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-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.

Association of systolic blood pressure variability with remote ischemic conditioning in acute ischemic stroke.

Systolic blood pressure variability (SBPV) is associated with outcome in acute ischemic stroke. Remote ischemic conditioning (RIC) has been demonstrated to be effective in stroke and may affect blood pressure. Relationship between SBPV and RIC treatment after stroke warrants investigation. A total of 1707 patients from per-protocol analysis set of RICAMIS study were included. The SBPV was calculated based on blood pressure measured at admission, Day 7, and Day 12. (I) To investigate the effect of SBPV on efficacy of RIC in stroke, patients were divided into High and Low categories in each SBPV parameter. Primary outcome was excellent functional outcome at 90 days. Compared with Control, efficacy of RIC in each category and interaction between categories were investigated. (II) To investigate the effect of RIC treatment on SBPV, SBPV parameters were compared between RIC and Control groups. Compared with Control, a higher likelihood of primary outcome in RIC was found in high category (max-min: adjusted risk difference [RD] = 7.2, 95% CI 1.2-13.1, P = 0.02; standard deviation: adjusted RD = 11.5, 95% CI 1.6-21.4, P = 0.02; coefficient of variation: adjusted RD = 11.2, 95% CI 1.4-21.0, P = 0.03). Significant interaction of RIC on outcomes were found between High and Low standard deviations (adjusted P < 0.05). No significant difference in SBPV parameters were found between treatment groups. This is the first report that Chinese patients with acute moderate ischemic stroke and presenting with higher SBPV, who were non-cardioemoblic stroke and not candidates for intravenous thrombolysis or endovascular therapy, would benefit more from RIC with respect to functional outcomes at 90 days, but 2-week RIC treatment has no effect on SBPV during hospital.

The association of gender with functional outcome in thrombolysed stroke: A secondary analysis of INTRECIS study.

Background and Purpose: Sex differences in acute ischemic stroke have been widely investigated, but the difference in acute ischemic stroke patients who received intravenous thrombolysis is not well understood. The current study was to investigate the issue based on a prospective cohort. Methods: From the Intravenous Thrombolysis Registry for Chinese Ischemic Stroke within 4.5h onset (INTRECIS) cohort, a total of 953 eligible patients with acute ischemic stroke were enrolled in final analysis. Based on 3-month modified Rankin scale score (mRS), patients were classified into good outcome group (mRS 0-1) and poor outcome group (mRS 2-6). Univariate and multivariate logistic regression analyses were used to identify predictive factors for clinical outcome in male or female patients. Results: Of the 953 patients treated with intravenous thrombolysis, 314 (32.9 %) were women. At day 90, we found no significant gender differences in good outcome (72.5 % vs 65.6 %, adjusted p = 0.414). We got the same results after propensity score matching (69.5 % vs 63.4 %, adjusted p = 0.637). Furthermore, we found that initial National Institute of Health Stroke Scale (NIHSS) score (odd ratio [OR] 0.877; 95 % CI 0.847-0.909, p < 0.001) and serum creatinine (OR 0.993; 95 % CI 0.986-1.000, p = 0 0.043) were found to be independent risk factors for poor outcome in male patients, while initial NIHSS score (OR 0.879; 95 % CI 0.839-0.920, p < 0.001), age (OR 0.970; 95 % CI 0.946-0.995, p = 0.017), systolic blood pressure (OR 0.984; 95 % CI 0.972-0.996, p = 0.007) and small artery occlusion (OR 2.718; 95 % CI 1.065-6.936, p = 0.036) in female patients. Conclusions: In this study, we found no gender difference in clinical outcome of thrombolysed stroke patients, but a difference in risk factors predicting outcome in male vs female patients was identified for the first time.

Systolic blood pressure and early neurological deterioration in minor stroke: A post hoc analysis of ARAMIS trial.

BACKGROUND: Systolic blood pressure (SBP) was a predictor of early neurological deterioration (END) in stroke. We performed a secondary analysis of ARAMIS trial to investigate whether baseline SBP affects the effect of dual antiplatelet versus intravenous alteplase on END. METHODS: This post hoc analysis included patients in the as-treated analysis set. According to SBP at admission, patients were divided into SBP ≥140 mmHg and SBP <140 mmHg subgroups. In each subgroup, patients were further classified into dual antiplatelet and intravenous alteplase treatment groups based on study drug actually received. Primary outcome was END, defined as an increase of ≥2 in the NIHSS score from baseline within 24 h. We investigated effect of dual antiplatelet vs intravenous alteplase on END in SBP subgroups and their interaction effect with subgroups. RESULTS: A total of 723 patients from as-treated analysis set were included: 344 were assigned into dual antiplatelet group and 379 into intravenous alteplase group. For primary outcome, there was more treatment effect of dual antiplatelet in SBP ≥140 mmHg subgroup (adjusted RD, -5.2%; 95% CI, -8.2% to -2.3%; p < 0.001) and no effect in SBP <140 mmHg subgroup (adjusted RD, -0.1%; 95% CI, -8.0% to 7.7%; p = 0.97), but no significant interaction between subgroups was found (adjusted p = 0.20). CONCLUSIONS: Among patients with minor nondisabling acute ischemic stroke, dual antiplatelet may be better than alteplase with respect to preventing END within 24 h when baseline SBP ≥140 mmHg.

Balloon angiopLasty for intracranial Atherosclerotic minor Stroke/TIA (BLAST): study protocol for a multicenter prospective cohort study.

Rationale/Aim: Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke in Asia and is significantly associated with stroke recurrence. The Balloon angiopLasty for intracranial Atherosclerotic minor Stroke/TIA (BLAST) study aims to evaluate the safety and effectiveness of early submaximal balloon angioplasty (SBA) combined with standard medical therapy vs. standard medical therapy alone in patients with minor stroke or transient ischemic attack (TIA) due to ICAS. Methods: The BLAST study is a multicenter prospective cohort study which will enroll patients with minor stroke or TIA due to symptomatic ICAS within 1 week of symptom onset from 20 centers in China. Eligible patients will receive either SBA with standard medical therapy or standard medical therapy alone based on the decision of the patient or legal representative. Participants will be followed up for 1 year. Study outcomes: The primary outcome is a composite of stroke or death within 30 days or ischemic stroke in the culprit artery territory from 30 days to 1 year. Secondary outcomes include stroke or death within 30 days, ischemic stroke in the culprit artery territory from 30 days to 1 year, restenosis rate of the culprit artery at 1 year, and neurological improvement at 90 days (assessed by mRS score). Safety outcomes include intracranial hemorrhage within 30 days and endovascular complications. Sample size estimate: According to previous studies, the incidence of the composite clinical outcomes is 15% in the group receiving medical therapy alone. We assumed the incidence would decrease to 5% in the SBA combined with the medical therapy group. The target sample size is 416 patients (208 per group), with 90% power and 5% type I error, allowing for a 10% loss to follow-up. Implications: The BLAST study will provide evidence regarding whether early SBA can reduce stroke recurrence and mortality in patients with minor stroke/TIA due to ICAS compared with medical therapy alone.Clinical trial registration:Clinicaltrials.gov, NCT06014723.

Intravenous tenecteplase for acute ischemic stroke between 4.5 and 6 h of onset (EXIT-BT2): Rationale and Design.

RATIONALE: To date, the benefit of intravenous thrombolysis for acute ischemic stroke (AIS) patients without advanced neuroimaging selection is confined to within 4.5 h of onset. Our phase II EXIT-BT (Extending the tIme window of Thrombolysis by ButylphThalide up to 6 h after onset) trial suggested the safety, feasibility, and potential benefit of intravenous tenecteplase (TNK) in AIS between 4.5 and 6 h of onset. The EXIT-BT2 trial is a pivotal study undertaken to confirm or refute this signal. AIM: To investigate the efficacy and safety of TNK for AIS between 4.5 and 6 h of onset with or without endovascular treatment. SAMPLE SIZE ESTIMATES: A maximum of 1440 patients are required to test the superiority hypothesis with 80% power according to a two-sided 0.05 level of significance, stratified by age, sex, history of diabetes, location of vessel occlusion, baseline National Institute of Health stroke scale score, stroke etiology, and plan for endovascular treatment. DESIGN: EXIT-BT2 is a prospective, randomized, open-label, blinded assessment of endpoint (PROBE), and multi-center study. Eligible AIS patients between 4.5 and 6 h of onset are randomly assigned 1:1 into a TNK group or control group. The TNK group will receive TNK (0.25 mg/kg, a single bolus over 5-10 s, maximum 25 mg). The control group will receive standard medical care in compliance with national guidelines for acute ischemic stroke. Both groups will receive standard stroke care from randomization to 90 days after stroke onset according to national guidelines. OUTCOME: The primary efficacy endpoint is excellent functional outcome, defined as a modified Rankin Scale score 0-1 at 90 days after randomization, while the primary safety endpoint is symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale score increase ⩾4 caused by intracranial hemorrhage within 24 (-6/+12) h after randomization. CONCLUSIONS: The results of EXIT-BT2 may determine whether intravenous TNK has a favorable risk/benefit profile in AIS between 4.5 and 6 h of onset.

Baseline neurological deficit and argatroban plus alteplase in acute ischemic stroke: A post hoc analysis of ARAIS trial.

BACKGROUND: The ARAIS trial didn't demonstrate argatroban significantly improve functional outcome at 90 days in acute ischemic stroke. We conducted post hoc analysis of ARAIS to investigate whether baseline neurological deficit was associated with outcomes. METHODS: Patients without endovascular therapy who met screening criteria as protocol and completed argatroban treatment were enrolled and classified into two subgroups according to NIHSS score at admission. Primary outcome was excellent functional outcome at 90 days, defined as mRS score of 0 to 1. Early neurological deterioration (END), defined as an increase of ≥4 in the NIHSS score from baseline within 48 hours, was investigated as secondary outcome. Compared with alteplase alone, we investigated treatment effect of argatroban plus alteplase on outcomes in subgroups and interaction with subgroups. RESULTS: A total of 675 patients from full analysis set were included: 390 were assigned into NIHSS score <10 subgroup and 285 into NIHSS score ≥10 subgroup. For primary outcome, there was similar treatment effect between argatroban plus alteplase and alteplase alone in NIHSS score ≥10 subgroup (adjusted RD, 5.8%; 95% CI, -6.0% to 17.5%; P = 0.33) and in NIHSS score <10 subgroup (adjusted RD, -1.4%; 95% CI, -9.9% to 7.1%; P = 0.75), and no significant interaction (P = 0.43). Occurrence of early neurological deterioration within 48 hours were significantly lower in NIHSS score ≥10 subgroup, compared with NIHSS score <10 subgroup (P = 0.006). CONCLUSION: Among patients with NIHSS score ≥10, argatroban plus alteplase could safely reduce END within 48 hours.

Baseline systolic blood pressure, hypertension history, and efficacy of remote ischemic conditioning.

OBJECTIVE: We performed a post hoc exploratory analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to determine whether hypertension history and baseline systolic blood pressure (SBP) affect the efficacy of remote ischemic conditioning (RIC). METHODS: Based on the full analysis set of RICAMIS, patients were divided into hypertension versus non-hypertension group, or <140 mmHg versus ≥140 mmHg group. Each group was further subdivided into RIC and control subgroups. The primary outcome was modified Rankin Scale (mRS) 0-1 at 90 days. Efficacy of RIC was compared among patients with hypertension versus nonhypertension history and SBP of <140 mmHg versus ≥140 mmHg. Furthermore, the interaction effect of treatment with hypertension and SBP was assessed. RESULTS: Compared with control group, RIC produced a significantly higher proportion of patients with excellent functional outcome in the nonhypertension group (RIC vs. control: 65.7% vs. 57.0%, OR 1.45, 95% CI 1.06-1.98; p = 0.02), but no significant difference was observed in the hypertension group (RIC vs. control: 69.1% vs. 65.2%, p = 0.17). Similar results were observed in SBP ≥140 mmHg group (RIC vs. control: 68.0% vs. 61.2%, p = 0.009) and SBP <140 mmHg group (RIC vs. control: 65.6% vs. 64.7%, p = 0.77). No interaction effect of RIC on primary outcome was identified. INTERPRETATION: Hypertension and baseline SBP did not affect the neuroprotective effect of RIC, but they were associated with higher probability of excellent functional outcome in patients with acute moderate ischemic stroke who received RIC treatment.

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

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

A nomogram for predicting cerebral white matter lesions in elderly men.

Objective: This study aimed to develop a nomogram tool to predict cerebral white matter lesions (WMLs) in elderly men. Methods: Based on a retrospective cohort from January 2017 to December 2019, a multivariate logistic analysis was performed to construct a nomogram for predicting WMLs. The nomogram was further validated using a follow-up cohort between January 2020 and December 2022. The calibration curve, receiver operating characteristics (ROC) curves, and the decision curves analysis (DCA) were used to evaluate discrimination and calibration of this nomogram. Result: A total of 436 male patients were enrolled in this study, and all 436 patients were used as the training cohort and 163 follow-up patients as the validation cohort. A multivariate logistic analysis showed that age, cystatin C, uric acid, total cholesterol, platelet, and the use of antiplatelet drugs were independently associated with WMLs. Based on these variables, a nomogram was developed. The nomogram displayed excellent predictive power with the area under the ROC curve of 0.951 [95% confidence interval (CI), 0.929-0.972] in the training cohort and 0.915 (95% CI, 0.864-0.966) in the validation cohort. The calibration of the nomogram was also good, as indicated by the Hosmer-Lemeshow test with p-value of 0.594 in the training cohort and 0.178 in the validation cohort. The DCA showed that the nomogram holds good clinical application value. Conclusion: We have developed and validated a novel nomogram tool for identifying elderly men at high risk of WMLs, which exhibits excellent predictive power, discrimination, and calibration.

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

Intravenous alteplase in minor nondisabling ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: Minor ischemic stroke, defined as National Institute of Health Stroke Scale score of 0-5 on admission, represents half of all acute ischemic strokes. The role of intravenous alteplase (IVA) among patients with minor stroke is inconclusive; therefore, we evaluated clinical outcomes of these patients treated with or without IVA. MATERIALS AND METHODS: We searched Medline, Embase, Scopus, and the Cochrane library until August 1, 2023. Inclusion was restricted to the English literature of studies that reported on minor nondisabling stroke patients treated with or without IVA. Odds ratios (ORs) with their corresponding 95% CIs were utilized using a random-effects model. Efficacy outcomes included rates of excellent (modified Rankin scale [mRS] of 0-1) and good (mRS of 0-2) functional outcome at 90 days. The main safety outcome was symptomatic intracerebral hemorrhage (sICH). RESULTS: Five eligible studies, two RCTs and three observational studies, comprising 2764 patients (31.8% female) met inclusion criteria. IVA was administered to 1559 (56.4%) patients. Pooled analysis of the two RCTs revealed no difference between the two groups in terms of 90-days excellent functional outcomes (OR 0.76 [95% CI, 0.51-1.13]; I2 = 0%) and sICH rates (OR 3.76 [95% CI, 0.61-23.20]). No significant differences were observed between the groups in terms of good functional outcomes, 90-day mortality, and 90-day stroke recurrence. CONCLUSION: This meta-analysis of minor nondisabling stroke suggests that IVA did not prove more beneficial compared to no-IVA.

Remote Ischemic Conditioning With Medical Management or Reperfusion Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date. METHODS: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073). RESULTS: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group (p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group. DISCUSSION: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Benefit of endovascular treatment for primary versus secondary medium vessel occlusion: A multi-center experience.

AIMS: This study aimed to compare the clinical outcomes and safety of endovascular treatment (EVT) in patients with primary versus secondary medium vessel occlusion (MeVO). METHODS: From the endovascular treatment for acute ischemic stroke in the China registry, we collected consecutive patients with MeVO who received EVT. The primary endpoint was a good outcome, defined as a modified Rankin Scale (mRS) 0 to 2 at 90 days. RESULTS: 154 patients were enrolled in the final analysis, including 74 primary MeVO and 80 secondary MeVO. A good outcome at 90 days was achieved in 42 (56.8%) patients with primary MeVO and 33 (41.3%) patients with secondary MeVO. There was a higher probability of good outcomes in patients with the primary vs secondary MeVO (adjusted odds ratio, 2.16; 95% confidence interval, 1.04 to 4.46; p = 0.04). There were no significant differences in secondary and safety outcomes between MeVO groups. In the multivariable analysis, baseline ASPECTS (p = 0.001), final modified thrombolysis in cerebral infarction score (p = 0.01), and any ICH (p = 0.03) were significantly associated with good outcomes in primary MeVO patients, while baseline National Institutes of Health Stroke Scale (p = 0.002), groin puncture to recanalization time (p = 0.02), and early neurological improvement (p < 0.001) were factors associated with good outcome in secondary MeVO patients. CONCLUSION: In MeVO patients who received EVT, there was a higher likelihood of poor outcomes in patients with secondary versus primary MeVO.

Clopidogrel Plus Aspirin vs Aspirin Alone in Patients With Acute Mild to Moderate Stroke: The ATAMIS Randomized Clinical Trial.

Importance: Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking. Objective: To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke. Design, Setting, and Participants: This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome. Interventions: Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio. Main Outcomes and Measures: The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points. Results: Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference -1.9%; 95% CI, -3.6 to -0.2; P = .03). Similar bleeding events were found between 2 groups. Conclusions and Relevance: Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT02869009.

Duration of Remote Ischemic Conditioning and Outcome in Acute Ischemic Stroke.

BACKGROUND: Remote ischemic conditioning has been found to be effective in improving functional outcomes in acute ischemic stroke. We conducted a post hoc analysis of the RICAMIS (Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke) trial to determine whether long-term remote ischemic conditioning duration after stroke onset is associated with better clinical outcomes in ischemic stroke. METHODS AND RESULTS: Patients from the full analysis set were included in this secondary analysis. The primary outcome was the proportion of patients with an excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. Among the 1776 patients, there were 55 patients in the 1 to 7 days remote ischemic conditioning group, 345 in the 8 to 10 days group, 412 in the 11 to 13 days group, 51 in the 14 to 16 days group, and 913 in the control group. Compared with the control group, a significantly higher proportion of excellent functional outcomes at 90 days was found in the 11 to 13 days remote ischemic conditioning group (adjusted absolute difference, 9.1% [95% CI, 3.7%-14.5%]; P =0.001), which was attenuated in the other groups (adjusted absolute difference in the 8-10 days group, 2.0% [95% CI, -4.0% to 8.0%]; P=0.51; adjusted absolute difference in the 14-16 days group, 7.4% [95% CI, -5.8% to 20.5%]; P=0.27), but compared to the control group, there was lower proportion of excellent functional outcomes in the 1 to 7 days group (adjusted absolute difference, -14.4% [95% CI, -27.8% to 0.0%]; P=0.05). CONCLUSIONS: Among patients with acute moderate ischemic stroke, a higher likelihood of excellent clinical outcome was found in patients with longer duration of remote ischemic conditioning.

PI3Kδ inhibition alleviates the brain injury during cerebral ischemia reperfusion via suppressing pericyte contraction in a TNF-α dependent manner.

The pericytes (PCs) surrounding capillaries are vital regulators of capillary constriction. Persistent PC contraction results in the increased capillary constriction, therefore leading to the impaired cerebral blood flow (CBF) recovery after reperfusion and worsening the clinical outcomes in stroke patients. However, the potential determinants of PC functions during ischemia/reperfusion are poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit Delta (PIK3CD/PI3Kδ) is a crucial factor involved with neuronflammation during ischemic stroke. PI3Kδ has shown the expression in PCs, while its effect on PC functions has not been explored yet. In this study, a rodent ischemia/reperfusion model was established in C57BL/6 mice via transient middle cerebral artery occlusion and reperfusion (MCAO/R). The PI3Kδ expression in ischemic penumbra was remarkably upregulated following MCAO/R induction. PI3Kδ inhibitor CAL-101 improved the CBF recovery, ischemic brain injury, and suppressed capillary constriction in MCAO/R mice. Besides, the production of tumor necrosis factor alpha (TNF-α), an inducer for tissue injury, and the expression of transient receptor potential vanilloid type 2 (TRPV2), a channel protein permitting calcium (Ca2+) uptake, were significantly reduced in ischemic penumbra after CAL-101 treatment. In vitro, oxygen-glucose deprivation and reoxygenation (OGD/R) enhanced the expression of PI3Kδ and TRPV2 in primary mouse PCs. CAL-101 suppressed the TNF-α-induced TRPV2 expression in OGD/R-treated PCs, thus inhibiting the Ca2+ uptake and PC contraction. Collectively, this study suggests that PI3Kδ is a critical regulator of PC function during ischemic stroke.

Geographic differences in pharmacotherapy patterns and outcomes of acute ischemic stroke in China.

BACKGROUND: Vast economic and healthcare status discrepancies exist among regions in China, contributing to different treatment patterns. This study was aimed to investigate the current status of pharmacotherapy for acute ischemic stroke (AIS) and outcomes in China and explore the geographic variation in stroke care. METHODS: This study was a multicenter prospective registry study, which collected the data of patients with AIS from 80 hospitals in 46 cities in 2015-2017 across China. Poor functional outcome defined as a modified Rankin Scale score of 3-6 was assessed at 3 and 12 months. Multivariate logistic regression was used. RESULTS: Among 9973 eligible patients, the number of receiving intravenous thrombolysis (IVT), antiplatelet agents, anticoagulants, statin and human urinary kallidinogenase was 429 (4.3%), 9363 (93.9%), 1063 (10.7%), 6828 (74.7%) and 5112 (51.2%), respectively. Multivariable analysis showed IVT use in northeastern was significantly more frequent than in eastern region (OR = 3.17, 95% CI, 2.53-3.99), while the antiplatelets agents use were less frequent (OR = 0.46, 95%CI: 0.38-0.57). The proportions of poor outcomes at 3 and 12 months were 20.7% and 15.8%, respectively. Multivariate analysis showed AIS patients from northeastern and central region had significantly lower risk of poor outcome at month 3 and 12 than those from eastern region (all P < 0.05). CONCLUSIONS: There was a low IVT use and a high antiplatelet agent and statin use for AIS in China. The pharmacotherapy and prognosis of AIS had variation by geographic region. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (NCT02470624).