Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

Angioplasty and/or stenting after thrombectomy in patients with underlying intracranial atherosclerotic stenosis.

PURPOSE: To investigate the imaging and clinical outcomes of emergent angioplasty and/or stenting or neither in patients of emergent large-vessel occlusion (ELVO) with underlying severe intracranial atherosclerotic stenosis (ICAS). METHODS: In this multicenter prospective cohort study, we included patients of ELVO with underlying ICAS. Patients received emergent angioplasty and/or stenting or neither after mechanical thrombectomy at the interventionists' discretion. The primary outcome was recanalization rate at 24 h, which was defined as a modified arterial occlusive lesion score of 2 or 3. RESULTS: A total of 113 consecutive patients with underlying ICAS > 70% in anterior cerebral circulation were enrolled in this study. Of these, 81 (71.7%) received emergent angioplasty and/or stenting after thrombectomy. Patients in the emergent angioplasty and/or stenting group were significantly more likely to have recanalization at 24 h (adjusted OR [aOR], 3.782; 95% confidence interval [CI], 1.821-9.125; P = 0.02) and less likely to have early neurologic deterioration (aOR, 0.299; 95% CI, 0.110-0.821; P = 0.01). However, emergent angioplasty and/or stenting was not significantly associated with symptomatic intracranial hemorrhage (aOR, 0.710; 95% CI, 0.199-2.622; P = 0.67), asymptomatic intracranial hemorrhage (aOR, 1.325; 95% CI, 0.567-3.031; P = 0.81), death at 90 days (aOR, 0.581; 95% CI, 0.186-2.314; P = 0.41), and functional independence at 90 days (aOR, 1.752; 95% CI, 0.774-3.257; P = 0.16), compared with patients that received neither. CONCLUSION: Emergent angioplasty and/or stenting is possible in patients of ELVO with ICAS and may reduce the risk of reocclusion and early neurologic deterioration with no increased risk of intracranial hemorrhage and death than those received neither.

Comparison of self-expanding stents with distal embolic protection to balloon-expandable stents without a protection device in the treatment of symptomatic vertebral artery origin stenosis: a prospective randomized trial.

PURPOSE: To compare the angiographic and clinical outcomes of self-expanding stents (SES) with distal embolic protection devices (EPD) vs balloon-expandable stents (BES) without EPD in the treatment of symptomatic atherosclerotic vertebral artery ostial stenosis (VAOS). METHODS: Between July 2011 and March 2013, a prospective randomized trial was conducted involving 127 patients (mean age 67.3±10.2 years; 94 men) with symptomatic VAOS randomly assigned to treatment with SES + EPD (Precise RX or RX Acculink stent + Spider FX EPD; n=61) or BES (Palmaz Blue or Resolute RX; n=66) without EPD. In-stent restenosis (ISR) >50% detected by duplex ultrasound was the primary endpoint. Technical success, clinical success, complications within 30 days, and signal intensity abnormalities on diffusion weighted imaging (DWI) after stenting were compared. RESULTS: The 30-day technical success rate was 95.5% (63/66) for SES+EPD vs 100% (70/70) for BES without EPD (p=0.072). DWI at 24 hours poststenting showed 2 hyperintense lesions in 2 (3.3%) SES + EPD cases and 15 hyperintense lesions in 13 (18.6%) BES patients (p<0.01). At a mean 18-month follow-up, the clinical success rate was 93.9% (62/66) for the SES + EPD group vs 85.7% (60/70) for the BES group (p=0.115). The ISR was seen in 16/70 (22.9%) arteries in the BES group and 2/66 (3.1%) arteries in SES + EPD group (p<0.01). Target vessel revascularization was performed in 7 (10.0%) BES arteries vs none in the SES + EPD group (p<0.01). CONCLUSION: SES with EPD in the treatment of symptomatic VAOS is technically feasible and safe, with low rates of ISR and significantly reduced thromboembolic events on imaging when compared to BES without EPD.

Rt-PA thrombolytic therapy in patients with acute posterior circulation stroke: A retrospective study.

At present, recombinant tissue-type plasminogen activator (rt-PA) thrombolytic therapy is widely used in patients with acute ischemic stroke within 4.5 h following stroke onset. However, the efficacy of intravenous alteplase thrombolytic therapy for posterior circulation stroke (PCS) has been rarely described. The present study aimed to predict the outcome of patients with PCS following rt-PA thrombolytic therapy in a more efficient manner. Data were collected from patients who had suffered from posterior circulation ischemic stroke, who had been treated with rt-PA over a period of 4 years (2016-2020), and had been treated at a stroke center. All patients were treated with alteplase at a standard dose of 0.9 mg/kg. According to the onset to needle time (ONT), these patients were divided into the 0-3 and 3-4.5 h groups, and the National Institutes of Health Stroke Scale (NIHSS) score was compared before thrombolysis and at 24 h after thrombolysis. Subsequently, the patients with acute PCS whose ONT was ≤3 h were divided into the NIHSS score >3 points and NIHSS score ≤3 points groups, and the NIHSS score improvement rate was compared 24 h later. A total of 989 patients were included in the study; there were 783 patients with acute anterior circulation stroke (ACS) and 203 patients with acute PCS (of note, 2 patients had negative results from brain magnetic resonance imaging); 63 patients were treated with urokinase (UK) thrombolysis and 140 patients were treated with alteplase intravenous thrombolysis. The 140 patients that received alteplase thrombolytic therapy were divided into two groups, namely the ≤3 h group and 3-4.5 h group, which, on the basis of the ONT, no significant differences were found between the two the groups according to the NIHSS score before thrombolysis (P>0.05). The NHISS scores in the ≤3 h group were significantly lower than those in the 3-4.5 h group following thrombolysis therapy, and the differences between the two groups were statistically significant (P<0.05); the patients with acute PCS treated with rt-PA in the ≤3 h group were divided into the NIHSS score ≤3 points group and the NIHSS score >3 points group. In this ≤3 h group, the average NIHSS score improvement rate following rt-PA thrombolysis was 0.535 (53.5%) in the NIHSS score ≤3 points group and that in the NIHSS score >3 points group was 0.336 (33.6%); the difference between the two groups was statistically significant (P<0.05). The patients treated with intravenous alteplase thrombolysis within 3 h following stroke onset benefited more than those treated with thrombolysis therapy within 3 to 4.5 h after stroke onset. On the whole, the present study demonstrates that the patients with mild stroke (NIHSS score ≤3 points) who were treated at an earlier stage (received alteplase thrombolysis therapy within 3 h after stroke onset) benefited to a greater extent from the therapy.

Phenotype Shifting in Astrocytes Account for Benefits of Intra-Arterial Selective Cooling Infusion in Hypertensive Rats of Ischemic Stroke.

The translational failure of neuroprotective therapies in stroke may be influenced by the mismatch of existing comorbidities between animal models and patients. Previous studies found that single-target neuroprotective agents reduced infarction in Sprague-Dawley but not in spontaneously hypertensive rats. It is of great interest to explore whether multi-target neuroprotectants and stroke models with comorbidities should be used in further translational researches. Ischemic stroke was induced in normotensive or hypertensive rats by 90- or 120-min middle cerebral artery occlusion (MCAO) and reperfusion. Intra-Arterial Selective Cooling Infusion (IA-SCI) was started at the onset of reperfusion for 30 minutes. Acute neurological deficits, infarct volumes, gene expression and markers of A1-like and A2-like astrocytes were evaluated. In further analysis, TNFα and IL-1α were administrated intracerebroventricularly, phenotype shifting of astrocytes and infarct volumes were assessed. Normobaric oxygen treatment, as a negative control, was also assessed in hypertensive rats. IA-SCI led to similar benefits in normotensive rats with 120-min MCAO and hypertensive rats with both 90-min and 120-min MCAO, including mitigated functional deficit and reduced infarct volumes. IA-SCI shifted astrocyte phenotypes partly by downregulating A1-like astrocytes and upregulating A2-like astrocytes in both RNA and protein levels. Upregulated A1-type astrocyte markers levels, induced by intracerebroventricular injection of TNFα and IL-1α, were closely related to increased infarct volumes in hypertensive rats, despite receiving IA-SCI treatment. In addition, infarct volumes and A1/A2-like genes were not affected by normobaric oxygen treatment. IA-SCI reduced infarction in both normotensive and hypertensive rats. Our results demonstrated the neuroprotective effects of IA-SCI in hypertensive rats may be related with phenotype shifting of astrocytes.

Safety and efficacy of remote ischemic conditioning for the treatment of intracerebral hemorrhage: A proof-of-concept randomized controlled trial.

BACKGROUND: Remote ischemic conditioning can promote hematoma resolution, attenuate brain edema, and improve neurological recovery in animal models of intracerebral hemorrhage. AIMS: This study aimed to evaluate the safety and preliminary efficacy of remote ischemic conditioning in patients with intracerebral hemorrhage. METHODS: In this multicenter, randomized, controlled trial, 40 subjects with supratentorial intracerebral hemorrhage presenting within 24-48 h of onset were randomly assigned to receive medical therapy plus remote ischemic conditioning for consecutive seven days or medical therapy alone. The primary safety outcome was neurological deterioration within seven days of enrollment, and the primary efficacy outcome was the changes of hematoma volume on CT images. Other outcomes included hematoma resolution rate at 7 days ([hematoma volume at 7 days - hematoma volume at baseline]/hematoma volume at baseline), perihematomal edema (PHE), and functional outcome at 90 days. RESULTS: The mean age was 59.3 ± 11.7 years and hematoma volume was 13.9 ± 4.5 mL. No subjects experienced neurological deterioration within seven days of enrollment, and no subject died or experienced remote ischemic conditioning-associated adverse events during the study period. At baseline, the hematoma volumes were 14.19 ± 5.07 mL in the control group and 13.55 ± 3.99 mL in the remote ischemic conditioning group, and they were 8.54 ± 3.99 mL and 6.95 ± 2.71 mL at seven days after enrollment, respectively, which is not a significant difference (p > 0.05 each). The hematoma resolution rate in the remote ischemic conditioning group (49.25 ± 9.17%) was significantly higher than in the control group (41.92 ± 9.14%; MD, 7.3%; 95% CI, 1.51-13.16%; p = 0.015). The absolute PHE volume was 17.27 ± 8.34 mL in the control group and 12.92 ± 7.30 mL in the remote ischemic conditioning group at seven days after enrollment, which is not a significant between-group difference (p = 0.087), but the relative PHE in the remote ischemic conditioning group (1.77 ± 0.39) was significantly lower than in the control group (2.02 ± 0.27; MD, 0.25; 95% CI, 0.39-0.47; p = 0.023). At 90-day follow-up, 13 subjects (65%) in the remote ischemic conditioning group and 12 subjects (60%) in the control group achieved favorable functional outcomes (modified Rankin Scale score ≤ 3), which is not a significant between-group difference (p = 0.744). CONCLUSIONS: Repeated daily remote ischemic conditioning for consecutive seven days was safe and well tolerated in patients with intracerebral hemorrhage, and it may be able to improve hematoma resolution rate and reduce relative PHE. However, the effects of remote ischemic conditioning on the absolute hematoma and PHE volume and functional outcomes in this patient population need further investigations.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03930940.

Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a multicentre, randomised, double-blind sham-controlled trial in China.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide, and it is associated with a high risk of recurrent stroke with currently recommended treatments. We aimed to evaluate the effect of chronic remote ischaemic conditioning on prevention of ischaemic events in patients with symptomatic ICAS. METHODS: The RICA trial is a multicentre, randomised, double-blind, sham-controlled trial at 84 stroke centres in China. Patients aged 40-80 years with ischaemic stroke or transient ischaemic attack attributable to angiographically verified 50-99% stenosis of a major intracranial artery were randomly assigned (1:1), via an interactive web-based system by computer-generated randomisation code, to either remote ischaemic conditioning or sham remote ischaemic conditioning once daily for 12 months and voluntarily thereafter. All investigators and patients were masked to treatment allocation. The primary efficacy endpoint was the time to first occurrence of non-fatal or fatal ischaemic stroke, with survival analysed by the Kaplan-Meier method. Primary and safety analyses were done in the intention-to-treat population. The RICA trial is registered with ClinicalTrials.gov, number NCT02534545. FINDINGS: Between Oct 28, 2015, and Feb 28, 2019, 3033 patients were enrolled and randomly assigned to either remote ischaemic conditioning (n=1517; intervention group) or sham remote ischaemic conditioning (n=1516; sham group). Median follow-up was 3·5 years (IQR 2·7-4·4). A non-fatal or fatal ischaemic stroke occurred in 257 (16·9%) patients in the intervention group compared with 288 (19·0%) patients in sham group. There was no difference in the survival distribution for time to first occurrence of non-fatal or fatal ischaemic stroke (hazard ratio 0·87, 95% CI 0·74-1·03; p=0·12). In the intervention group, 79 (5·2%) patients died from any cause, and in the sham group, 84 (5·5%) patients died from any cause (hazard ratio 0·93, 95% CI 0·68-1·27; p=0·65). No intervention-related serious adverse events were observed. INTERPRETATION: No evidence was found for a difference between remote ischaemic conditioning and sham remote ischaemic conditioning in lowering the risk of ischaemic stroke in patients with symptomatic ICAS. The benefit of remote ischaemic conditioning might have been diluted by poor compliance. Future studies of remote ischaemic conditioning in this population should address challenges in patients' compliance and assess longer term treatment. FUNDING: Ministry of Science and Technology China, Beijing Municipal Education Commission, Beijing Municipal Finance Bureau. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Preventing Ischemic Cerebrovascular Events in High-Risk Patients With Non-disabling Ischemic Cerebrovascular Events Using Remote Ischemic Conditioning: A Single-Arm Study.

Background: Secondary stroke prevention after a high-risk, non-disabling ischemic cerebrovascular event needs to be enhanced. The study was conducted to investigate whether remote ischemic conditioning (RIC) is effective in preventing recurrent ischemic events within 3 months. Methods: This was a four-center, single-arm, open-label Phase IIa futility trial (PICNIC-One Study). Adult patients (≥18 years of age) who had an acute minor ischemic stroke (AMIS) with a National Institutes of Health Stroke Scale score ≤ 3 or a transient ischemic attack (TIA) with moderate-to-high risk of stroke recurrence (ABCD score ≥ 4) within 14 days of symptom onset were recruited. Patients received RIC as adjunctive therapy to routine secondary stroke prevention regimen. RIC consisted of five cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuffs (45 min) on bilateral upper limbs twice a day for 90 days. Results: A total of 285 patients met the study criteria, of which 167 provided signed informed consent and were enrolled. Data from 162 were analyzed with five subjects excluded. Recurrent AIS/TIA occurred in 6/162 (3.7%) patients within 3 months, with no occurrence of hemorrhagic stroke. The top three adverse events were upper limb pain (44/162, 27.2%), petechia (26/162, 16.0%), and heart palpitation (5/162, 3.1%). About 68 (42.0%) subjects completed ≥ 50% of 45-min RIC sessions. Conclusions: RIC is a safe add-on procedure and it has a potential benefit in reducing recurrent cerebrovascular events in patients with high-risk, non-disabling ischemic cerebrovascular events as the risk of stroke/TIA events is lower than expected; however, its compliance needs to be improved. Our study provides critical preliminary data to plan a large sample size, randomized controlled clinical study to systematically investigate the safety and efficacy of RIC in this population.

Remote Ischemic Conditioning for Intracerebral Hemorrhage (RICH-1): Rationale and Study Protocol for a Pilot Open-Label Randomized Controlled Trial.

Background and rationale: Although many therapies have been investigated for intracerebral hemorrhage (ICH), none have succeeded in improving the functional outcomes. Remote ischemic conditioning (RIC) has been proven to promote hematoma resolution and improve neurological outcomes in an ICH model; whether it is safe and feasible in patients with ICH remains unknown. This trial aims to assess the safety, feasibility, and preliminary efficacy of RIC in patients with ICH and to plan for a phase-2 study. Methods: A proof-of-concept, assessor-blinded, pilot open-label randomized controlled trial will be carried out with patients with ICH within 24-48 h of ictus. All participants will be randomly allocated to the intervention group and the control group with a 1:1 ratio (n = 20) and will be treated with standard managements according to the guidelines. Participants allocated to the intervention group will receive RIC once daily for 7 consecutive days. Cranial computed tomography examinations will be performed at baseline, and on days 3, 7, and 14. Neurological outcomes will be assessed at baseline, and on days 1 to 14, 30, and 90. The primary outcome to be tested is safety. Secondary tested outcomes include changes of hematoma and perihematomal edema volume, incidence of hematoma expansion, functional outcomes, and frequency of adverse events. Discussions: This study will be the first proof-of-concept randomized controlled trial to ascertain the safety, feasibility, and preliminary efficacy of RIC in patients with ICH, results of which will provide parameters for future studies and provide insights into the treatment of ICH. Trial Registration: Clinicaltrials.gov, identifier: NCT03930940.

Triiodothyronine levels were positively correlated with opening of collateral circulation in cerebral infarction patients with large artery atherosclerosis.

INTRODUCTION: Non-thyroidal illness syndrome (NTIS) is one of the signs for poor prognosis of cerebral infarction (CI), but its risk factors had never been explored. In this study, we analyzed the potential effect of collateral circulation on prognosis prediction of triiodothyronine for large artery atherosclerosis cerebral infarction (LAA-CI) patients. MATERIAL AND METHODS: Clinical data of CI patients between 2012 and 2014 were collected. Imaging inspection was used for determining TOAST classification and evaluating collateral circulation. One-year follow-up was conducted for mRS score by telephone. RESULTS: T3 level in the NTIS group (p = 0.001) was significantly decreased while TSH level (p < 0.001) was increased. Patients in the NTIS group had a poorer prognosis (p = 0.008) and the main reason was the high mortality (p = 0.002). NTIS predicted poor collateral circulation (p = 0.026) and good collateral circulation tended to be less likely concomitant with NTIS (p = 0.001). Logistic regression analysis showed that triiodothyronine concentrations (OR = 4.760, 95% CI: 1.981-11.456, p < 0.001) were positively correlated with but advanced age (OR = 0.756, 95% CI: 0.645-0.886, p = 0.001) negatively with opening of collateral circulation. CONCLUSIONS: Poor opening of collateral circulation was likely to mediate the prediction of NTIS for prognosis of LAA-CI patients.

RETRACTED: Astragaloside IV reduces the hypoxia-induced injury in PC-12 cells by inhibiting expression of miR-124.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Given the comments of Dr Elisabeth Bik regarding this article "… the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains. All bands are placed on similar looking backgrounds, suggesting they were copy/pasted from other sources, or computer generated", the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.

Influence of renal function on the association between homocysteine level and risk of ischemic stroke.

We examined whether the association between total homocysteine (tHCY) and risk of ischemic stroke (IS) varies depending on renal function to gain insight into why tHCY-lowering vitamins do not reduce the incidence of cardiovascular disease in clinical trials. We analyzed data from 542 IS patients with large artery atherosclerosis (LAA) or small artery occlusion (SAO) after stratification by estimated glomerular filtration rate (eGFR) to evaluate renal function. We found that tHCY level was positively associated with the occurrence of IS in both LAA (OR: 1.159, 95% CI: 1.074-1.252, P<0.001) and SAO (OR: 1.143, 95% CI: 1.064-1.228, P<0.001) patients and in LAA (OR: 1.135, 95% CI: 1.047-1.230, P=0.002) and SAO (OR: 1.159, 95% CI: 1.060-1.268, P=0.001) subgroups with normal renal function but not in LAA or SAO subgroups with renal insufficiency. eGFR level was positively associated with IS in LAA (OR: 1.022, 95% CI: 1.010-1.034, P<0.001) and SAO (OR: 1.024, 1.012-1.037, P<0.001) subgroups with normal renal function but was negatively associated with IS in LAA (OR: 0.875, 95% CI: 0.829-0.925, P<0.001) and SAO (OR: 0.890, 95% CI: 0.850-0.932, P<0.001) subgroups with renal insufficiency. Folic acid level was negatively associated with IS in LAA (OR: 0.734, 95% CI: 0.606-0.889, P=0.002) and SAO (OR: 0.861, 95% CI: 0.767-0.967, P=0.012) subgroups with renal insufficiency. Therefore, renal function as evaluated by eGFR exerts a significant influence on the association between tHCY and risk of IS.