Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy.

BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment within 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered within 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).

Effectiveness of a Quality Improvement Intervention on Reperfusion Treatment for Patients With Acute Ischemic Stroke: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Reperfusion therapy is the most effective treatment for acute ischemic stroke but remains underused in China. Objective: To evaluate the effect of a problem-oriented, culturally adapted, targeted quality improvement intervention on reperfusion therapy for patients with acute ischemic stroke in China. Design, Setting, and Participants: In this stepped-wedge cluster randomized clinical trial, patients from 16 secondary and 33 tertiary hospitals in China with acute ischemic stroke within 6 hours of symptom onset were consecutively recruited between July 1, 2018, and June 30, 2020. Interventions: Hospitals were randomly assigned to 1 of 3 sequences to receive the targeted quality improvement intervention (n = 5689), in which workflow reconstruction was promoted to reduce in-hospital reperfusion treatment delays, or usual care (n = 6443), in which conventional stroke care was left to the discretion of the stroke team. Main Outcomes and Measures: The primary outcome was the reperfusion therapy rate, a composite outcome of intravenous recombinant tissue plasminogen activator (IV rtPA) or endovascular thrombectomy (EVT) for eligible patients who arrived within 3.5 or 4.5 hours of symptom onset. Secondary outcomes were the IV rtPA administration rate among eligible patients who arrived within 3.5 hours of symptom onset, the EVT rate among eligible participants who arrived within 4.5 hours of symptom onset, the proportion of patients with door-to-needle time within 60 minutes, the proportion of patients with door-to-puncture time within 90 minutes, in-hospital mortality, and 3-month disability as measured by a modified Rankin Scale score greater than 2. Results: All 12 132 eligible patients (mean [SD] age, 66 [12.1] years; 7759 male [64.0%]) completed the trial. The reperfusion rate was 53.5% (3046 of 5689) for the eligible patients in the intervention period and 43.9% (2830 of 6443) in the control period. No significant improvement in primary outcomes was found for the intervention after adjusting for cluster, period, and imbalanced baseline covariates (adjusted risk difference [ARD], 5.5%; 95% CI, -8.0% to 19.0%; adjusted odds ratio [AOR], 1.26; 95% CI, 0.72-2.21) or for the secondary outcomes. However, significant improvements were found in secondary hospitals for reperfusion therapy (1081 of 1870 patients [57.8%] vs 945 of 2022 patients [42.9%]; ARD, 19.0%; 95% CI, 6.4%-31.6%; AOR, 2.24; 95% CI, 1.29-3.88), IV rtPA administration (1062 of 1826 patients [58.2%] vs 916 of 2170 patients [42.2%]; ARD, 20.3%; 95% CI, 7.4%-33.1%; AOR, 2.37; 95% CI, 1.34-4.19), and EVT (51 of 231 patients [22.1%] vs 37 of 259 patients [14.3%]; ARD, 13.6%; 95% CI, 1.0%-26.3%; AOR, 3.03; 95% CI, 1.11-8.25) in subgroup analyses. Conclusions and Relevance: In this stepped-wedge cluster randomized clinical trial of patients with acute ischemic stroke in China, the use of a targeted quality improvement intervention compared with usual care did not improve the reperfusion therapy rate. However, the intervention may be effective in secondary hospitals. Trial Registration: ClinicalTrials.gov Identifier: NCT03578107.

Rationale and design of a stepped wedge cluster randomised trial to improve acute reperfusion treatment quality for stroke: IMPROVE stroke care in China.

BACKGROUND: Reperfusion therapy is the most effective treatment for acute ischaemic stroke (AIS) but remains underutilised in China. There is an urgent need to develop tailored strategies to increase adherence to intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) within the guideline-recommended time window for eligible patients. AIMS: This study aims to investigate the efficacy of a comprehensive quality improvement intervention on adherence to guideline-recommended reperfusion therapy for patients with AIS in China. DESIGN: The Improve Acute Reperfusion Treatment Quality for Stroke in China (IMPROVE Stroke Care in China) trial is designed as a stepped wedge cluster randomised trial within 51 hospitals. We developed the comprehensive intervention 'STEP' (Strategies, Toolkit, Exploration, Paradigm) to promote the reconstruction of workflow in stroke centres and shorten in-hospital delay of reperfusion treatment for patients with AIS. The participating hospitals (clusters) were randomised to three groups (cohorts) for different predefined steps to intervention implementation. The primary outcome was the adherent rate of IVT or EVT for eligible patients within the time window. The sample size was estimated to be 7644, and was determined by the number of cases to be enrolled in five study periods to detect a relative increase of 30% (from 19% to 25%) with 90% power and intraclass correlation coefficient of 0.03. All efficacy analyses will be conducted based on the intention-to-treat principle. The primary outcome will be analysed using a mixed-effects logistic regression with a random effect for the cluster (hospital), and a fixed effect for the strategy and period. CONCLUSIONS: If the efficacy is well established, this targeted comprehensive intervention STEP will inform national strategies to increase adherence to guideline-recommended performance on reperfusion therapy. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier: NCT003578107.

Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of the management of high-risk population.

AIM: Cerebrovascular disease is the leading cause of death and disability in China, causing a huge burden among patients and their families. Hence, stroke prevention is critical, especially in the high-risk population. Here, we present the evidence-based guideline suitable for the Chinese population. METHODS: Literature search of PubMed and Cochrane library (from January 1964 to June 2019) was done. After thorough discussion among the writing group members, recommendations were listed and summarised. This guideline was reviewed and discussed by the fellow writing committees of the Chinese Stroke Association's Stroke. RESULTS: This evidence-based guideline was written in three parts: controlling the risk factors of stroke, utilisation of antiplatelet agents and assessing the risks of first-ever stroke. All recommendations were listed along with the recommending classes and levels of evidence. CONCLUSIONS: This guideline provides recommendations for primary prevention of cerebrovascular disease among high-risk population in China. Controlling related risk factors, appropriately using antiplatelet agents, assessing the risk of developing first-ever stroke should help reduce the rate of cerebrovascular disease in China.

Cerebral small vessel disease or intracranial large vessel atherosclerosis may carry different risk for future strokes.

BACKGROUND: The effect of cerebral small vessel disease (CSVD) and intracranial arterial stenosis (ICAS) on stroke outcomes remains unclear. METHODS: Data of 1045 patients with minor stroke or transient ischaemic attack (TIA) were obtained from 45 sites of the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. We assessed the associations of burdens of CSVD and ICAS with new strokes and bleeding events using multivariate Cox regression models and those with modified Rankin Scale (mRS) scores using ordinal logistic regression models. RESULTS: Among the 1045 patients, CSVD was present in 830 cases (79.4%) and ICAS in 460 (44.0%). Patients with >1 ICAS segment showed the highest risk of new strokes (HR 2.03, 95% CI 1.15 to 3.56, p=0.01). No association between CSVD and the occurrence of new strokes was found. The presence of severe CSVD (common OR (cOR) 2.01, 95% CI 1.40 to 2.89, p<0.001) and >1 ICAS segment (cOR 2.15, 95% CI 1.57 to 2.93, p<0.001) was associated with higher mRS scores. Severe CSVD (HR 10.70, 95% CI 1.16 to 99.04, p=0.04), but not ICAS, was associated with a higher risk of bleeding events. Six-point modified CSVD score improved the predictive power for bleeding events and disability. INTERPRETATION: CSVD is associated with more disability and bleeding events, and ICAS is associated with an increased risk of stroke and disability in patients with minor stroke and TIA at 3 months. CSVD and ICAS may represent different vascular pathologies and play distinct roles in stroke outcomes. TRIAL REGISTRATION NUMBER: NCT00979589.

The association of white matter hyperintensities with stroke outcomes and antiplatelet therapy in minor stroke patients.

BACKGROUND: To characterize the severity and distribution of white matter hyperintensities (WMHs) and to assess the relationship of WMHs with initial stroke severity, 3-month functional outcome, stroke recurrence and response to antiplatelet therapies. METHODS: In Clopidogrel High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, 787 minor stroke patients with baseline magnetic resonance imaging (MRI) information were included in this analysis. Deep and periventricular WMHs (DWMHs and PVWMHs) were rated using the Fazekas scale and categorized into mild (grades 0-2), moderate (grades 3-4) and severe (grades 5-6). Multivariable logistic regression was used to examine the associations between WMHs severities and outcomes, including initial stroke severity by the National Institutes of Health Stroke Scale (NIHSS) scores, 3-month functional outcome by modified Rankin Scale (mRS), and stroke recurrence. Cox proportional hazards model was used to assess the treatment-by-subgroup interaction effect. RESULTS: Among the 787 patients in this analysis, 432 (54.9%) had moderate or severe WMHs (3-6). Compared with mild WMHs, the adjusted odds ratio (OR) of severe WMHs for risk of higher NIHSS was 2.10, 95% confidence interval (CI), 1.26-3.48 (P=0.004). Both severities of SDWMHs (OR 1.66; 95% CI, 1.15-2.40; P=0.007) and PVWMHs (OR 1.47; 95% CI, 1.02-2.10; P=0.04) were associated with higher NIHSS scores. There were no statistically significant associations of WMHs with 3-month functional outcome and stroke recurrence. There were no significant interactions between WMHs and antiplatelet therapy. CONCLUSIONS: In patients with minor stroke, both SDWMHs and PVWMHs might related with initial stroke severity. No interaction was detected between the severity of WMHs and antiplatelet treatment.Trial registration: ClinicalTrials.gov identifier: NCT00979589. Date of registration: Sep 18, 2009.

Alkaline Phosphatase and Outcomes in Patients With Preserved Renal Function: Results From China National Stroke Registry.

BACKGROUND AND PURPOSE: Alkaline phosphatase (ALP) is associated with risk of adverse cardiovascular events in patients with kidney failure. However, there is little data about effects of ALP on stroke outcomes in patients with preserved kidney function. The study aimed to explore the association between serum ALP level and clinical outcomes after stroke in patients with preserved kidney function. METHODS: We included 16 367 stroke patients with preserved kidney function from the China National Stroke Registry for current analysis. Serum ALP levels were tested by automated enzymatic method using unfrozen samples in each center. Participants were divided into 5 groups according to ALP quintiles. Composite end point comprised of recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Poor functional outcome is defined as modified Rankin Scale score of 3 to 6. Multivariable logistic regression was used to evaluate the independent association of serum ALP with 1-year all-cause mortality, recurrent stroke, composite end point, and poor functional outcome. RESULTS: The mean age of the included 16 367 patients was 63.9 years, and 63.3% of them were men. Among the top ALP quintile (>98.0 U/L), 1-year incidences of all-cause mortality, recurrent stroke, composite end point, and poor functional outcome were 12.6%, 5.7%, 14.4%, and 27.0%, respectively. Compared with the lowest ALP quintile (≤59.0 U/L), the adjusted odds ratios of the top quintile were 1.36 (1.10-1.68) for all-cause mortality, 1.45 (1.11-1.90) for stroke recurrence, 1.35 (1.12-1.63) for composite end point, and 1.36 (1.17-1.60) for poor functional outcome. There was no significant interaction between age, sex, or alcohol consumption and ALP (P for interaction ≥0.10) for all outcomes. CONCLUSIONS: In patients with preserved kidney function, ALP may be an independent predictor of all-cause mortality, stroke recurrence, composite end point, and poor functional outcome after stroke.

Kidney function is associated with severity of white matter hyperintensity in patients with acute ischemic stroke/TIA.

BACKGROUND: Previous studies suggested the potential interactions between cerebrovascular diseases and impaired renal function. However, the relationship between renal function and white matter hyperintensity (WMH), marker of cerebral small vessel disease, in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) remains unknown. METHODS: We consecutively enrolled 1632 subjects with AIS or TIA who underwent brain MRI for this analysis. The severity of WMH in both of periventricular (PVH) and deep subcortical white matter (SDWMH) was evaluated using Fazekas scale. Estimated glomerular filtration rate (eGFR) was calculated by the equation of the Modification Diet for Renal Disease. Multinomial logistic regression was performed to evaluate the association between the severity of WMH and eGFR. RESULTS: Advanced age and hypertension were independently associated with the severity of both PVH and SDWMH (all p < 0.001). There is a significantly inverse association between eGFR and PVH. Patients having each 30 ml/min/1.73 m2 increase in eGFR was associated with 75 % of risk of having degree 3 of WMH in periventricular areas compared with degree 0 (p = 0.04, OR = 0.75, 95 % CI 0.61-0.92). However this inverse association was not found between eGFR and SDWMH (P = 0.50, OR = 0.93, 95 % CI0.75-1.14). CONCLUSION: Our study demonstrates that renal dysfunction (eGFR) is independently associated with the severity of PVH but not SDWMH in patients with acute ischemic stroke. This results highlighted different pathological mechanism and risk factors of PVH and SDWMH.

Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Aß3-10 reduces AD-like pathology and cognitive impairment in Tg-APPswe/PSEN1dE9 mice.

To develop a safe and efficient vaccine for AD treatment, we constructed an adenovirus vector vaccine encoding ten repeats of Aß3-10 and CpG motif as a molecular adjuvant. We demonstrated that therapeutic immunization with Ad-10×Aß3-10-CpG elicits Aß3-10 specific Th2-polarized immune response with high titers of anti-Aß antibodies in APPswe/PSEN1dE9 mice, which in turn reduced Aß deposits in brains and cognitive impairment. In addition, Ad-10×Aß3-10-CpG reduced astrocytosis without increasing the incidence of microhemorrhage. Our findings of this study raise the possibility that the adenovirus vaccine Ad-10×Aß3-10-CpG would be a safe and effective alternative for AD immunotherapy.

In vivo electroporation of a new gene vaccine encoding ten repeats of Aß3-10 prevents brain Aß deposition and delays cognitive impairment in young Tg-APPswe/PSEN1dE9 mice.

Active immunization holds great promise for the treatment of Alzheimer's disease but the infiltration of T-lymphocytes and associated meningoencephalitis observed in clinical trials needs to be overcome. To avoid this toxicity, previous studies have used synthetic truncated derivatives of Aß to promote humoral immunity. In this study, we developed a novel vaccine [p(Aß3-10)10-MT] that expresses ten repeats of Aß3-10 with melatonin (MT) as an adjuvant, and administered it intramuscularly in three-month-old Tg-APPswe/PSEN1dE9 (Tg) mice by in vivo electroporation. The p(Aß3-10)10-MT vaccine induced high titers of anti-Aß antibodies, which in turn reduced Aß deposits in the mouse brains and decreased cognitive impairment. Immunoglobulin isotyping revealed a predominantly IgG1 response, indicating a Th2 anti-inflammatory response. Ex vivo cultured splenocytes exhibited a low IFN-γ and high IL-4 response. Immunohistochemical analysis revealed that glial cell activation was also attenuated. These results indicate that p(Aß3-10)10-MT may potentially be an effective vaccine to reduce accumulated Aß and attenuate cognitive deficits.

Immunization with a new DNA vaccine for Alzheimer's disease elicited Th2 immune response in BALB/c mice by in vivo electroporation.

Immunization with synthetic amyloid ß-protein (Aß) peptide has resulted in preventing and clearing Aß deposits as well as improving cognitive function in transgenic mouse models of Alzheimer's disease (AD). But similar immunization studies in humans were halted due to the risk of inducing T cell-mediated meningoencephalitis. A safe and effective vaccine for AD requires not only therapeutic levels of anti-Aß antibodies but also the prevention of an adverse T cell-mediated, proinflammatory autoimmune response. In this study, we developed a DNA vaccine, p(Aß(3-10))(10)-IL-4, encoding ten tandem repeats of Aß(3-10) fused with mouse cytokine interleukin-4 (IL-4) as a molecular adjuvant. Wild-type mice were injected intramuscularly with p(Aß(3-10))(10)-IL-4 followed by in vivo electroporation. The p(Aß(3-10))(10)-IL-4 vaccine elicited high titer anti-Aß antibodies which bound to Aß plaque in brain tissue from a ten-month-old APP/PS1 transgenic mouse. The antibody isotype was mainly IgG(1) and the IgG(1)/IgG(2a) ratio in the p(Aß(3-10))(10)-IL-4 group was approximately eight times greater than that of the Aß(42) group. Ex vivo cultured splenocytes isolated from mice immunized with p(Aß(3-10))(10)-IL-4 exhibited a low IFN-γ response and a high IL-4 response compared with the control group. These results indicate that immunization with the p(Aß(3-10))(10)-IL-4 vaccine induced effective anti-Aß antibodies and elicited a Th2-polarized immune response that had a lower potential to cause an inflammatory T cell response. Thus, the DNA vaccine, p(Aß(3-10))(10)-IL-4, may be a safe and efficient vaccine for AD.

Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Aß3-10 induces Th2 immune response against amyloid-ß in wild-type mouse.

To develop a safe and efficient vaccine for the treatment of Alzheimer's disease, we constructed a novel adenovirus vaccine encoding ten repeats of Aß3-10 and CpG motif as an adjuvant and investigated the immune response in BALB/c mouse after intranasal inoculation with this vaccine. The Ad-10×Aß3-10-CpG induces an IgG1 predominant humoral response and production of IL-4 and IL-10 in splenocytes in vitro, indicating a Th2-polarized immune response. Stimulation of splenocytes with Aß3-10 peptide induces robust proliferation but not with full-length Aß42 peptide, demonstrating that Ad-10×Aß3-10-CpG does not induces Aß42 specific T cell immune response. The findings raise the possibility that the adenovirus vaccine Ad-10×Aß3-10-CpG could be a safe and effective alternative for immunotherapy in Alzheimer's disease.

Improving memory and decreasing cognitive impairment in Tg-APPswe/PSEN1dE9 mice with Aß3-10 repeat fragment plasmid by reducing Aß deposition and inflammatory response.

The present study aimed to investigate the effects of Aß3-10 repeat fragment plasmid for the treatment of Tg-APPswe/PSEN1dE9 (Tg) mice. The plasmid pcDNA3.1-(Aß3-10)10-CpG was constructed and intramuscularly injected into 12-month-old Tg mice. Through the use of behavioral tests, anti-Aß antibody and Aß assays, cytokine assay, Aß deposition, and astrocytes analysis results demonstrated that Aß3-10 repeat fragment plasmid exhibited immunogenicity and reduced memory impairment in Tg mice via clearance of cerebral Aß deposition, without significant side effects. Aß3-10 repeat fragment plasmid immunization reduced Th1 cell-mediated immunity, secretion of interferon-γ, and stimulation to astrocytes. These data showed that the Aß3-10 repeat fragment plasmid improved memory and decreased cognitive impairment in Tg mice by reducing Aß deposition and inflammatory responses.