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

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

Trial of Endovascular Thrombectomy for Large Ischemic Strokes.

BACKGROUND: Trials of the efficacy and safety of endovascular thrombectomy in patients with large ischemic strokes have been carried out in limited populations. METHODS: We performed a prospective, randomized, open-label, adaptive, international trial involving patients with stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery to assess endovascular thrombectomy within 24 hours after onset. Patients had a large ischemic-core volume, defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower scores indicating larger infarction) or a core volume of at least 50 ml on computed tomography perfusion or diffusion-weighted magnetic resonance imaging. Patients were assigned in a 1:1 ratio to endovascular thrombectomy plus medical care or to medical care alone. The primary outcome was the modified Rankin scale score at 90 days (range, 0 to 6, with higher scores indicating greater disability). Functional independence was a secondary outcome. RESULTS: The trial was stopped early for efficacy; 178 patients had been assigned to the thrombectomy group and 174 to the medical-care group. The generalized odds ratio for a shift in the distribution of modified Rankin scale scores toward better outcomes in favor of thrombectomy was 1.51 (95% confidence interval [CI], 1.20 to 1.89; P<0.001). A total of 20% of the patients in the thrombectomy group and 7% in the medical-care group had functional independence (relative risk, 2.97; 95% CI, 1.60 to 5.51). Mortality was similar in the two groups. In the thrombectomy group, arterial access-site complications occurred in 5 patients, dissection in 10, cerebral-vessel perforation in 7, and transient vasospasm in 11. Symptomatic intracranial hemorrhage occurred in 1 patient in the thrombectomy group and in 2 in the medical-care group. CONCLUSIONS: Among patients with large ischemic strokes, endovascular thrombectomy resulted in better functional outcomes than medical care but was associated with vascular complications. Cerebral hemorrhages were infrequent in both groups. (Funded by Stryker Neurovascular; SELECT2 ClinicalTrials.gov number, NCT03876457.).

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.

Tensor-valued diffusion MRI of human acute stroke.

PURPOSE: Tensor-valued diffusion encoding can disentangle orientation dispersion and subvoxel anisotropy, potentially offering insight into microstructural changes after cerebral ischemia. The purpose was to evaluate tensor-valued diffusion MRI in human acute ischemic stroke, assess potential confounders from diffusion time dependencies, and compare to Monte Carlo diffusion simulations of axon beading. METHODS: Linear (LTE) and spherical (STE) b-tensor encoding with inherently different effective diffusion times were acquired in 21 acute ischemic stroke patients between 3 and 57 h post-onset at 3 T in 2.5 min. In an additional 10 patients, STE with 2 LTE yielding different effective diffusion times were acquired for comparison. Diffusional variance decomposition (DIVIDE) was used to estimate microscopic anisotropy (µFA), as well as anisotropic, isotropic, and total diffusional variance (MKA , MKI , MKT ). DIVIDE parameters, and diffusion tensor imaging (DTI)-derived mean diffusivity and fractional anisotropy (FA) were compared in lesion versus contralateral white matter. Monte Carlo diffusion simulations of various cylindrical geometries for all b-tensor protocols were used to interpret parameter measurements. RESULTS: MD was ˜40% lower in lesions for all LTE/STE protocols. The DIVIDE parameters varied with effective diffusion time: higher µFA and MKA in lesion versus contralateral white matter for STE with longer effective diffusion time LTE, whereas the shorter effective diffusion time LTE protocol yielded lower µFA and MKA in lesions. Both protocols, regardless of diffusion time, were consistent with simulations of greater beading amplitude and intracellular volume fraction. CONCLUSION: DIVIDE parameters depend on diffusion time in acute stroke but consistently indicate neurite beading and larger intracellular volume fraction.

Association between serum triglycerides and stroke type, severity, and prognosis. Analysis in 6558 patients.

BACKGROUND AND OBJECTIVES: Hypertriglyceridemia (HT) may increase the risk of stroke. Limited studies have shown that stroke severity and infarction size are smaller in patients with HT. We explored the relationship between triglyceride levels and stroke risk factors, severity and outcome in a large prospective database. DESIGN: Prospective Cross-sectional study. SETTING: We retrospectively interrogated the Qatar Stroke Database in all patients admitted between 2014-2022 with acute ischemic stroke and evaluated the relationship between triglyceride, diabetes, stroke severity (measured on NIHSS), stroke type (TOAST classification) and the short- (mRS at 90 days) and long-term outcomes (MACE at 1 year) in patients with HT. PARTICIPANTS: Six thousand five hundred fifty-eight patients ≥20 years were included in this study RESULTS: Six thousand five hundred fifty-eight patients with ischemic stroke [mean age 54.6 ± 12. 9; male 82.1%) were included. Triglyceride levels upon admission were low-normal (≤1.1 mmol/L) in 2019 patients, high-normal (1.2-1.7 mmol/L) in 2142 patients, borderline-high (1.8-2.2 mmol/L) in 1072 patients and high (≥2.3 mmol/L) in 1325 patients. Higher triglyceride levels were associated with stroke and increased likelihood of having diabetes, obesity, active smoking, and small vessel/lacunar stroke type. An inverse relationship was noted whereby higher triglyceride levels were associated with lower stroke severity and reduced likelihood of poorer outcome (mRS 3-6) at discharge and 90 days. Long-term MACE events were less frequent in patients with higher triglyceride levels. After adjusting age, gender, diabetes, prior stroke, CAD, and obesity, multivariate analysis showed that hypertension and triglyceride levels were higher in mild ischemic strokes patients. CONCLUSIONS: Increasing triglycerides are associated with higher risk of small vessel disease and requires further prospective cohort studies for confirmation.

Direct to Angiosuite in Acute Stroke with Mobile Stroke Unit.

BACKGROUND: Early reperfusion has the best likelihood for a favorable outcome in acute ischemic stroke (AIS) with large vessel occlusion (LVO). Our experience with mobile stroke unit (MSU) for direct to angiosuite (DTAS) transfer in AIS patients with suspected LVO is presented. METHODS: Retrospective review of prospectively collected data from November 2019 to August 2022, of patients evaluated and transferred by the University of Alberta Hospital MSU and moved to angiosuite for endovascular thrombectomy (EVT). RESULT: A total of 41 cases were included. Nine were chosen for DTAS and 32 were shifted to angiosuite after stopping for computed tomography (CT) angiography of the head and neck (no-DTAS). Stroke severity measured by NIHSS (median with interquartile range (IQR)) was higher in patients of DTAS, 22 (14-24) vs 14.5 (5-25) in no-DTAS (p = 0.001). The non-contrast CT head in MSU showed hyperdense vessels in 8 (88.88%) DTAS vs 11 (34.35%) no-DTAS patients (p = 0.003). The EVT timelines (median with IQR, 90th percentile) including "door to artery puncture time" were 31 (23-50, 49.2) vs 79 (39-264, 112.8) minutes, and "door to recanalization time" was 69 (49-110, 93.2) vs 105.5 (52-178, 159.5) minutes in DTAS vs no-DTAS group, respectively. The workflow times were significantly shorter in the DTAS group (p < 0.001). Eight (88.88%) out of 9 DTAS patients had LVO and underwent thrombectomy. CONCLUSIONS: MSU for DTAS in patients with high NIHSS scores, cortical signs, and CT showing hyperdense vessel is an effective strategy to reduce the EVT workflow time.

Accreditation of stroke programs at the MENA + region; between aspiration and reality.

INTRODUCTION: Despite global progress in stroke care, challenges persist, especially in Low- and Middle-Income countries (LMIC). The Middle East and North Africa Stroke and Interventional Neurotherapies Organization (MENA-SINO) Stroke Program Accreditation Initiative aims to improve stroke care regionally. MATERIAL & METHOD: A 2022 survey assessed stroke unit readiness in the Middle East and North Africa (MENA) + region, revealing significant regional disparities in stroke care between high-income and low-income countries. Additionally, it demonstrated interest in the accreditation procedure and suggested that regional stroke program accreditation will improve stroke care for the involved centers. CONCLUSION: An accreditation program that is specifically tailored to the regional needs in the MENA + countries might be the solution. In this brief review, we will discuss potential challenges faced by such a program and we will put forward a well-defined 5-step accreditation process, beginning with a letter of intent, through processing the request and appointment of reviewers, the actual audit, the certification decisions, and culminating in granting a MIENA-SINO tier-specific certificate with recertification every 5 years.

Endovascular thrombectomy for acute ischemic stroke in Saudi Arabia: A single-center experience.

PURPOSE: This study aimed to investigate the outcomes of endovascular thrombectomy-treated patients in King Fahad Medical City, Riyadh, Saudi Arabia. METHODS: A retrospective cohort study of acute ischemic stroke patients treated with endovascular thrombectomy. Patients were included in the study between January 2015 and December 2022. Good outcomes were defined as a modified Rankin Scale (mRS) of 0-2 at 90 days. Multivariate logistic regression analysis was performed to identify the independent factors associated with good outcomes. RESULTS: During the study period, 369 patients with acute ischemic stroke (mean ± SD age, 61/- 15.1 yrs; 55.4 % male) underwent mechanical thrombectomy. Median National Institute of Health Stroke Scale (NIHSS) 15. Intravenous thrombolysis was administered to 34.5 % of the patients. Successful recanalization in the anterior circulation was achieved in 84.8 % of patients. Data from mRS performed after 90 days in the anterior circulation were available for 71.2 % of the patients. Of these, 41 % showed a good outcome, and the mortality rate was 22.4 %. The significant factors associated with good outcomes were age, NIHSS score, Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and short arterial puncture to recanalization. CONCLUSION: The number of patients who underwent endovascular thrombectomy has increased over time. The treatment outcomes and mortality were comparable with those of previous endovascular thrombectomy registries despite the high prevalence of DM, lower ASPECT score, and prolonged onset-to-recanalization time.

Prevalence, Trajectory, and Predictors of Poststroke Pain: Retrospective Analysis of Pooled Clinical Trial Data Set.

BACKGROUND: Poststroke pain remains underdiagnosed and inadequately managed. To inform the optimum time to initiate interventions, we examined prevalence, trajectory, and participant factors associated with poststroke pain. METHODS: Eligible studies from the VISTA (Virtual International Stroke Trials Archives) included an assessment of pain. Analyses of individual participant data examined demography, pain, mobility, independence, language, anxiety/depression, and vitality. Pain assessments were standardized to the European Quality of Life Scale (European Quality of Life 5 Dimensions 3 Level) pain domain, describing no, moderate, or extreme pain. We described pain prevalence, associations between participant characteristics, and pain using multivariable models. RESULTS: From 94 studies (n>48 000 individual participant data) in VISTA, 10 (n=10 002 individual participant data) included a pain assessment. Median age was 70.0 years (interquartile range [59.0-77.1]), 5560 (55.6%) were male, baseline stroke severity was National Institutes of Health Stroke Scale score 10 (interquartile range [7-15]). Reports of extreme pain ranged between 3% and 9.5% and were highest beyond 2 years poststroke (31/328 [9.5%]); pain trajectory varied by study. Poorer independence was significantly associated with presence of moderate or extreme pain (5 weeks-3 months odds ratio [OR], 1.5 [95% CI, 1.4-1.6]; 4-6 months OR, 1.7 [95% CI, 1.3-2.1]; >6 months OR, 1.5 [95% CI, 1.2-2.0]), and increased severity of pain (5 weeks-3 months: OR, 1.2 [95% CI, 1.1-1.2]; 4-6 months OR, 1.1 [95% CI, 1.1-1.2]; >6 months, OR, 1.2 [95% CI, 1.1-1.2]), after adjusting for covariates. Anxiety/depression and lower vitality were each associated with pain severity. CONCLUSIONS: Between 3% and 9.5% of participants reported extreme poststroke pain; the presence and severity of pain were independently associated with dependence at each time point. Future studies could determine whether and when interventions may reduce the prevalence and severity of poststroke pain.

Adherence to Anticoagulation Interruption Guidelines in Patients with Atrial Fibrillation.

INTRODUCTION: Annually, 15% of patients who receive oral anticoagulation require interruption for surgery or an invasive procedure. This study evaluates the adherence of patients with atrial fibrillation with a history of stroke or transient ischemic attack to the Thrombosis Canada Perioperative guidelines for the discontinuation and reinitiation of anticoagulation treatment. METHODS: We collected data from a prospective patient survey at the Stroke Prevention Clinic in the University of Alberta hospital. Patients' charts were reviewed from the electronic medical records, and adherence was looked at according to the Thrombosis Canada Perioperative guidelines for the interruption of anticoagulants. RESULTS: During the study period (2016-2019), there were 509 patients surveyed. Anticoagulation treatment was interrupted in 150 patients with 98 interrupted for surgical or invasive procedures. The interruption was adherent to guidelines in only 29 (29.6%) of patients and inappropriate or nonadherent in 69 (70.4%) patients. There were seven ischemic strokes recorded during the period of interruption. The proportion of strokes was higher in patients whose anticoagulation interruption was longer than what the guidelines recommended (6/61 or 9.8%) when compared to those who adhered to recommended perioperative anticoagulation guidelines (1/29 or 3.4%). CONCLUSION: Our results indicate that significant discrepancy with following the recommended perioperative anticoagulation guidelines is common in real-life practice. Delay in re-anticoagulation may increase the risk of complications.

How to Define Fast and Slow Progressors in Any-Type Occlusion Acute Ischemic Stroke.

The variable rate of infarct progression in acute ischemic stroke as assessed by various thresholds excludes a substantial proportion of patients due to time or core constraints. We evaluated 106 patients with any-type occlusion to compare these thresholds and assessed performance of hypoperfusion index (HI) for fast and slow rate of infarct progression. Seven (12.5%) were classified fast progressors and 23 (46%), 25 (50%), 12 (24%), and 33 (66%) slow progressors using different core and time criteria. In comparison, HI categorized 100% (n = 106) of cohort with optimal cutoff 0.5 for any-type occlusion (slow progressors: HI ≤ 0.5), sensitivity/specificity 100%/91%, AUC 0.94, and indicative of eligibility for reperfusion and clinical outcomes (median 90-day modified Rankin Scale; 2 for HI ≤ 0.5 versus 5). Estimation of progressors by HI seems comprehensive but needs external validation.

Thrombolysis in Stroke Mimics: Comprehensive Stroke Centers vs Telestroke Sites.

BACKGROUND: Hyperacute treatment of acute stroke may lead to thrombolysis in stroke mimics (SM). Our aim was to determine the frequency of thrombolysis in SM in primary stroke centers (PSC) dependent on telestroke versus comprehensive stroke centers (CSC). METHOD: Retrospective review of prospectively collected data from the Quality improvement and Clinical Research (QuICR) registry, the Discharge Abstract Database (DAD), and The National Ambulatory Care Reporting System (NACRS) of consecutive patients treated with intravenous thrombolysis for acute ischemic stroke in Alberta (Canada) from April 2016 to March 2021. RESULT: A total of 2471 patients who received thrombolysis were included. Linking the QuICR registry to DAD 169 (6.83%) patients were identified as SM; however, on our review of the records, only 112 (4.53%) were actual SM. SMs were younger with a mean age of 61.66 (±16.15) vs 71.08 (±14.55) in stroke. National Institute of Health Stroke Scale was higher in stroke with a median (IQR) of 10 (5-17) vs 7 (5-10) in SM. Only one patient (0.89 %) in SM groups had a small parenchymal hemorrhage versus 155 (6.57%) stroke patients had a parenchymal hemorrhage. There was no death among patients of thrombolysed SM during hospitalization versus 276 (11.69%) in stroke. There was no significant difference in the rate of SM among thrombolysed patients between PSC 27 (5.36%) versus CSC 85 (4.3%) (P = 0.312). The most responsible diagnosis of SM was migraine/migraine equivalent, functional disorder, seizure, and delirium. CONCLUSION: The diagnosis of SM may not always be correct when the information is extracted from databases. The rate of thrombolysis in SM via telestroke is similar to treatment in person at CSC.

The impact of leptomeningeal collaterals in acute ischemic stroke: a systematic review and meta-analysis.

OBJECTIVES: Leptomeningeal collaterals provide an alternate pathway to maintain cerebral blood flow in stroke to prevent ischemia, but their role in predicting the outcome is still unclear. So, our study aims at assessing the significance of collateral blood flow (CBF) in acute stroke. METHODS: Electronic databases were searched under different MeSH terms from January 2000 to February 2019. Studies were included if there was available data on good and poor CBF in acute ischemic stroke (AIS). The clinical outcomes included were modified Rankin scale (mRS), recanalization, mortality, and symptomatic intracranial hemorrhage (sICH) at 90 days. Data was analyzed using a random-effect model. RESULTS: A total of 47 studies with 8194 patients were included. Pooled meta-analysis revealed that there exist twofold higher likelihood of favorable clinical outcome (mRS ≤ 2) at 90 days with good CBF compared with poor CBF (RR: 2.27; 95% CI: 1.94-2.65; p < 0.00001) irrespective of the thrombolytic therapy [RR with IVT: 2.90; 95% CI: 2.14-3.94; p < 0.00001, and RR with IAT/EVT: 1.99; 95% CI: 1.55-2.55; p < 0.00001]. Moreover, there exists onefold higher probability of successful recanalization with good CBF (RR: 1.31; 95% CI: 1.15-1.49; p < 0.00001). However, there was 54% and 64% lower risk of sICH and mortality respectively in patients with good CBF in AIS (p < 0.00001). CONCLUSIONS: The relative risk of favorable clinical outcome is more in patients with good pretreatment CBF. This could be explained due to better chances of recanalization combined with a lesser risk of intracerebral hemorrhage with good CBF status.

Predictors of 30-day mortality using machine learning approach following carotid endarterectomy.

BACKGROUND: Preoperative prognostication of 30-day mortality in patients with carotid endarterectomy (CEA) can optimize surgical risk stratification and guide the decision-making process to improve survival. This study aims to develop and validate a set of predictive variables of 30-day mortality following CEA. METHODS: The patient cohort was identified from the American College of Surgeons National Surgical Quality Improvement Program (2005-2016). We performed logistic regression (enter, stepwise, and forward) and least absolute shrinkage and selection operator (LASSO) method for the selection of variables, which resulted in 28-candidate models. The final model was selected based upon clinical knowledge and numerical results. RESULTS: Statistical analysis included 65,807 patients with 30-day mortality in 0.7% (n = 466) patients. The median age of our cohort was 71.0 years (range, 16-89 years). The model with 9 predictive factors which included age, body mass index, functional health status, American Society of Anesthesiologist grade, chronic obstructive pulmonary disorder, preoperative serum albumin, preoperative hematocrit, preoperative serum creatinine, and preoperative platelet count-performed best on discrimination, calibration, Brier score, and decision analysis to develop a machine learning algorithm. Logistic regression showed higher AUCs than LASSO across these different models. The predictive probability derived from the best model was converted into an open-accessible scoring system. CONCLUSION: Machine learning algorithms show promising results for predicting 30-day mortality following CEA. These algorithms can be useful aids for counseling patients, assessing preoperative medical risks, and predicting survival after surgery.

Characteristics and comparisons of acute stroke in "recovered" to "active COVID-19 and "pre-pandemic" in Qatar database.

Understanding the relationship of COVID-19 to stroke is important. We compare characteristics of pre-pandemic stroke (PPS), cases in acute COVID infection (CS) and in patients who have recovered from COVID-19 infection (RCS). We interrogated the Qatar stroke database for all stroke admissions between Jan 2020 and Feb 2021 (PPS) to CS and RCS to determine how COVID-19 affected ischemic stroke sub-types, clinical course, and outcomes prior to, during and post-pandemic peak. There were 3264 cases admitted (pre-pandemic: 3111, stroke in COVID-19: 60 and recovered COVID-19 stroke: 93). Patients with CS were significantly younger, had more severe symptoms, fever on presentation, more ICU admissions and poor stroke recovery at discharge when compared to PPS and RCS. Large vessel disease and cardioembolic disease was significantly higher in CS compared to PPS or RCS. There was a significant decline in stroke mimics in CS. Stroke in RCS has characteristics similar to PPS with no evidence of lasting effects of the virus on the short-term. However, CS is a more serious disease and tends to be more severe and have a poor prognosis.

Identification of Novel Circulating miRNAs in Patients with Acute Ischemic Stroke.

Ischemic strokes are associated with significant morbidity and mortality, but currently there are no reliable prognostic or diagnostic blood biomarkers. MicroRNAs (miRNAs) regulate various molecular pathways and may be used as biomarkers. Using RNA-Seq, we conducted comprehensive circulating miRNA profiling in patients with ischemic stroke compared with healthy controls. Samples were collected within 24 h of clinical diagnosis. Stringent analysis criteria of discovery (46 cases and 95 controls) and validation (47 cases and 96 controls) cohorts led to the identification of 10 differentially regulated miRNAs, including 5 novel miRNAs, with potential diagnostic significance. Hsa-miR-451a was the most significantly upregulated miRNA (FC; 4.8, FDR; 3.78 × 10-85), while downregulated miRNAs included hsa-miR-574-5p and hsa-miR-142-3p, among others. Importantly, we computed a multivariate classifier based on the identified miRNA panel to differentiate between ischemic stroke patients and healthy controls, which showed remarkably high sensitivity (0.94) and specificity (0.99). The area under the ROC curve was 0.97 and it is superior to other current available biomarkers. Moreover, in samples collected one month following stroke, we found sustained upregulation of hsa-miR-451a and downregulation of another 5 miRNAs. Lastly, we report 3 miRNAs that were significantly associated with poor clinical outcomes of stroke, as defined by the modified Rankin scores. The clinical translation of the identified miRNA panel may be explored further.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention.

BACKGROUND: Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. METHODS: We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. CONCLUSION: The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

Circulating MicroRNA Profiling Identifies Distinct MicroRNA Signatures in Acute Ischemic Stroke and Transient Ischemic Attack Patients.

Transient ischemic attack (TIA) refers to a momentary neurologic deficit caused by focal cerebral, spinal or retinal ischemic insult. TIA is associated with a high risk of impending acute ischemic stroke (AIS), a neurologic dysfunction characterized by focal cerebral, spinal or retinal infarction. Understanding the differences in molecular pathways in AIS and TIA has merit for deciphering the underlying cause for neuronal deficits with long-term effects and high risks of morbidity and mortality. In this study, we performed comprehensive investigations into the circulating microRNA (miRNA) profiles of AIS (n = 191) and TIA (n = 61) patients. We performed RNA-Seq on serum samples collected within 24 hrs of clinical diagnosis and randomly divided the study populations into discovery and validation cohorts. We identified a panel of 11 differentially regulated miRNAs at FDR < 0.05. Hsa-miR-548c-5p, -20a-5p, -18a-5p, -484, -652-3p, -486-3p, -24-3p, -181a-5p and -222-3p were upregulated, while hsa-miR-500a-3p and -206 were downregulated in AIS patients compared to TIA patients. We also probed the previously validated gene targets of our identified miRNA panel to highlight the molecular pathways affected in AIS. Moreover, we developed a multivariate classifier with potential utilization as a discriminative biomarker for AIS and TIA patients. The underlying molecular pathways in AIS compared to TIA may be explored further in functional studies for therapeutic targeting in clinical translation.

Nitroglycerin Is Not Associated with Improved Cerebral Perfusion in Acute Ischemic Stroke.

OBJECTIVE: The study was conducted to test the hypothesis that nitroglycerin (NTG) increases cerebral perfusion focally and globally in acute ischemic stroke patients, using serial perfusion-weighted imaging (PWI) magnetic resonance imaging measurements. PATIENTS AND METHODS: Thirty-five patients underwent PWI immediately before and 72 h after administration of a transdermal NTG patch or no treatment. Patients with baseline mean arterial pressure (MAP) > 100 mmHg (NTG group, n = 20) were treated with transdermal NTG (0.2 mg/h) for 72 h, without a nitrate-free interval. Patients with MAP ≤ 100 mmHg (untreated group, n = 15) were not treated. The primary outcome measure was absolute cerebral blood flow (CBF) in the hypoperfused region at 72 h. RESULTS: The mean baseline absolute CBF in the hypoperfused region was similar in the NTG group (33.3 ± 10.2 ml/100 g/min) and untreated (32.7 ± 8.4 ml/100 g/min, p = 0.4) groups. The median (IQR) baseline infarct volume was 10.4 (2.5-49.3) ml in the NTG group and 32.6 (8.6-96.7) ml in the untreated group (p = 0.09). MAP change in the NTG group was 1.2 ± 12.6 and 8 ± 20.7 mmHg at 2 h and 72 h, respectively. Mean absolute CBF in the hypoperfused region at 72 h was similar in the NTG (29.9 ± 12 ml/100 g/min) and untreated groups (24.1 ± 10 ml/100 g/min, p = 0.8). The median infarct volume increased in untreated (11.8 (5.7-44.2) ml) than the NTG group (3.2 (0.5-16.5) ml; p = 0.033) on univariate analysis, however, there was no difference on regression analysis. CONCLUSION: NTG was not associated with improvement in cerebral perfusion in acute ischemic stroke patients.

Sex Differences in Endovascular Treatment for Stroke: A Population-based Analysis.

BACKGROUND: Acute ischemic stroke may affect women and men differently. We aimed to evaluate sex differences in outcomes of endovascular treatment (EVT) for ischemic stroke due to large vessel occlusion in a population-based study in Alberta, Canada. METHODS AND RESULTS: Over a 3-year period (April 2015-March 2018), 576 patients fit the inclusion criteria of our study and constituted the EVT group of our analysis. The medical treatment group of the ESCAPE trial had 150 patients. Thus, our total sample size was 726. We captured outcomes in clinical routine using administrative data and a linked database methodology. The primary outcome of our study was home-time. Home-time refers to the number of days that the patient was back at their premorbid living situation without an increase in the level of care within 90 days of the index stroke event. In adjusted analysis, EVT was associated with an increase of 90-day home-time by an average of 6.08 (95% CI -2.74-14.89, p-value 0.177) days in women compared to an average of 11.20 (95% CI 1.94-20.46, p-value 0.018) days in men. Further analysis revealed that the association between EVT and 90-day home-time in women was confounded by age and onset-to-treatment time. CONCLUSIONS: We found a nonsignificant nominal reduction of 90-day home-time gain for women compared to men in this province-wide population-based study of EVT for large vessel occlusion, which was only partially explained by confounding.