Endovascular management of acute stroke.

Stroke related to large vessel occlusion is a leading cause of disability and death worldwide. Advances in endovascular therapy to reopen occluded arteries have been shown to reduce patient disability and mortality. Expanded indications to treat patients with large vessel occlusion in the late window (>6 h from symptom onset), with basilar artery occlusion, and with large ischaemic core at presentation have enabled treatment of more patients with simplified imaging methods. Ongoing knowledge gaps include an understanding of which patients with large ischaemic infarct are more likely to benefit from endovascular therapy, the role of endovascular therapy in patients who present with low National Institutes of Health Stroke Scale scores or medium or distal vessel occlusion, and optimal management of patients with underlying intracranial atherosclerotic disease. As reperfusion can now be facilitated by intravenous thrombolysis, mechanical thrombectomy, or both, the development of cytoprotective or adjunctive drugs to slow infarct growth, enhance reperfusion, or decrease haemorrhagic risk has gained renewed interest with the hope to improve patient outcomes.

Dual Antiplatelet Versus Alteplase for Early Neurologic Deterioration in Minor Stroke With Versus Without Large Vessel Occlusion: Prespecified Post Hoc Analysis of the ARAMIS Trial.

BACKGROUND: Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO). METHODS: This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments. RESULTS: Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P<0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P=0.82). The interaction was marginally significant between groups (P=0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P<0.001). Other safety outcomes were similar between the 2 treatments. CONCLUSIONS: Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411.

Time from Onset to Remote Ischemic Conditioning and Clinical Outcome After Acute Moderate Ischemic Stroke.

OBJECTIVE: We conducted a post hoc exploratory analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to determine whether early remote ischemic conditioning (RIC) initiation after stroke onset was associated with clinical outcome in patients with acute moderate ischemic stroke. METHODS: In RICAMIS, patients receiving RIC treatment in the intention-to-treat analysis were divided into 2 groups based on onset-to-treatment time (OTT): early RIC group (OTT ≤ 24 hours) and late RIC group (OTT 24-48 hours). Patients receiving usual care without RIC treatment from intention-to-treat analysis were assigned as the control group. The primary outcome was excellent functional outcome at 90 days. RESULTS: Among 1,776 patients from intention-to-treat analysis, 387 were in the early RIC group, 476 in the late RIC group, and 913 in the control group. In the post hoc exploratory analysis, a higher proportion of excellent functional outcome was found in the early RIC versus control group (adjusted absolute difference = 8.1%, 95% confidence interval [CI] = 2.5%-13.8%, p = 0.005), but no difference in outcomes was detected in the late RIC versus control group (adjusted absolute difference = 3.3%, 95% CI = -2.1% to 8.6%, p = 0.23), or in the early RIC versus late RIC group (adjusted absolute difference = 5.0%, 95% CI = -1.3% to 11.2%, p = 0.12). Similar results were found in the per-protocol analysis. INTERPRETATION: Among patients with acute moderate ischemic stroke who are not candidates for intravenous thrombolysis or endovascular therapy, early RIC initiation within 24 hours of onset may be associated with higher likelihood of excellent clinical outcome. ANN NEUROL 2023;94:561-571.

Differential efficacy of remote ischaemic conditioning in anterior versus posterior circulation stroke: A prespecified secondary analysis of the RICAMIS trial.

BACKGROUND AND PURPOSE: The benefit of remote ischaemic conditioning (RIC) in acute moderate ischaemic stroke has been demonstrated by the Remote Ischaemic Conditioning for Acute Moderate Ischaemic Stroke (RICAMIS) study. This prespecified exploratory analysis aimed to determine whether there was a difference of RIC efficacy in anterior versus posterior circulation stroke based on RICAMIS data. METHODS: In this analysis, eligible patients presenting within 48 h of stroke onset were divided into two groups: anterior circulation stroke (ACS) and posterior circulation stroke (PCS) groups. The primary endpoint was an excellent functional outcome, defined as a modified Rankin Scale (mRS) score 0-1 at 90 days. RESULTS: In all, 1013 patients were included in the final analysis, including 642 with ACS and 371 with PCS. Compared with the control group, RIC was significantly associated with an increased proportion of mRS scores 0-1 within 90 days in the PCS group (unadjusted odds ratio 1.6, 95% confidence interval 1.0-2.4, p = 0.04; adjusted odds ratio 2.0, 95% confidence interval 1.2-3.3, p = 0.005), but not in the ACS group (p = 0.29). Similar results were found regarding secondary outcomes including mRS score 0-2 at 90 days, mRS distribution at 90 days and change in National Institutes of Health Stroke Scale score at day 12 from baseline. However, there was no significant interaction effect between stroke location and intervention on the primary outcome (pinteraction = 0.21). CONCLUSION: Amongst patients with acute PCS who are not candidates for reperfusion treatment, RIC may be associated with a higher probability of improved functional outcomes. These findings need to be validated in prospective trials.

Small vessel disease burden and prognosis of recent subcortical ischaemic stroke differ by parent artery atherosclerosis.

BACKGROUND AND PURPOSE: Parent artery atherosclerosis is an important aetiology of recent subcortical ischaemic stroke (RSIS). However, comparisons of RSIS with different degrees of parent artery atherosclerosis are lacking. METHODS: Prospectively collected data from our multicentre cohort (all were tertiary centres) of the Stroke Imaging Package Study between 2015 and 2017 were retrospectively reviewed. The patients with RSIS defined as a single clinically relevant diffusion-weighted imaging positive lesion in the territory of lenticulostriate arteries were categorized into three subgroups: (1) normal middle cerebral artery (MCA) on magnetic resonance angiography and high-resolution magnetic resonance imaging (HR-MRI); (2) low-grade MCA atherosclerosis (normal or <50% stenosis on magnetic resonance angiography and with MCA plaques on HR-MRI); (3) steno-occlusive MCA atherosclerosis (stenosis ≥50% or occlusion). The primary outcome was 90-day functional dependence (modified Rankin Scale score >2). The clinical and imaging findings were compared between subgroups. RESULTS: A total of 239 patients (median age 60.0 [52.0-67.0] years, 72% male) were enrolled, including 140 with normal MCA, 64 with low-grade MCA atherosclerosis and 35 with steno-occlusive MCA atherosclerosis. Patients with steno-occlusive MCA atherosclerosis had the largest infarct volume. Low-grade MCA atherosclerosis was independently associated with cerebral microbleeding, more severe perivascular spaces in basal ganglia and higher total cerebral small vessel disease burden. Low-grade MCA atherosclerosis was an independent determinant of 90-day functional dependence (odds ratio 3.897; 95% confidence interval 1.309-11.604). CONCLUSIONS: Our study suggested RSIS with varying severity of parent artery atherosclerosis exhibits distinctive clinical and neuroimaging characteristics, with low-grade MCA atherosclerosis associating with higher cerebral small vessel disease burden and worse prognosis.

Quantitative Assessment of Acute Intracranial Clot and Collaterals on High-Resolution Magnetic Resonance Imaging.

INTRODUCTION: There has been an increasing demand for imaging methods that provide a comprehensive evaluation of intracranial clot and collateral circulation, which are helpful for clinical decision-making and predicting functional outcomes. We aimed to quantitatively evaluate acute intracranial clot burden and collaterals on high-resolution magnetic resonance imaging (HR-MRI). METHODS: We analyzed acute ischemic stroke patients with internal carotid artery or middle cerebral artery occlusion in a prospective multicenter study. The clot burden was scored on a scale of 0-10 based on the clot location on HR-MRI. The collateral score was assigned on a scale of 0-3 using the minimum intensity projection from HR-MRI. Uni- and multivariable logistic regression analyses were performed to assess their correlation with clinical outcome (modified Rankin Scale >2 at 90 days). Thresholds were defined to dichotomize into low- and high-score groups, and predictive performances were assessed for clinical and radiologic outcomes. RESULTS: Ninety-nine patients (mean age of 60.77 ± 11.54 years) were included in the analysis. The interobserver correlation was 0.89 (95% CI: 0.77-0.95) for the clot burden score and 0.78 (95% CI: 0.53-0.90) for the collateral score. Multivariable logistic regression analysis demonstrated that the collateral score (odds ratio: 0.41, 95% CI: 0.19-0.90) was significantly associated with clinical outcomes. A better functional outcome was observed in the group with clot burden scores greater than 7 (p = 0.011). A smaller final infarct size and a higher diffusion-weighted imaging-based Alberta Stroke Program Early Computed Tomography Score were observed in the group with collateral scores greater than 1 (all p < 0.05). CONCLUSIONS: HR-MRI offers a new tool for quantitative assessment of clot burden and collaterals simultaneously in future clinical practices and research endeavors.

Remote Ischemic Conditioning and Outcomes in Acute Ischemic Stroke With Versus Without Large Artery Atherosclerosis.

BACKGROUND: RICAMIS trial (The Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke) has demonstrated efficacy of remote ischemic conditioning (RIC) in acute ischemic stroke. We conducted a post hoc analysis of RICAMIS to investigate whether large artery atherosclerosis (LAA) subtype contributed to the outcomes. METHODS: This is a post hoc analysis of the RICAMIS trial. Patients randomized to RIC group and Control group in full analysis set of RICAMIS were classified into LAA and non-LAA subtypes. The primary outcome was excellent functional outcome at 90 days, defined as modified Rankin Scale score of 0 to 1. Compared with patients receiving usual care, we investigated the association of RIC effect with outcomes in stroke subtypes and the interaction between RIC effect and stroke subtypes. The primary analysis was adjusted analysis. RESULTS: Among 1773 patients, 516 were assigned to LAA subtype (229 in the RIC group and 287 in the control group) and 1257 to non-LAA subtype (633 in the RIC group and 624 in the control group). Median age was 65 years, and 34.2% were women. A higher proportion of primary outcome was found to be associated with RIC treatment in LAA subtype (adjusted risk difference, 11.4% [95% CI, 3.6%-19.2%]; P=0.004), but not in non-LAA subtype (adjusted risk difference, 4.1% [95% CI, -1.1% to 9.3%]; P=0.12). There was no significant interaction between RIC effect and stroke subtypes (P=0.12). CONCLUSIONS: Patients with LAA subtype may benefit from RIC after stroke with respect to excellent functional outcome at 90 days. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03740971.

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

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

The effect of head-down tilt in experimental acute ischemic stroke.

BACKGROUND: Collateral therapeutics exert a promising protective effect on the outcome of acute ischemic stroke. Cerebral blood flow (CBF) may be modulated by different head positioning. The current study aimed to determine the effect of head-down tilt (HDT) on stroke in a rodent model. METHODS: The model of middle cerebral artery occlusion and reperfusion (MCAO/R) was used in this study. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride staining, brain water content, perivascular aquaporin protein-4 (AQP4) localization, pericyte marker platelet-derived growth factor receptor ß (PDGFRß), and CBF velocity were evaluated at 24 h after MCAO/R and HDT treatment. RESULTS: In the rat model of MCAO/R, brain infarct volume and neurological deficit score were significantly alleviated in the -30° and -60° groups compared to those in the lying flat (0°) group. Compared with the 0° group, an increase in CBF velocity was detected in the -30° group through two-photon microscopy imaging at 24 h after MCAO/R. Compared with the SHAM group, a decrease in PDGFRß was observed in both the MCAO/R and HDT treatment (-30°) groups. The integrated optical density of PDGFRß was found to be higher in the HDT treatment (-30°) group than in the MCAO/R group. An impairment in perivascular AQP4 polarity and an increase in brain water content were observed after MCAO/R, which were not exacerbated by HDT treatment (-30°). CONCLUSIONS: Our findings suggest that HDT treatment at certain degrees may exert a neuroprotective effect after MCAO/R through improving CBF velocity and the protection of pericytes.

Vulnerable plaque of the petrous internal carotid artery in embolic stroke of undetermined source.

BACKGROUND AND PURPOSE: The association between nonstenotic plaque at the petrous internal carotid artery (ICA) and embolic stroke of undetermined source (ESUS) remains unknown. We aimed to test the hypothesis that the presence of a larger build-up of petrous plaque is more prevalent in the ipsilateral versus the contralateral side among ESUS patients without plaque in the intracranial and proximal ICA. METHODS: From a total of 243 patients with ESUS and 160 patients with small-vessel disease (SVD) without proximal ICA plaque, we enrolled 88 ESUS and 103 SVD patients without ipsilateral nonstenotic intracranial and proximal ICA plaque in the present study. Targeting the petrous segment of the ICA on two sides, plaque burden including plaque thickness, lumen area, vessel area, wall area, and percentage of luminal stenosis, and composition features (presence/absence of the ruptured fibrous cap, ulcer plaque, thrombus, discontinuity of plaque surface [DPS], intraplaque hemorrhage and complicated plaque) were assessed by high-resolution magnetic resonance imaging. RESULTS: We found a higher prevalence of petrous plaque thickness ≥3.5 mm ipsilateral versus contralateral to the stroke (25/88 [28.4%] vs. 12/88 [13.6%], odds ratio [OR] 3.60, 95% confidence interval [CI] 1.34-9.70), but this imbalance was not seen in SVD. In patients with plaque thickness ≥3.5 mm, the presence of DPS (OR 4.05, 95% CI 1.11-14.78) and complicated plaque (OR 5.00, 95% CI 1.10-22.82) was more closely related to an index ESUS, a finding that was not evident in the subgroup with petrous plaque <3.5 mm (p for interaction = 0.027). CONCLUSIONS: The present study provided the first evidence supporting a potential etiological role of vulnerable petrous plaque in ESUS.

Efficacy of remote ischemic conditioning does not differ between men and women: A secondary analysis of the RICAMIS study.

BACKGROUND AND PURPOSE: The present study aimed to determine sex difference in clinical outcomes after Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS). METHODS: In this secondary analysis of the RICAMIS study, eligible patients aged 18 years or older with acute moderate ischemic stroke who received remote ischemic conditioning (RIC) within 48 h of stroke onset were divided into two groups: men and women. The primary endpoint was an excellent functional outcome, defined as a modified Rankin Scale score of 0-1 at 90 days. Binary logistic regression analyses and generalized linear models were used. RESULTS: Of 1707 eligible patients, 34% (579) were women. Women had a higher burden of hypertension and diabetes, and less alcohol and smoking consumption than men. The mean systolic blood pressure and blood glucose level at randomization were higher in women than in men. Compared with the control group, RIC was associated with an increased rate of primary endpoint in men (unadjusted odds ratio [OR] = 1.277; 95% confidence interval [CI] 0.933-1.644; p = 0.057) and women (unadjusted OR = 1.454; 95% CI 1.040-2.032; p = 0.028). Furthermore, a higher absolute risk difference in primary endpoint between control and RIC groups was found in women (9.2%) than in men (5.7%), but there was no significant interaction effect between sex and intervention on primary outcome (p interaction = 0.545). CONCLUSION: Compared with men, women may have a higher probability of excellent functional outcomes at 90 days in the RIC group than in the control group; however, no interaction effect between sex and intervention was found.

High-resolution magnetic resonance imaging of acute intracranial artery thrombus.

BACKGROUND AND PURPOSE: The development of high-resolution magnetic resonance imaging (HR-MRI) has enabled submillimeter-level evaluation of intracranial artery plaque and luminal thrombus. We sought to investigate the value of HR-MRI in assessing the pathogenesis of acute intracranial artery thrombus. METHODS: We examined the presence of intracranial thrombus on three-dimensional T1-weighted HR-MRI in acute ischemic stroke patients with intracranial artery occlusion on magnetic resonance angiography. We defined two thrombus-related HR-MRI features (peri-thrombus plaque and distal residual flow beyond the thrombus) and analyzed their association with potential embolic sources. RESULTS: Luminal thrombus and a shrunken artery without luminal thrombus were detected in 162 (96.4%) and six (3.6%) of 168 patients with intracranial artery occlusion, respectively. Among 111 patients with culprit major artery thrombus, peri-thrombus plaques were observed in 46.8% and distal residual flow beyond the thrombus in 64.0%. Patients with peri-thrombus plaque had a higher prevalence of diabetes (44.2% vs. 25.4%; p = 0.037), a lower prevalence of potential sources of cardioembolism (0% vs. 16.9%; p = 0.002), and a nonsignificantly lower prevalence of potential embolic sources from extracranial arteries (9.6% vs. 20.3%; p = 0.186) than those without. Patients with distal residual flow beyond the thrombus had a lower prevalence of potential sources of cardioembolism (1.4% vs. 22.5%; p < 0.001) and smaller infarct volumes (5.0 [1.4-12.7] mL vs. 16.6 [2.4-94.6] mL; p = 0.012) than those without. CONCLUSIONS: Our study showed that HR-MRI helps clarify the pathogenesis of acute intracranial artery thrombus. The presence of peri-thrombus plaque and distal residual flow beyond the thrombus favor the stroke mechanism of atherosclerosis rather than cardioembolism.

Endovascular Thrombectomy for Anterior Circulation Large Vessel Occlusion Stroke: An Evolution of Trials.

The last decade's progress in demonstrating the clinical benefit of endovascular thrombectomy (EVT) in patients with large vessel occlusion stroke has transformed the paradigm of care for these patients. This review presents the milestones in implementing EVT as standard of care, demonstrates the current state of evidence, provides guidance for identifying the candidate patient for EVT, and highlights unsolved and controversial issues. Ongoing trials investigate broadening of EVT indications for patients who present with large core infarction, adjunctive intra-arterial thrombolysis, medium vessel occlusion, low NIHSS, and tandem occlusion.

Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke: The ARAIS Randomized Clinical Trial.

Importance: Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking. Objective: To assess the efficacy of argatroban plus alteplase for AIS. Design, Setting, and Participants: This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Interventions: Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous argatroban (100 µg/kg bolus over 3-5 minutes followed by an infusion of 1.0 µg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n = 415), which received intravenous alteplase alone. Both groups received guideline-based treatments. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, -1.0% [95% CI, -8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P = .78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group. Conclusions and Relevance: Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03740958.

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial.

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.

Changes in blood gas values and electrolytes in the occluded artery predict outcomes after endovascular treatment in ischemic stroke.

BACKGROUND AND PURPOSE: Endovascular treatment (EVT) is the best treatment for acute ischemic stroke with large vessel occlusion (LVO) and makes it possible to analyze the blood contents from the occluded vascular compartments. In this study, we attempted to evaluate regional changes in blood gas values and electrolytes in the occluded vessels, aiming to determine whether these changes can predict outcomes in LVO patients receiving EVT. MATERIALS AND METHODS: We prospectively observed 45 consecutive ischemic stroke patients with LVO of the anterior circulation who underwent EVT. We collected the arterial blood proximal to the occlusion site before and after EVT, and the blood within the core of the occluded vascular compartment (distal to the thrombus) and evaluated the labs for blood gas values and electrolytes. Femoral samples were obtained under physiological flow conditions to represent systemic arterial blood. RESULTS: Compared with the femoral arterial blood samples, significant decreases in K+, Ca2+, HCO3-, BE, HCT, tHbc, and TCO2 levels were observed in the proximal luminal blood before EVT. Decreases in K+ and Ca2+ levels were also observed in the proximal luminal blood after EVT. Proximal/femoral ratio of pH and Na+ was associated with short-term clinical outcomes at 72 hours after EVT. A higher proximal/femoral Na+ ratio was associated with successful recanalization. Further analysis after propensity score matching showed significant changes in blood gas and electrolyte among different arterial locations in ICA and MCA LVO participants. Linear regression analyses indicated that the proximal/femoral ratio of pH, Na+, pCO2, HCO3, and TCO2 before EVT were associated with decrease in NIHSS score at 72 hours in ICA-LVO group. CONCLUSIONS: Obvious changes in several parameters of arterial blood gas and electrolyte from the ischemic vasculature occur during hyperacute stroke. Proximal/femoral pH and Na+ ratio before EVT may be associated with short-term clinical outcome, which deserve to be further investigated.

Atrial cardiopathy and non-stenotic intracranial complicated atherosclerotic plaque in patients with embolic stroke of undetermined source.

OBJECTIVE: To assess (1) the association between atrial cardiopathy (AC) and non-stenotic intracranial complicated atherosclerotic plaque (NICAP) in patients with embolic stroke of undetermined source (ESUS) or small-vessel disease (SVD), and (2) the performance of previously proposed biomarkers to identify AC as the underlying aetiology in ESUS. METHODS: Based on our high-resolution MRI (HR-MRI) cohort, 403 subjects (243 ESUS and 160 SVD) were enrolled in the final analysis. All patients underwent intracranial HR-MRI to assess the presence of ipsilateral NICAP. Biomarkers of AC (ie, P-wave terminal force in lead V1 (PTFV1) on ECG, N-terminal probrain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T and left atrial diameter) were collected within 24 hours after admission. RESULTS: Among patients without ipsilateral NICAP, we found an association between the presence of AC (adjusted OR (aOR): 4.76, 95% CI 2.48 to 9.14), increased PTFV1 (aOR: 5.70, 95% CI: 2.43 to 13.39) and NT-proBNP (aOR: 1.65, 95% CI: 1.16 to 2.35) with ESUS. This association was not evident among patients with ipsilateral NICAP. The discrimination between ESUS versus SVD by AC/AC-related biomarkers was significantly improved after excluding ipsilateral NICAP. Similarly, the discrimination between ESUS and SVD by ipsilateral NICAP was notably augmented after excluding AC, PTFV1 and NT-proBNP. INTERPRETATION: AC is more prevalent in patients who had ESUS without ipsilateral NICAP compared with patients with, implying that AC and ipsilateral NICAP are two distinct, competing aetiologies of ESUS. Among the AC biomarkers studied in this analysis, PTFV1 seems to be the most informative.

The characteristics of intracranial plaques of unilateral, anterior circulation embolic stroke of undetermined source: An analysis of different subtypes based on high-resolution imaging.

BACKGROUND AND PURPOSE: The aim was to investigate the characteristics of non-stenotic intracranial plaque (NSIP) in embolic stroke of undetermined source (ESUS) subtypes by high-resolution magnetic resonance imaging. METHODS: Consecutive patients with ESUS who were mandatory for high-resolution magnetic resonance imaging were retrospectively enrolled. Based on the location and arterial supply of the infarct, the ESUS were categorized into three types: cortical ESUS, subcortical ESUS and mixed ESUS. The NSIP parameters including plaque location, morphology (plaque distribution, remodeling index and plaque burden) and composition (thick fibrous cap, discontinuity of plaque surface, intraplaque hemorrhage and complicated plaque) were evaluated amongst the subtypes. RESULTS: Of 243 patients, there were 87 (35.8%) cortical ESUS, 127 (52.3%) subcortical ESUS and 29 (11.9%) mixed ESUS. Significant differences were found in plaque location (p < 0.001), plaque quadrant (p < 0.001), remodeling index (p < 0.001), plaque burden (p < 0.001), discontinuity of plaque surface (p < 0.001), intraplaque hemorrhage (p = 0.001) and complicated plaque (p < 0.001) of ipsilateral NISP amongst the different ESUS subtypes, except for fibrous cap (p = 0.135). However, no differences were found amongst contralateral NISP. In addition, the clinical characteristics of the differences between ESUS subtypes were striking, including age (p = 0.004), initial National Institutes of Health Stroke Scale (p < 0.001), coronary artery disease (p = 0.039), serum urea (p = 0.011) and creatinine (p = 0.002). CONCLUSION: This is the first report of significantly heterogeneous characteristics of ipsilateral NSIP and clinical findings amongst ESUS subtypes, which may suggest their different underlying mechanisms.

Long-term atorvastatin improves cognitive decline by regulating gut function in naturally ageing rats.

BACKGROUND: Statins have been widely used to prevent cardiovascular disease in middle-aged and elderly populations; however, the effect of long-term treatment on cognitive function is controversial. To simulate clinical conditions, middle-aged rats were given atorvastatin for 9 consecutive months to investigate the effect on natural cognitive decline and the possible mechanisms. RESULTS: The results showed that compared with the control group, long-term atorvastatin treatment naturally improved cognitive decline. Furthermore, long-term treatment regulated intestinal retinoic acid (RA) metabolism and storage by altering retinol dehydrogenase 7 (Rdh7) expression in the intestine, while RA metabolism affected the proliferation of intestinal Treg cells and inhibited IL-17+γδ T-cell function. In addition, long-term atorvastatin increased intestinal flora richness and decreased IL-17 expression in hippocampal tissue. CONCLUSION: Collectively, these findings provide the first evidence that long-term atorvastatin intervention may prevent cognitive decline in naturally ageing rats by inhibiting neuroinflammation via the gut-brain axis.

Effect of Remote Ischemic Conditioning vs Usual Care on Neurologic Function in Patients With Acute Moderate Ischemic Stroke: The RICAMIS Randomized Clinical Trial.

Importance: Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking. Objective: To assess the efficacy of RIC for acute moderate ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021. Interventions: Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971). Main Outcomes and Measures: The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group. Conclusions and Relevance: Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention. Trial Registration: ClinicalTrials.gov Identifier: NCT03740971.