Introduction There is a downward trend of stroke-related mortality in the USA.By reviewing all published articles on stroke mortality in China,we analysed its trend and possible factors that have influenced the trend....Introduction There is a downward trend of stroke-related mortality in the USA.By reviewing all published articles on stroke mortality in China,we analysed its trend and possible factors that have influenced the trend.Methods Both English and Chinese literatures were searched on the mortality of stroke or cerebrovascular diseases in China.Potential papers related to this topic were identified from PubMed,Medline,Embase,Cochrane Library,Wanfang Database,SINOMED and China National Knowledge Infrastructure databases.Results Comparing the results from the most recent population-based epidemiological survey and databank from the national Center for Disease Control and Prevention,the age-adjusted stroke mortality rate has shown a downward trend among both urban and rural population in the past 30 years in China.Comparing with 30 years ago,the rate of stroke mortality has decreased by more than 31%in urban/suburban population and 11%in rural population.In men,the age-adjusted stroke mortality rate decreased by 18.9%and in women by 24.9%between 1994 and 2013.Factors that may have contributed to the trend of decreased stroke mortality rate include(1)improved healthcare coverage and healthcare environment;(2)improved treatment options and medical technology;(3)support by government to educate the public on stroke and stroke prevention;and(4)improved public knowledge on stroke.Conclusions The age-adjusted stroke mortality rate in China has shown a downward trend among both urban and rural population in the past 30 years.The major influencing factors that helped in reducing stroke mortality in China included improved healthcare coverage,healthcare environment,the updated treatment options and modern medical technology.展开更多
Objective：To assess the long-term（up to 6 months）safety profile of a 3-month regimen of NeuroAiD for acute ischemic stroke.Methods：A total of 190 patients with acute ischemic stroke were identified for eligibility...Objective：To assess the long-term（up to 6 months）safety profile of a 3-month regimen of NeuroAiD for acute ischemic stroke.Methods：A total of 190 patients with acute ischemic stroke were identified for eligibility in a randomized,double-blind,placebo-controlled clinical trial,of which 150 patients allocated to either receiving NeuroAiD（80 cases）or placebo（70 cases）were analyzed after dropouts due to absence of baseline data,early death,or noncompliance.Both groups received treatment for three months and followed up for another three months after the completion of the treatment.Occurrence of clinical adverse events and laboratory parameters were assessed at 1 month,3 months（while under treatment）and 6 months（3 months after the completion of treatment）.Statistical comparisons between groups were performed using chi-square test or t-test whenever appropriate.Results：The two groups had comparable baseline characteristics.Mild nausea was more commonly reported in patients taking NeuroAid compared with placebo（P=0.01）,of which 9 out of10 were observed only during the first month of treatment.However,none of the adverse events reported were considered severe or required discontinuation of the study drug.There was no significant change observed in mean arterial blood pressure,haemoglobin,renal and liver laboratory parameters during treatment with NeuroAid and up to 3 months after completion of a 3-month regimen.Conclusion：NeuroAiD is safe and does not affect hematologic,hepatic,and renal functions during and long after completion of treatment.展开更多
background and purpose Recent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases(MMPs)in rats and the detrimental role of MMP-12 in post-stroke brain da...background and purpose Recent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases(MMPs)in rats and the detrimental role of MMP-12 in post-stroke brain damage.We hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other MMPs.We tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout mice.Methods Focal cerebral ischaemia was induced in wildtype and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament suture.One hour after ischaemia,reperfusion was initiated by removing the monofilament.One day after reperfusion,ischaemic brain tissues from various groups of mice were collected,and total RNA was isolated and subjected to cDNA synthesis followed by PCR analysis.results Although the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats,there is a clear species similarity in the expression of MMP-12,which was found to be predominantly upregulated in both species.Further,the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type mice.Moreover,the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type mice.Conclusions In the ischaemic brain,MMP-12 upregulates several fold higher than any other MMP.Mice derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.展开更多
Background The benefit of intravenous alteplase in acute ischaemic stroke(AIS)is time-dependent.Tenecteplase is non-inferior to alteplase among patients with AIS.We aimed to delineate the association of the stroke ons...Background The benefit of intravenous alteplase in acute ischaemic stroke(AIS)is time-dependent.Tenecteplase is non-inferior to alteplase among patients with AIS.We aimed to delineate the association of the stroke onset to treatment time(OTT)with tenecteplase compared with alteplase on therapeutic benefit and clinical risks.Methods This is a post hoc analysis of the Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-2 an open-label,randomised,controlled,non-inferior trial.A total of 1430 AIS within 4.5 hours onset at 53 sites in China from 12 June 2021 to 29 May 2022 were randomly assigned(1:1)to receive either tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg.The primary efficacy outcome was the proportion of participants with a modified Rankin Scale score of 0–1 at 90 days.A post hoc subgroup analysis was conducted with the OTT divided into three intervals(0–90 min,91–180 min and 181–270 min).The primary safety outcome was symptomatic intracranial haemorrhage within 36 hours post-thrombolytic treatment.Results Treatment was initiated within 270 min of stroke onset in 1412 patients who were randomly allocated to either tenecteplase(n=707)or alteplase(n=705).The OR of primary efficacy outcome was similar as OTT increased(p=0.84).Adjusted odds of an excellent functional outcome were 0.99(95%CI 0.37 to 2.67)for 0–90 min,1.23(95%CI 0.88 to 1.71)for 91–180 min and 1.21(95%CI 0.88 to 1.65)for 181–270 min.All were in favour of the tenecteplase group.Meta-analysis of 2949 patients yielded a pooled risk difference of 5.54(95%CI-0.18 to 11.26;p=0.82)in favour of tenecteplase for more than 180 min and 1.77(95%CI-2.66 to 6.20;p=0.58)for 0–180 min.Conclusions In AIS patients who were treated with either tenecteplase or alteplase within 4.5 hours onset,there was no difference observed in the efficacy and safety between the two groups at the three different OTT time intervals.展开更多
Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is unclear.Here,we assess the safety and eff...Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is unclear.Here,we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2).Methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4hours of onset.The primary outcome was a shift in scores on the modified Rankin scale(mRS)at day 90.Secondary outcomes included death;a global analysis(Wei-Lachin test)containing Barthel Index,EuroQol-5D,mRS,telephone interview for cognitive status-modified and Zung depression scale;and neuroimaging-determined‘brain frailty’markers.Data were reported as n(%),mean(SD),median[IQR],adjusted common OR(acOR),mean difference or Mann-Whitney difference(MWD)with 95%CI.Results 597 of 1149(52%)patients had a final diagnosis of ischaemic stroke;age 75(12)years,premorbid mRS>2107(18%),Glasgow Coma Scale 14(2)and time from onset to randomisation 67[45,108]min.Neuroimaging‘brain frailty’was common:median score 2[2,3](range 0–3).At day 90,GTN did not influence the primary outcome(acOR for increased disability 1.15,95%CI 0.85 to 1.54),death or global analysis(MWD 0.00,95%CI-0.10 to 0.09).In subgroup analyses,there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1hour of symptom onset and in those with more severe stroke.Conclusions In patients who had an ischaemic stroke,ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.WHAT IS ALREADY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those with acute stroke treated within 6hours of stroke onset in a systematic review and individual patient data meta-analysis from two randomised controlled tri-als.The Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2)assessed the effect of GTN given prehospital in patients with pre-sumed stroke within 4hours of onset.This subgroup analysis details the effect of GTN in those with clini-cally diagnosed ischaemic stroke.WHAT THIS STUDY ADDS⇒Transdermal GTN did not influence clinical or radio-logical outcomes despite lowering blood pressure compared with sham.GTN may be associated with more death and dependency in those randomised within 1hour of symptom onset and in those with more severe stroke,but these interactions were non-significant.The population recruited in RIGHT-2 was more dependent and frailer(both clinically and radiologically)than in prior trials of transdermal GTN within 6hours of stroke onset performed in hospital,and may account for the differences in results.HOW THIS STUDY MIGHT AFFECT RESEARCH,PRACTICE OR POLICY⇒Transdermal GTN should not be administered to pa-tients with presumed stroke prehospital outside of a trial environment.Clinical and radiological frailty should be taken into consideration in the design and interpretation of future ultra-acute stroke trials.展开更多
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...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.展开更多
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 rhT...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.展开更多
Rationale Unsuccessful thrombectomy of acute large vessel occlusions(LVOs)has been associated with unfavourable outcomes.Multiple randomised controlled trials(RCTs)have reported a failure rate of 12%–41%for thrombect...Rationale Unsuccessful thrombectomy of acute large vessel occlusions(LVOs)has been associated with unfavourable outcomes.Multiple randomised controlled trials(RCTs)have reported a failure rate of 12%–41%for thrombectomy procedures.Various factors contribute to failed thrombectomy,including technical difficulties in accessing the occlusion,unsuccessful thrombus retrieval,thrombotic reocclusion and pre-existing intracranial atherosclerotic stenosis.Although some studies have explored balloon dilation or permanent stenting as rescue intracranial angioplasty for failed thrombectomy in individual cases,there is currently no evidence from RCTs on this specific topic.Aim To evaluate the potential superiority of bailout angioplasty over standard treatment in cases of unsuccessful recanalisation(eTICI 0 to 2a)or residual severe stenosis(>70%)after thrombectomy in acute LVO patients within 24 hours of stroke onset.Design This study is a multicentre,prospective,randomised,controlled clinical trial designed by investigators.It compares bailout angioplasty with standard therapy and follows an open-label treatment approach while maintaining a blinded outcome assessment(PROBE design).Our objective is to allocate 348 patients in a 1:1 ratio to either receive bailout angioplasty as an intervention or standard therapy as a control,following unsuccessful thrombectomy.Outcome The main measure of interest is the modified Rankin Scale(mRS)Score,which will be assessed in a blinded manner at 90(±14)days following randomisation.The primary effect size will be determined using ordered logistic regression to calculate the common OR,representing the shift on the six-category mRS Scale at the 90-day mark.Additionally,the safety outcomes will be evaluated,including symptomatic intracranial haemorrhage within 18–36hours,severe procedure-related complications and mortality within 90(±14)days,among others.Discussion The ANGEL-REBOOT study aims to generate substantial evidence regarding the efficacy and safety of bailout intracranial angioplasty as a treatment option for patients with LVO who have experienced unsuccessful thrombectomy.Trial registration number NCT05122286.展开更多
Time is of essence in saving brain cells in patients with acute ischaemic stroke,the faster the treatment,the better the outcome.The time window for intravenous tissue plasminogen activator(tPA)treatment is<3 hours...Time is of essence in saving brain cells in patients with acute ischaemic stroke,the faster the treatment,the better the outcome.The time window for intravenous tissue plasminogen activator(tPA)treatment is<3 hours.With the recent success of multiple bridging trials,the treatment time window has been opened up to 6-8 hours.In fact,both Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset and Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trials have treated patients between 8 and 12 hours from the onset.12 We know that the number needed to treat(NNT)to have the benefit for intrave-nous tPA is 1 in 3.In bridging therapy,intra-venous tPA plus intra-arterial thrombectomy within 6 hours of onset,the NNT is 1 in 2-4.展开更多
文摘Introduction There is a downward trend of stroke-related mortality in the USA.By reviewing all published articles on stroke mortality in China,we analysed its trend and possible factors that have influenced the trend.Methods Both English and Chinese literatures were searched on the mortality of stroke or cerebrovascular diseases in China.Potential papers related to this topic were identified from PubMed,Medline,Embase,Cochrane Library,Wanfang Database,SINOMED and China National Knowledge Infrastructure databases.Results Comparing the results from the most recent population-based epidemiological survey and databank from the national Center for Disease Control and Prevention,the age-adjusted stroke mortality rate has shown a downward trend among both urban and rural population in the past 30 years in China.Comparing with 30 years ago,the rate of stroke mortality has decreased by more than 31%in urban/suburban population and 11%in rural population.In men,the age-adjusted stroke mortality rate decreased by 18.9%and in women by 24.9%between 1994 and 2013.Factors that may have contributed to the trend of decreased stroke mortality rate include(1)improved healthcare coverage and healthcare environment;(2)improved treatment options and medical technology;(3)support by government to educate the public on stroke and stroke prevention;and(4)improved public knowledge on stroke.Conclusions The age-adjusted stroke mortality rate in China has shown a downward trend among both urban and rural population in the past 30 years.The major influencing factors that helped in reducing stroke mortality in China included improved healthcare coverage,healthcare environment,the updated treatment options and modern medical technology.
基金Supported by funds from the Joundishapour Medical University
文摘Objective：To assess the long-term（up to 6 months）safety profile of a 3-month regimen of NeuroAiD for acute ischemic stroke.Methods：A total of 190 patients with acute ischemic stroke were identified for eligibility in a randomized,double-blind,placebo-controlled clinical trial,of which 150 patients allocated to either receiving NeuroAiD（80 cases）or placebo（70 cases）were analyzed after dropouts due to absence of baseline data,early death,or noncompliance.Both groups received treatment for three months and followed up for another three months after the completion of the treatment.Occurrence of clinical adverse events and laboratory parameters were assessed at 1 month,3 months（while under treatment）and 6 months（3 months after the completion of treatment）.Statistical comparisons between groups were performed using chi-square test or t-test whenever appropriate.Results：The two groups had comparable baseline characteristics.Mild nausea was more commonly reported in patients taking NeuroAid compared with placebo（P=0.01）,of which 9 out of10 were observed only during the first month of treatment.However,none of the adverse events reported were considered severe or required discontinuation of the study drug.There was no significant change observed in mean arterial blood pressure,haemoglobin,renal and liver laboratory parameters during treatment with NeuroAid and up to 3 months after completion of a 3-month regimen.Conclusion：NeuroAiD is safe and does not affect hematologic,hepatic,and renal functions during and long after completion of treatment.
基金This work was supported by the Illinois Neurological Institute,OSF HealthCare Foundation.
文摘background and purpose Recent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases(MMPs)in rats and the detrimental role of MMP-12 in post-stroke brain damage.We hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other MMPs.We tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout mice.Methods Focal cerebral ischaemia was induced in wildtype and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament suture.One hour after ischaemia,reperfusion was initiated by removing the monofilament.One day after reperfusion,ischaemic brain tissues from various groups of mice were collected,and total RNA was isolated and subjected to cDNA synthesis followed by PCR analysis.results Although the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats,there is a clear species similarity in the expression of MMP-12,which was found to be predominantly upregulated in both species.Further,the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type mice.Moreover,the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type mice.Conclusions In the ischaemic brain,MMP-12 upregulates several fold higher than any other MMP.Mice derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.
基金National Natural Science Foundation of China(81870905,U20A20358,82111530203)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M 5-029)The National Science and Technology Major Project(2017ZX09304018).
文摘Background The benefit of intravenous alteplase in acute ischaemic stroke(AIS)is time-dependent.Tenecteplase is non-inferior to alteplase among patients with AIS.We aimed to delineate the association of the stroke onset to treatment time(OTT)with tenecteplase compared with alteplase on therapeutic benefit and clinical risks.Methods This is a post hoc analysis of the Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-2 an open-label,randomised,controlled,non-inferior trial.A total of 1430 AIS within 4.5 hours onset at 53 sites in China from 12 June 2021 to 29 May 2022 were randomly assigned(1:1)to receive either tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg.The primary efficacy outcome was the proportion of participants with a modified Rankin Scale score of 0–1 at 90 days.A post hoc subgroup analysis was conducted with the OTT divided into three intervals(0–90 min,91–180 min and 181–270 min).The primary safety outcome was symptomatic intracranial haemorrhage within 36 hours post-thrombolytic treatment.Results Treatment was initiated within 270 min of stroke onset in 1412 patients who were randomly allocated to either tenecteplase(n=707)or alteplase(n=705).The OR of primary efficacy outcome was similar as OTT increased(p=0.84).Adjusted odds of an excellent functional outcome were 0.99(95%CI 0.37 to 2.67)for 0–90 min,1.23(95%CI 0.88 to 1.71)for 91–180 min and 1.21(95%CI 0.88 to 1.65)for 181–270 min.All were in favour of the tenecteplase group.Meta-analysis of 2949 patients yielded a pooled risk difference of 5.54(95%CI-0.18 to 11.26;p=0.82)in favour of tenecteplase for more than 180 min and 1.77(95%CI-2.66 to 6.20;p=0.58)for 0–180 min.Conclusions In AIS patients who were treated with either tenecteplase or alteplase within 4.5 hours onset,there was no difference observed in the efficacy and safety between the two groups at the three different OTT time intervals.
基金British Heart Foundation(grant number CS/14/4/30972)JPA is supported by an NIHR Health and Care Research Scholarship.PMB is Stroke Association Professor of Stroke Medicine and an NIHR Senior Investigator.TR is an NIHR Senior Investigator.GM is the Stroke Association Edith Murphy Foundation Senior Clinical Lecturer(SA L-SMP 18\1000).
文摘Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is unclear.Here,we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2).Methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4hours of onset.The primary outcome was a shift in scores on the modified Rankin scale(mRS)at day 90.Secondary outcomes included death;a global analysis(Wei-Lachin test)containing Barthel Index,EuroQol-5D,mRS,telephone interview for cognitive status-modified and Zung depression scale;and neuroimaging-determined‘brain frailty’markers.Data were reported as n(%),mean(SD),median[IQR],adjusted common OR(acOR),mean difference or Mann-Whitney difference(MWD)with 95%CI.Results 597 of 1149(52%)patients had a final diagnosis of ischaemic stroke;age 75(12)years,premorbid mRS>2107(18%),Glasgow Coma Scale 14(2)and time from onset to randomisation 67[45,108]min.Neuroimaging‘brain frailty’was common:median score 2[2,3](range 0–3).At day 90,GTN did not influence the primary outcome(acOR for increased disability 1.15,95%CI 0.85 to 1.54),death or global analysis(MWD 0.00,95%CI-0.10 to 0.09).In subgroup analyses,there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1hour of symptom onset and in those with more severe stroke.Conclusions In patients who had an ischaemic stroke,ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.WHAT IS ALREADY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those with acute stroke treated within 6hours of stroke onset in a systematic review and individual patient data meta-analysis from two randomised controlled tri-als.The Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2)assessed the effect of GTN given prehospital in patients with pre-sumed stroke within 4hours of onset.This subgroup analysis details the effect of GTN in those with clini-cally diagnosed ischaemic stroke.WHAT THIS STUDY ADDS⇒Transdermal GTN did not influence clinical or radio-logical outcomes despite lowering blood pressure compared with sham.GTN may be associated with more death and dependency in those randomised within 1hour of symptom onset and in those with more severe stroke,but these interactions were non-significant.The population recruited in RIGHT-2 was more dependent and frailer(both clinically and radiologically)than in prior trials of transdermal GTN within 6hours of stroke onset performed in hospital,and may account for the differences in results.HOW THIS STUDY MIGHT AFFECT RESEARCH,PRACTICE OR POLICY⇒Transdermal GTN should not be administered to pa-tients with presumed stroke prehospital outside of a trial environment.Clinical and radiological frailty should be taken into consideration in the design and interpretation of future ultra-acute stroke trials.
基金supported by the National Natural Science Foundation of China(81870905)the National Key R&D Program of China(2017YFC1308204)+1 种基金the National Science and Technology Major Project(2017ZX09304018)funded by Guangzhou Recomgen Biotech Co.,Ltd.
文摘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.
基金supported by the National Natural Science Foundation of China(81870905,82171272)Beijing Municipal Science&Technology Committee(Z211100003521019)Beijing Hospitals Authority(PX2022019).
文摘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.
基金funded by the Beijing Natural Science Foundation(No.220016)National Natural Science Foundation of China(No.62272325)+1 种基金National Key R&D Program(No.2018AAA0102600)Beijing Municipal Administration of Hospitals Incubating Program(No.PX2023022),Shanghai HeartCare Medical Technology,HeMo(China)Bioengineering and Sino Medical Sciences Technology.
文摘Rationale Unsuccessful thrombectomy of acute large vessel occlusions(LVOs)has been associated with unfavourable outcomes.Multiple randomised controlled trials(RCTs)have reported a failure rate of 12%–41%for thrombectomy procedures.Various factors contribute to failed thrombectomy,including technical difficulties in accessing the occlusion,unsuccessful thrombus retrieval,thrombotic reocclusion and pre-existing intracranial atherosclerotic stenosis.Although some studies have explored balloon dilation or permanent stenting as rescue intracranial angioplasty for failed thrombectomy in individual cases,there is currently no evidence from RCTs on this specific topic.Aim To evaluate the potential superiority of bailout angioplasty over standard treatment in cases of unsuccessful recanalisation(eTICI 0 to 2a)or residual severe stenosis(>70%)after thrombectomy in acute LVO patients within 24 hours of stroke onset.Design This study is a multicentre,prospective,randomised,controlled clinical trial designed by investigators.It compares bailout angioplasty with standard therapy and follows an open-label treatment approach while maintaining a blinded outcome assessment(PROBE design).Our objective is to allocate 348 patients in a 1:1 ratio to either receive bailout angioplasty as an intervention or standard therapy as a control,following unsuccessful thrombectomy.Outcome The main measure of interest is the modified Rankin Scale(mRS)Score,which will be assessed in a blinded manner at 90(±14)days following randomisation.The primary effect size will be determined using ordered logistic regression to calculate the common OR,representing the shift on the six-category mRS Scale at the 90-day mark.Additionally,the safety outcomes will be evaluated,including symptomatic intracranial haemorrhage within 18–36hours,severe procedure-related complications and mortality within 90(±14)days,among others.Discussion The ANGEL-REBOOT study aims to generate substantial evidence regarding the efficacy and safety of bailout intracranial angioplasty as a treatment option for patients with LVO who have experienced unsuccessful thrombectomy.Trial registration number NCT05122286.
文摘Time is of essence in saving brain cells in patients with acute ischaemic stroke,the faster the treatment,the better the outcome.The time window for intravenous tissue plasminogen activator(tPA)treatment is<3 hours.With the recent success of multiple bridging trials,the treatment time window has been opened up to 6-8 hours.In fact,both Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset and Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trials have treated patients between 8 and 12 hours from the onset.12 We know that the number needed to treat(NNT)to have the benefit for intrave-nous tPA is 1 in 3.In bridging therapy,intra-venous tPA plus intra-arterial thrombectomy within 6 hours of onset,the NNT is 1 in 2-4.
