Rationale and design of Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events III (TRACE III): a randomised, phase III, open- label, controlled trial

Background and purpose Recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)was not inferior to alteplase for ischaemic stroke within 4.5hours.Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion(LVO)of anterior circulation beyond 4.5hours.Methods and design Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III(TRACE III)is a multicentre,prospective,randomised,open-label,blind endpoint,controlled clinical trial.Patients who had an ischaemic stroke due to anterior circulation LVO(internal carotid artery,middle cerebral artery M1 and M2 segments)within 4.5–24hours from last known well(including wake-up stroke and no witness stroke)and with salvageable tissue(ischaemic core volume<70mL,mismatch ratio≥1.8 and mismatch volume≥15mL)based on CT perfusion or MRI perfusion-weighted imaging(PWI)were included and randomised to rhTNK-tPA 0.25mg/kg(single bolus)to a maximum of 25mg or standard medical therapy.Specially,we will exclude patients who are intended for direct thrombectomy.All will be followed up for 90 days.Study outcomes Primary efficacy outcome is modified Rankin Scale(mRS)score≤1 at 90 days.Secondary efficacy outcomes include ordinal distribution of mRS at 90 days,major neurological improvement defined by a decrease≥8 points compared with the initial deficit or a score≤1 on the National Institutes of Health Stroke Scale(NIHSS)at 72 hours,mRS score≤2 at 90 days,the rate of improvement on Tmax>6s at 24 hours and NIHSS score change from baseline at 7days.Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days.Discussion TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5hours.Trial registration number NCT05141305.

Improving detection of cerebral small vessel disease aetiology in patients with isolated lobar intracerebral haemorrhage

Background and purpose We evaluate whether non-haemorrhagic imaging markers(NHIM)(white matter hyperintensity patterns,lacunes and enlarged perivascular spaces(EPVS))can discriminate cerebral amyloid angiopathy(CAA)from hypertensive cerebral small vessel disease(HTN-cSVD)among patients with isolated lobar intracerebral haemorrhage(isolated-LICH).Methods In patients with isolated-LICH,four cSVD aetiologic groups were created by incorporating the presence/distribution of NHIM:HTN-cSVD pattern,CAA pattern,mixed NHIM and no NHIM.CAA pattern consisted of patients with any combination of severe centrum semiovale EPVS,lobar lacunes or multiple subcortical spots pattern.HTN-cSVD pattern consisted of any HTN-cSVD markers:severe basal ganglia PVS,deep lacunes or peribasal ganglia white matter hyperintensity pattern.Mixed NHIM consisted of at least one imaging marker from either pattern.Our hypothesis was that patients with HTN-cSVD pattern/mixed NHIM would have a higher frequency of left ventricular hypertrophy(LVH),which is associated with HTN-cSVD.Results In 261 patients with isolated-LICH,CAA pattern was diagnosed in 93 patients,HTN-cSVD pattern in 53 patients,mixed NHIM in 19 patients and no NHIM in 96 patients.The frequency of LVH was similar among those with HTN-cSVD pattern and mixed NHIM(50%vs 39%,p=0.418)but was more frequent in HTN-cSVD pattern compared with CAA pattern(50%vs 20%,p<0.001).In a regression model,HTN-cSVD pattern(OR:7.38;95%CI 2.84 to 19.20)and mixed NHIM(OR:4.45;95%CI 1.25 to 15.90)were found to be independently associated with LVH.Conclusion Among patients with isolated-LICH,NHIM may help differentiate HTN-cSVD from CAA,using LVH as a marker for HTN-cSVD.

Temporal trends and rural-urban disparities in cerebrovascular risk factors,in-hospital management and outcomes in ischaemic strokes in China from 2005 to 2015:a nationwide serial cross-sectional survey

Background Stroke is the leading cause of mortality in China,with limited evidence of in-hospital burden obtained from nationwide surveys.We aimed to monitor and track the temporal trends and rural-urban disparities in cerebrovascular risk factors,management and outcomes from 2005 to 2015.Methods We used a two-stage random sampling survey to create a nationally representative sample of patients admitted for ischaemic stroke in 2005,2010 and 2015.We sampled participating hospitals with an economic-geographical region-stratified random-sampling approach first and then obtained patients with a systematic sampling approach.We weighed our survey data to estimate the national-level results and assess changes from 2005 to 2015.Results We analysed 28277 ischaemic stroke admissions from 189 participating hospitals.From 2005 to 2015,the estimated national hospital admission rate for ischaemic stroke per 100000 people increased(from 75.9 to 402.7,Ptrend<0.001),and the prevalence of risk factors,including hypertension,diabetes,dyslipidaemia and current smoking,increased.The composite score of diagnostic tests for stroke aetiology assessment(from 0.22 to 0.36,Ptrend<0.001)and secondary prevention treatments(from 0.46 to 0.70,Ptrend<0.001)were improved.A temporal decrease was found in discharge against medical advice(DAMA)(from 15.2%(95%CI 13.7%to 16.7%)to 8.6%(8.1%to 9.0%);adjusted Ptrend=0.046),and decreases in in-hospital mortality(0.7%in 2015 vs 1.8%in 2005;adjusted OR(aOR)0.52;95%CI 0.32 to 0.85)and the composite outcome of in-hospital mortality or DAMA(8.4%in 2015 vs 13.9%in 2005;aOR 0.65;95%CI 0.47 to 0.89)were observed.Disparities between rural and urban hospitals narrowed;however,disparities persisted in in-hospital management(brain MRI:rural-urban difference from−14.4%to−11.2%;cerebrovascular assessment:from−20.3%to−16.7%;clopidogrel:from−2.1%to−10.3%;anticoagulant for atrial fibrillation:from−10.9%to−8.2%)and in-hospital outcomes(DAMA:from 2.7%to 5.0%;composite outcome of in-hospital mortality or DAMA:from 2.4%to 4.6%).Conclusions From 2005 to 2015,improvements in hospital admission and in-hospital management for ischaemic stroke in China were found.A temporal improvement in DAMA and improvements in in-hospital mortality and the composite outcome of in-hospital mortality or DAMA were observed.Disparities between rural and urban hospitals generally narrowed but persisted.

Trends in characteristics of neurologists who provide stroke consultations in the USA,2008-2021

Introduction Patients with acute ischaemic strokes(AIS),on average,fare better with timely neurologist consultation,and a growing proportion of them receive one.However,little is known about trends in the characteristics of neurologists who treat AIS.Methods We identified AIS and transient ischaemic attack(TIA)episodes with neurologist consults in fee-for service Medicare from January 2008 to September 2021.For each episode,we determined whether the neurologist was a vascular neurologist,was a high-volume provider,whether the patient was transferred between hospitals and the distance between the patient’s home and physician’s practice.Results From 2008 to 2021,the share of AIS/TIA episodes(n=5073294)with neurologist consults increased(52.9%to 61.7%).Among episodes with consults,the fraction conducted by a vascular neurologist(5.2%to 13.7%)or by a high-volume neurologist(13.2%to 14.9%)also increased.The fraction with the patient’s home and neurologist greater than 100 miles apart(4.8%to 9.6%)or in different states(5.1%to 8.1%)increased,as did the fraction with transfers(4.2%to 8.5%).Discussion Over the study period,the proportion of AIS/TIA episodes with consultations from neurologists with either vascular neurology certifications or high volumes increased substantially.

The American Heart Association’s Get With the Guidelines(GWTG)-Stroke development and impact on stroke care

The American Heart Association’s Get With the Guidelines(GWTG)-Stroke programme has changed stroke care delivery in the USA since its establishment in 2003.GWTG is a voluntary registry and continuous quality improvement initiative that collects data on patient characteristics,hospital adherence to guidelines and inpatient outcomes.Implementation of the programme saw increased provision of evidence-based care and improved patient outcomes.This review will describe the development of the programme and discuss the impact on stroke outcomes and transformation of stroke care delivery that followed its implementation.

Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-Ⅱ (TRACE Ⅱ): rationale and design

Background and purpose Tenecteplase(TNK)is a promising agent for treatment of acute ischaemic stroke(AIS).We hypothesised that recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)is non-inferior to rt-PA in achieving excellent functional outcome at 90 days,when administered within 4.5 hours of ischaemic stroke onset.Methods and design Tenecteplase Reperfusion therapy in Acute ischemic Cerebrovascular Events(TRACE)is a phase Ⅲ,multicentre,prospective,randomised,open-label,blinded-end point non-inferiority study.Patients eligible for intravenous thrombolysis therapy are randomised to rhTNK-tPA 0.25 mg/kg(single bolus)to a maximum of 25 mg or rt-PA 0.9 mg/kg(10%bolus+90%infusion/1 hour)to a maximum of 90 mg.Medications considered necessary for the patient’s health may be given at the discretion of the investigator during 90-day follow-up.Study outcomes The primary study outcome is excellent functional outcome defined as modified Rankin Scale(mRS)0–1 at 90 days.Secondary efficacy outcomes include favourable functional outcome defined as mRS≤2 at 90 days,ordinal distribution of mRS and major neurological improvement on the National Institutes of Health Stroke Scale.Safety outcomes are symptomatic intracranial haemorrhage within 36 hours and death from any cause.Discussion There is no completed registration study of TNK in AIS worldwide.TRACE Ⅱ strives to provide evidence for a new drug application for rhTNK-tPA in AIS within 4.5 hours through a well-designed and rigorously executed randomised trial in China.

Prestroke selective serotonin reuptake inhibitor use and functional outcomes after ischaemic stroke

background Selective serotonin reuptake inhibitors(SSRIs)have been implicated in contributing to recovery after acute ischaemic stroke.In particular,poststroke initiation of an SSRI has been demonstrated to improve motor recovery.The role of prestroke SSRI use on functional outcomes and stroke recovery is less clear.We aimed to examine the effect of prestroke SSRI use on metrics of hospitalisation and functional recovery.Methods We included 4968 consecutive patients from January 2006 to June 2015 in our local Get With The Guidelines-Stroke registry in whom a preadmission drug list could be extracted from an administrative research data registry.Univariate and multivariate analyses were performed to identify predictors of functional outcomes.results On univariate analysis,among 4698 ischaemic strokes(740 SSRI users and 3948 non-users),SSRI use before acute ischaemic stroke did not impact the National Institutes of Health Stroke Scale(NIHSS)admission score,length of stay or rate of symptomatic haemorrhage.Patients using SSRIs prior to their stroke were more likely to present with weakness(57% vs 47.3%;P<0.001)and have hospitalisations complicated by pneumonia(7.6% vs 5.7%;P<0.001).Moreover,prestroke SSRI use was associated with a negative impact on ambulatory status at discharge and discharge to home.On multivariate regression analysis,SSRI use was associated with lower likelihood of discharge to home(adjusted OR 0.79,95% CI 0.62 to 0.997,P<0.05).Conclusions SSRI use preceding an acute ischaemic stroke is associated with lower rates of discharge to home despite no significant increase in length of stay or NIHSS score.

Linking the Paul Coverdell National Acute Stroke Program to commercial claims to establish a framework for real-world longitudinal stroke research

Background Non-interventional large-scale research on real-world patients who had a stroke requires the use of multiple data sources ensuring access to longitudinal data from large populations with clinically-detailed information.We sought to establish a framework for longitudinal research on patients hospitalised with stroke by linking information-rich,deidentified inpatient data from the Paul Coverdell National Acute Stroke Program(PCNASP)to commercial and Medicare Advantage longitudinal claims data.Methods All stroke admissions in PCNASP between 2008 and 2015 were evaluated for linkage to longitudinal claims from a commercial insurer using an algorithm based on six available common data fields(patient age,gender,admission date,discharge date,discharge diagnosis and state)and a hospital match.We evaluated the linkage quality(via the percentage of unique records in the linked dataset)and the representativeness of the linked population.We also described medical history,stroke severity and patterns of medication use among the PCNASP-claims linked cohort.Results The linkage produced uniqueness equal to 99.1%.We identified 5644 linked and 98896 unlinked patients who had an ischaemic stroke hospitalisation in claims data.Linked patients were younger than unlinked(69.7 vs 72.5 years),but otherwise similar by medical history,prestroke medication use or lab values.Stroke severity was mild and most patients were discharged home.Prestroke and discharge use of antihypertensive and statins in the PCNASP were greater than their use as measured by filled prescriptions in claims.Conclusions High-quality linkage between the PCNASP and commercial claims data is feasible.This linkage identified differences between reported or recommended versus actual out-of-hospital medication utilisation,highlighting the importance of longitudinal data availability for research aimed to improve the care of patients who had a stroke.

Patterns of antidepressant therapy and clinical outcomes among ischaemic stroke survivors

Background and purpose Depression is common after stroke and is often treated with antidepressant medications(AD).ADs have also been hypothesised to improve stroke recovery,although recent randomised trials were neutral.We investigated the patterns of in-hospital AD initiation after ischaemic stroke and association with clinical and readmission outcomes.Methods All Medicare fee-for-service beneficiaries aged 65 or older hospitalised for ischaemic stroke in participating Get With The Guidelines-Stroke hospitals between April and December 2014 were eligible for this analysis.Outcome measures included days alive and not in a healthcare institution(home time),all-cause mortality and readmission within 1-year postdischarge.Propensity score(PS)-adjusted logistic regression models were used to evaluate the associations between AD use and each outcome measure.We also compared outcomes in patients prescribed selective serotonin reuptake inhibitors(SSRIs)AD versus those prescribed non-SSRI ADs.Results Of 21805 AD naive patients included in this analysis,1835(8.4%)were started on an AD at discharge.Patients started on an AD had higher rates of depression and prior ischaemic stroke,presented with higher admission National Institutes of Health Stroke Scale score and were less likely to be discharged home.Similarly,patients started on an SSRI had lower rates of discharge to home.Adjusting for stroke severity,patients started on an AD had worse all-cause mortality,all-cause readmission,major adverse cardiac events,readmission for depression and decreased home-time.However,AD use was also associated with an increased risk for the sepsis,a falsification endpoint,suggesting the presence of residual confounding.Conclusions Patients with ischaemic stroke initiated on AD therapy are at increased risk of poor clinical outcomes and readmission even after PS adjustment,suggesting that poststroke depression requiring medication is a poor prognostic sign.Further research is needed to explore the reasons why depression is associated with worse outcome,and whether AD treatment modifies this risk or not.

Strategy for reliable identification of ischaemic stroke, thrombolytics and thrombectomy in large administrative databases

Background Administrative data are frequently used in stroke research.Ensuring accurate identification of patients who had an ischaemic stroke,and those receiving thrombolysis and endovascular thrombectomy(EVT)is critical to ensure representativeness and generalisability.We examined differences in patient samples based on mode of identification,and propose a strategy for future patient and procedure identification in large administrative databases.Methods We used non-public administrative data from the state of California to identify all patients who had an ischaemic stroke discharged from an emergency department(ED)or inpatient hospitalisation from 2010 to 2017 based on International Classification of Disease(ICD-9)(2010-2015),ICD-10(2015-2017)and Medicare Severity-Diagnosis-related Group(MS-DRG)discharge codes.We identified patients with interhospital transfers,patients receiving thrombolytics and patients treated with EVT based on ICD,Current Procedural Terminology(CPT)and MS-DRG codes.We determined what proportion of these transfers and procedures would have been identified with ICD versus MS-DRG discharge codes.Results Of 365099 ischaemic stroke encounters,most(87.70%)had both a stroke-related ICD-9 or ICD-10 code and stroke-related MS-DRG code;12.28% had only an ICD-9 or ICD-10 code and 0.02% had only an MS-DRG code.Nearly all transfers(99.99%)were identified using ICD codes.We identified 32433 thrombolytic-treated patients(8.9% of total)using ICD,CPT and MS-DRG codes;the combination of ICD and CPT codes identified nearly all(98%).We identified 7691 patients treated with EVT(2.1%of total)using ICD and MS-DRG codes;both MS-DRG and ICD-9/ICD-10 codes were necessary because ICD codes alone missed 13.2%of EVTs.CPT codes only pertain to outpatient/ED patients and are not useful for EVT identification.Conclusions ICD-9/ICD-10 diagnosis codes capture nearly all ischaemic stroke encounters and transfers,while the combination of ICD-9/ICD-10 and CPT codes are adequate for identifying thrombolytic treatment in administrative datasets.However,MS-DRG codes are necessary in addition to ICD codes for identifying EVT,likely due to favourable reimbursement for EVT-related MS-DRG codes incentivising accurate coding.

Resource utilisation among patients transferred for intracerebral haemorrhage

background Patients with intracerebral haemorrhage(ICH)are frequently transferred between hospitals for higher level of care.We aimed to identify factors associated with resource utilisation among patients with ICH admitted to a single academic hospital.Methods We used a prospectively collected registry of consecutive patients with primary ICH at an urban academic hospital between 1 January 2005 and 31 December 2015.The primary outcome was use of either intensive care unit(ICU)admission or surgical intervention.Logistic regression examined factors associated with the outcome,controlling for age,sex,Glasgow coma score(GCS)and ICH score.results Of the 2008 patients included,887(44.2%)received ICU stay or surgical intervention.These patients were younger(71 vs 74 years,p<0.001),less often white(83.9% vs 89.3%,p<0.001),had lower baseline GCS(12 vs 14,p<0.001)and more frequently had intraventricular haemorrhage(58.6%vs 43.4%,p<0.001).Factors independently associated with ICU stay or surgical intervention were age>65 years(OR 0.38,95% CI 0.21 to 0.69),GCS<15(1.23,95% CI 1.01 to 1.52)and ICH score>0(OR 2.23,95% CI 1.70 to 2.91).Conclusion Among this cohort of primary patients with ICH,GCS of 15 and ICH score of 0 were associated with less frequent use of ICU or intervention.These results should be validated in a larger sample but may be valuable for hospitals considering which patients with ICH could safely remain at the referring facility.

通过研究解密大脑——脑健康的未来

David Z Wang和同事们研究了大脑研究的最新进展,以及它们如何影响大脑疾病的治疗。整个世界都在积极地解决大脑之奥秘,人们已经在了解大脑对人类意识产生中发挥的基本作用以及发现脑疾病的治疗方法方面走了很长一段路。公元前430年希波克拉底的《神圣疾病》(The Sacred Disease)中就有记载,大脑是用来容纳心室的,其主要目的是作为身体从外部呼吸空气的容器和转运点,从而为我们的生命带来喜怒哀乐。