hypoperfused tissue (Tmax > 6 seconds) volumes (median [IQR]: 64 [26-96] ml vs MMpri : 40 [14-76] ml, p < 0.001) and higher presentation NIHSS (median [IQR]: 4 [2-5] vs MMpri : 3 [2-4], p < 0.001). Functional independence was similar (EVTpri : 77.4% vs MMpri : 75.6%, adjusted odds ratio [aOR] = 1.29, 95% confidence interval [CI] = 0.82-2.03, p = 0.27). EVT had worse safety regarding sICH (EVTpri : 16.3% vs MMpri : 1.3%, p < 0.001) and neurological worsening (EVTpri : 19.6% vs MMpri : 6.7%, p < 0.001). In 414 subjects (76.7%) with target mismatch, EVT was associated with improved functional independence (EVTpri : 77.4% vs MMpri : 72.7%, aOR = 1.68, 95% CI = 1.01-2.81, p = 0.048), whereas there was a trend toward less favorable outcomes with primary EVT (EVTpri : 77.4% vs MMpri : 83.3%, aOR = 0.39, 95% CI = 0.12-1.34, p = 0.13) without target mismatch (pinteraction  = 0.06). Similar findings were observed in a propensity score-matched subpopulation. INTERPRETATION: Overall, EVT was not associated with improved clinical outcomes in mild strokes due to LVO, and sICH was increased. However, in patients with target mismatch profile, EVT was associated with increased functional independence. Perfusion imaging may be helpful to select mild stroke patients for EVT. ANN NEUROL 2022;92:364-378.

Subarachnoid Blood Clearance and Aneurysmal Subarachnoid Hemorrhage Outcomes: A Retrospective Review.

BACKGROUND: Delayed cerebral ischemia (DCI) continues to be a significant contributor to morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Subarachnoid blood and its degradation products have been implicated in DCI, and faster blood clearance has been hypothesized to confer better outcomes. This study evaluates the relationship between blood volume and its clearance on DCI (primary outcome) and location at 30 days (secondary outcome) after aSAH. METHODS: This is a retrospective review of adult patients presenting with aSAH. Hijdra sum scores (HSS) were assessed independently for each computed tomography (CT) scan of patients with available scans on post-bleed days 0-1 and 2-10. This cohort was used to evaluate the course of subarachnoid blood clearance (group 1). A subset of patients in the first cohort with available CT scans on both post-bleed days 0-1 and post-bleed days 3-4 composed the second cohort (group 2). This group was used to evaluate the association between initial subarachnoid blood (measured via HSS post-bleed days 0-1) and its clearance (measured via percentage reduction [HSS %Reduction] and absolute reduction [HSS-Abs-Reduction] in HSS between days 0-1 and 3-4) on outcomes. Univariable and multivariable logistic regression models were used to identify outcome predictors. RESULTS: One hundred fifty-six patients were in group 1, and 72 patients were in group 2. In this cohort, HSS %Reduction was associated with decreased risk of DCI in univariate (odds ratio [OR] = 0.700 [0.527-0.923], p = 0.011) and multivariable (OR = 0.700 [0.527-0.923], p = 0.012) analyses. Higher HSS %Reduction was significantly more likely to have better outcomes at 30 days in the multivariable analysis (OR = 0.703 [0.507-0.980], p = 0.036). Initial subarachnoid blood volume was associated with outcome location at 30 days (OR = 1.331 [1.040-1.701], p = 0.023) but not DCI (OR = 0.945 [0.780-1.145], p = 0.567). CONCLUSIONS: Early blood clearance after aSAH was associated with DCI (univariable and multivariable analyses) and outcome location at 30 days (multivariable analysis). Methods facilitating subarachnoid blood clearance warrant further investigation.

Mobile Stroke Units: Evidence, Gaps, and Next Steps.

Mobile stroke units (MSUs) are specialized ambulances equipped with the personnel, equipment, and imaging capability to diagnose and treat acute stroke in the prehospital setting. Over the past decade, MSUs have proliferated throughout the world, particularly in European and US cities, culminating in the formation of an international consortium. Randomized trials have demonstrated that MSUs increase stroke thrombolysis rates and reduce onset-to-treatment times but until recently it was uncertain if these advantages would translate into better patient outcomes. In 2021, 2 pivotal, large, controlled clinical trials, B_PROUD and BEST-MSU, demonstrated that as compared with conventional emergency care, treatment aboard MSUs was safe and led to improved functional outcomes in patients with stroke. Further, the observed benefit of MSUs appeared to be primarily driven by the higher frequency of ultra-early thrombolysis within the golden hour. Nevertheless, questions remain regarding the cost-effectiveness of MSUs, their utility in nonurban settings, and optimal infrastructure. In addition, in much of the world, MSUs are currently not reimbursed by insurers nor accepted as standard care by regulatory bodies. As MSUs are now established as one of the few proven acute stroke interventions with an effect size that is comparable to that of intravenous thrombolysis and stroke units, stroke leaders and organizations should work with emergency medical services, governments, and community stakeholders to determine how MSUs might benefit individual communities, and their optimal organization and financing. Future research to explore the effect of MSUs on intracranial hemorrhage and thrombectomy outcomes, cost-effectiveness, and novel models including the use of rendezvous transports, helicopters, and advanced neuroimaging is ongoing. Recommended next steps for MSUs include reimbursement by insurers, integration with ambulance networks, recognition by program accreditors, and inclusion in registries that monitor care quality.

Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials. METHODS: We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence. RESULTS: We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio [OR],0.73 [95% CI, 0.53-1.00]; moderate certainty; absolute risk reduction (ARR), -3.35%). Nimodipine (OR, 1.46 [95% CI, 1.07-1.99]; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 [95% CI, 1.14-12.18]; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 [95% CI, 0.22-0.68]; high certainty; ARR, -16.65%), nicardipine (OR, 0.48 [95% CI, 0.24-0.94]; moderate certainty; ARR, -13.70%), fasudil (OR, 0.55 [95% CI, 0.31-0.98]; moderate certainty; ARR, -11.54%), and magnesium (OR, 0.66 [95% CI, 0.46-0.94]; high certainty; ARR, -8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia. CONCLUSIONS: Nimodipine and cilostazol are likely the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019122183.

Hemorrhage Enlargement Is More Frequent in the First 2 Hours: A Prehospital Mobile Stroke Unit Study.

BACKGROUND: Hematoma enlargement (HE) after intracerebral hemorrhage (ICH) is a therapeutic target for improving outcomes. Hemostatic therapies to prevent HE may be more effective the earlier they are attempted. An understanding of HE in first 1 to 2 hours specifically in the prehospital setting would help guide future treatment interventions in this time frame and setting. METHODS: Patients with spontaneous ICH within 4 hours of symptom onset were prospectively evaluated between May 2014 and April 2020 as a prespecified substudy within a multicenter trial of prehospital mobile stroke unit versus standard management. Baseline computed tomography scans obtained <1, 1 to 2, and 2 to 4 hours postsymptom onset on the mobile stroke unit in the prehospital setting were compared with computed tomography scans repeated 1 hour later and at 24 hours in the hospital. HE was defined as >6 mL if baseline ICH volume was <20 mL and 33% increase if baseline volume >20 mL. The association between time from symptom onset to baseline computed tomography (hours) and HE was investigated using Wilcoxon rank-sum test when time was treated as a continuous variable and using Fisher exact test when time was categorized. Kruskal-Wallis and Wilcoxon rank-sum tests evaluated differences in baseline volumes and HE. Univariable and multivariable logistic regression analyses were conducted to identify factors associated with HE and variable selection was performed using cross-validated L1-regularized (Lasso regression). This study adhered to STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology) for cohort studies. RESULTS: One hundred thirty-nine patients were included. There was no difference between baseline ICH volumes obtained <1 hour (n=43) versus 1 to 2 hour (n=51) versus >2 hours (n=45) from symptom onset (median [interquartile range], 13 mL [6-24] versus 14 mL [6-30] versus 12 mL [4-19]; P=0.65). However, within the same 3 time epochs, initial hematoma growth (volume/time from onset) was greater with earlier baseline scanning (median [interquartile range], 17 mL/hour [9-35] versus 9 mL/hour [5-23]) versus 4 mL/hour [2-7]; P<0.001). Forty-nine patients had repeat scans 1 hour after baseline imaging (median, 2.3 hours [interquartile range. 1.9-3.1] after symptom onset). Eight patients (16%) had HE during that 1-hour interval; all of these occurred in patients with baseline imaging within 2 hours of onset (5/18=28% with baseline imaging within 1 hour, 3/18=17% within 1-2 hour, 0/13=0% >2 hours; P=0.02). HE did not occur between the scans repeated at 1 hour and 24 hours. No association between baseline variables and HE was detected in multivariable analyses. CONCLUSIONS: HE in the next hour occurs in 28% of ICH patients with baseline imaging within the first hour after symptom onset, and in 17% of those with baseline imaging between 1 and 2 hours. These patients would be a target for ultraearly hemostatic intervention.

Machine Learning Automated Detection of Large Vessel Occlusion From Mobile Stroke Unit Computed Tomography Angiography.

BACKGROUND: Prehospital automated large vessel occlusion (LVO) detection in Mobile Stroke Units (MSUs) could accelerate identification and treatment of patients with LVO acute ischemic stroke. Here, we evaluate the performance of a machine learning (ML) model on CT angiograms (CTAs) obtained from 2 MSUs to detect LVO. METHODS: Patients evaluated on MSUs in Houston and Los Angeles with out-of-hospital CTAs were identified. Anterior circulation LVO was defined as an occlusion of the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery vessels and determined by an expert human reader. A ML model to detect LVO was trained and tested on independent data sets consisting of in-hospital CTAs and then tested on MSU CTA images. Model performance was determined using area under the receiver-operator curve statistics. RESULTS: Among 68 patients with out-of-hospital MSU CTAs, 40% had an LVO. The most common occlusion location was the middle cerebral artery M1 segment (59%), followed by the internal carotid artery (30%), and middle cerebral artery M2 (11%). Median time from last known well to CTA imaging was 88.0 (interquartile range, 59.5-196.0) minutes. After training on 870 in-hospital CTAs, the ML model performed well in identifying LVO in a separate in-hospital data set of 441 images with area under receiver-operator curve of 0.84 (95% CI, 0.80-0.87). ML algorithm analysis time was under 1 minute. The performance of the ML model on the MSU CTA images was comparable with area under receiver-operator curve 0.80 (95% CI, 0.71-0.89). There was no significant difference in performance between the Houston and Los Angeles MSU CTA cohorts. CONCLUSIONS: In this study of patients evaluated on MSUs in 2 cities, a ML algorithm was able to accurately and rapidly detect LVO using prehospital CTA acquisitions.

The Applicability of Thromboelastography in Acute Ischemic Stroke: A Literature Review.

Acute ischemic stroke (AIS) due to cerebral artery occlusion is often treated by thrombolytics or antithrombotic drugs. Thromboelastography (TEG) is a noninvasive test that provides a dynamic overview of the coagulation process. TEG may help guide thrombolytic and antithrombotic therapy in AIS. This article aims to highlight the potential use of TEG in AIS patients by reviewing available studies. We conducted a literature review, including PubMed and Cochrane library databases. The following keywords were used to find relevant studies: thromboelastography, TEG, acute ischemic stroke, stroke, coagulopathy, antiplatelet, and anticoagulant treatment. We identified 142 papers and after abstract review, we included 24 studies in this report. TEG identified a hypercoagulable state in AIS patients represented by short R, K, and greater α: angle in all papers included. Modification of TEG parameters induced by intravenous thrombolysis was inconsistent but prolonged lysis (increased LY30) and weaker clots (lower maximum amplitude) were most frequent. TEG detected hypo-coagulopathy induced by dual antiplatelet therapy as well as antiplatelet drug resistance, with ticagrelor and aspirin having greater inhibition of platelet activity. A prolonged R-value seems to be the most reliable TEG parameter in detecting the anticoagulant effect of factor Xa inhibitor treatment. TEG might represent a useful point-of-care test for emergency decision-making in AIS patients and a tool for individualized treatment options. This hypothesis needs validation in a large cohort of prospectively studied AIS patients.

Mobile Stroke Units: Current Evidence and Impact.

PURPOSE OF REVIEW: Several approaches have been developed to optimize prehospital systems for acute stroke given poor access and significant delays to timely treatment. Specially equipped ambulances that directly initiate treatment, known as Mobile Stroke Units (MSUs), have rapidly proliferated across the world. This review provides a comprehensive summary on the efficacy of MSUs in acute stroke, its various applications beyond thrombolysis, as well as the establishment, optimal setting and cost-effectiveness of incorporating an MSU into healthcare systems. RECENT FINDINGS: MSUs speed stroke treatment into the first "golden hour" when better outcomes from thrombolysis are achieved. While evidence for the positive impact of MSUs on outcomes was previously unavailable, two recent landmark controlled trials, B_PROUD and BEST-MSU, show that MSUs result in significantly lesser disability compared to conventional ambulance care. Emerging literature prove the significant impact of MSUs. Adaptability however remains limited by significant upfront financial investment, challenges with reimbursements and pending evidence on their cost-effectiveness.

The Spot Sign and Intraventricular Hemorrhage are Associated with Baseline Coagulopathy and Outcome in Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is the second most prevalent subtype of stroke and has high mortality and morbidity. The utility of radiographic features to predict secondary brain injury related to hematoma expansion (HE) or increased intracranial pressure has been highlighted in patients with ICH, including the computed tomographic angiography (CTA) spot sign and intraventricular hemorrhage (IVH). Understanding the pathophysiology of spot sign and IVH may help identify optimal therapeutic strategies. We examined factors related to the spot sign and IVH, including coagulation status, hematoma size, and location, and evaluated their prognostic value in patients with ICH. METHODS: Prospectively collected data from a single center between 2012 and 2015 were analyzed. Patients who underwent thromboelastography within 24 h of symptom onset and completed follow-up brain imaging and CTA within 48 h after onset were included for analysis. Multivariate logistic regression analyses were performed to identify determinants of the spot sign and IVH and their predictive value for HE, early neurological deterioration (END), in-hospital mortality, and functional outcome at discharge. RESULTS: Of 161 patients, 50 (31.1%) had a spot sign and 93 (57.8%) had IVH. In multivariable analysis, the spot sign was associated with greater hematoma volume (odds ratio [OR] 1.02; 95% confidence interval [CI] 1.00-1.03), decreased white blood cell count (OR 0.88; 95% CI 0.79-0.98), and prolonged activated partial thromboplastin time (OR 1.14; 95% CI 1.06-1.23). IVH was associated with greater hematoma volume (OR 1.02; 95% CI 1.01-1.04) and nonlobar location of hematoma (OR 0.23; 95% CI 0.09-0.61). The spot sign was associated with greater risk of all adverse outcomes. IVH was associated with an increased risk of END and reduced HE, without significant impact on mortality or functional outcome. CONCLUSIONS: The spot sign and IVH are associated with specific hematoma characteristics, such as size and location, but are related differently to coagulation status and clinical course. A combined analysis of the spot sign and IVH can improve the understanding of pathophysiology and risk stratification after ICH.

How Frequent is the One-Hour tPA Infusion Interrupted or Delayed?

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) requires a one-hour infusion after the bolus. The frequency of delay or interruption of the tPA infusion may be useful in weighing the advantages of Tenecteplase (TNKase, TNK) which does not require an infusion. METHODS: Utilizing the Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services study database, we calculated the frequency and magnitude of tPA infusion delay or interruption. RESULTS: Of 497 patients treated with tPA on the Houston Mobile Stroke Unit (MSU), 41 (8.3%) had delay or interruption of the infusion for reasons that did not reflect a side effect of, or contraindication to, tPA. Nine received less than 90% of their calculated dose (median 62%, range 28-88%), and eleven had more than a 10% prolongation of their infusion (median 19 min, range 7-210 min). Six patients (1.2%) had infusion stopped for a valid concern for tPA side effect or contraindication. CONCLUSIONS: Interruption or discontinuation of the tPA infusion occurs in 8% of patients treated on a MSU providing an opportunity for more complete and faster treatment with TNK.