Prehospital transdermal glyceryl trinitrate for ultra- acute ischaemic stroke: data from the RIGHT- 2 randomised sham- controlled ambulance trial

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.

Measures of intracranial compartments in acute intracerebral haemorrhage:data from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial(RIGHT-2)

Background and purpose Intracerebral haemorrhage volume(ICHV)is prognostically important but does not account for intracranial volume(ICV)and cerebral parenchymal volume(CPV).We assessed measures of intracranial compartments in acute ICH using computerised tomography scans and whether ICHV/ICV and ICHV/CPV predict functional outcomes.We also assessed if cistern effacement,midline shift,old infarcts,leukoaraiosis and brain atrophy were associated with outcomes.Methods Data from 133 participants from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial trial were analysed.Measures included ICHV(using ABC/2)and ICV(XYZ/2)(by independent observers);ICHV,ICV and CPV(semiautomated segmentation,SAS);atrophy(intercaudate distance,ICD,Sylvian fissure ratio,SFR);midline shift;leukoaraiosis and cistern effacement(visual assessment).The effects of these measures on death at day 4 and poor functional outcome at day 90(modified Rankin scale,mRS of>3)was assessed.Results ICV was significantly different between XYZ and SAS:mean(SD)of 1357(219)vs 1420(196),mean difference(MD)62 mL(p<0.001).There was no significant difference in ICHV between ABC/2 and SAS.There was very good agreement for ICV measured by SAS,CPV,ICD,SFR,leukoaraiosis and cistern score(all interclass correlations,n=10:interobserver 0.72-0.99,intraobserver 0.73-1.00).ICHV/ICV and ICHV/CPV were significantly associated with mRS at day 90,death at day 4 and acute neurological deterioration(all p<0.05),similar to ICHV.Midline shift and cistern effacement at baseline were associated with poor functional outcome but old infarcts,leukoaraiosis and brain atrophy were not.Conclusions Intracranial compartment measures and visual estimates are reproducible.ICHV adjusted for ICH and CPV could be useful to prognosticate in acute stroke.The presence of midline shift and cistern effacement may predict outcome but the mechanisms need validation in larger studies.

Blood pressure management in acute stroke

Blood pressure(BP)is elevated in 75%or more of patients with acute stroke and is associated with poor outcomes.Whether to modulate BP in acute stroke has long been debated.With the loss of normal cerebral autoregulation,theoretical concerns are twofold:high BP can lead to cerebral oedema,haematoma expansion or haemorrhagic transformation;and low BP can lead to increased cerebral infarction or perihaematomal ischaemia.Published evidence from multiple large,high-quality,randomised trials is increasing our understanding of this challenging area,such that BP lowering is recommended in acute intracerebral haemorrhage and is safe in ischaemic stroke.Here we review the evidence for BP modulation in acute stroke,discuss the issues raised and look to on-going and future research to identify patient subgroups who are most likely to benefit.

Relationship between nitrate headache and outcome in patients with acute stroke: results from the efficacy of nitric oxide in stroke (ENOS) trial

Introduction Nitrate-induced headache is common and may signify responsive cerebral vasculature.We assessed the relationship between nitrate headache and outcome in patients with acute stroke.Materials and methods Patients were those randomised to glyceryl trinitrate(GTN)versus no GTN in the efficacy of nitric oxide in stroke trial.Development of headache by end of treatment(day 7),and functional outcome(modified Rankin Scale,primary outcome)at day 90,were assessed.Analyses are adjusted for baseline prognostic factors and give OR and mean difference(MD)with 95%CI.Results In 4011 patients,headache was more common in GTN than control(360,18.0% vs 170,8.5%;p<0.001).Nitrate-related headache was associated with:younger age,female sex,higher diastolic blood pressure,non-total anterior circulation syndrome,milder stroke and absence of dysphasia(p<0.05).Nitrate headache was not associated with improved functional outcome(OR 0.90,95% CI 0.73 to 1.10,p=0.30)or death(day 90)(HR 0.64,95% CI 0.40 to 1.02,p=0.062),but reduced death or deterioration(day 7)(OR 0.45,95% CI 0.25 to 0.82),death in hospital(OR 0.44,95% CI 0.22 to 0.88)and improved activities of daily living(Barthel index,MD 3.7,95% CI 0.3 to 7.1)and cognition(telephone interview cognitive screen,MD 2.0,95% CI 0.7 to 3.3)(day 90).Non-nitrate headache was not associated with death,disability or cognition.Discussion and conclusion Development of a nitrate headache by day 7 after stroke may be associated with improved activities of daily living and cognitive impairment at day 90,which was not seen with non-nitrate headache.

Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease:baseline data and statistical analysis plan for the Lacunar Intervention Trial-2(LACI-2)(ISRCTN14911850)

Background Cerebral small vessel disease(SVD)causes lacunar strokes(25%of all ischaemic strokes),physical frailty and cognitive impairment and vascular and mixed dementia.There is no specific treatment to prevent progression of SVD.Methods The LACunar Intervention Trial-2 is an investigator-initiated prospective randomised open-label blinded-endpoint phase II feasibility study assessing cilostazol and isosorbide mononitrate for preventing SVD progression.We aimed to recruit 400 patients with clinically evident lacunar ischaemic stroke and randomised to cilostazol,isosorbide mononitrate,both or neither,in addition to guideline secondary ischaemic stroke prevention,in a partial factorial design.The primary outcome is feasibility of recruitment and adherence to medication;key secondary outcomes include:drug tolerability;recurrent vascular events,cognition and function at 1 year after randomisation;and safety(bleeding,falls,death).Data are number(%)and median(IQR).Results The trial commenced on 5 February 2018 and ceased recruitment on 31 May 2021 with 363 patients randomised,with the following baseline characteristics:average age 64(56.0,72.0)years,female 112(30.9%),stroke onset to randomisation 79.0(27.0,244.0)days,hypertension 267(73.6%),median blood pressures 143.0(130.0,157.0)/83.0(75.0,90.0)mm Hg,current smokers 67(18.5%),educationally achieved end of school examinations(A-level)or higher 118(32.5%),modified Rankin scale 1.0(0.0,1.0),National Institutes Health stroke scale 1.0(1.4),Montreal Cognitive Assessment 26.0(23.0,28.0)and total SVD score on brain imaging 1.0(0.0,2.0).This publication summarises the baseline data and presents the statistical analysis plan.Summary The trial is currently in follow-up which will complete on 31 May 2022 with results expected in October 2022.Trial registration number ISRCTN14911850.

Rationale and design of a randomised double-blind 2×2 factorial trial comparing the effect of a 3-month intensive statin and antiplatelet therapy for patients with acute mild ischaemic stroke or high-risk TIA with intracranial or extracranial atherosclerosis(INSPIRES)

Background It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe.Methods The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis(INSPIRES)trial is a randomised,double-blind,placebo-controlled,multicentre and 2×2 factorial trial.6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack(TIA)within the previous 72 hours that is attributed to≥50%atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial.Eligible subjects will be randomised 1:1:1:1 to one of four groups:(1)intensive antiplatelet therapy(combined clopidogrel and aspirin for days 1-21,then aspirin placebo and clopidogrel for days 22-90)plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days,then 40 mg daily for days 22-90);(2)intensive antiplatelet therapy plus delayed intensive statin therapy(atorvastatin placebo for days 1-3,followed by 40 mg per day of atorvastatin for days 4-90);(3)standard antiplatelet therapy(combination of clopidogrel placebo with aspirin for 90 days)plus immediate intensive statin therapy and(4)standard antiplatelet therapy plus delayed intensive statin therapy.The primary efficacy endpoint is any new stroke(ischaemic or haemorrhagic)within 90 days after randomisation.The primary safety endpoint is moderate to severe bleeding at 90 days.Conclusion The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin.

轻型缺血性卒中或短暂性脑缺血发作的早期双联抗血小板治疗

王拥军及同事探讨了应用双联抗血小板治疗预防卒中复发或短暂性脑缺血发作的最新证据。轻型缺血性卒中和短暂性脑缺血发作(TIA)患者在头几周内有较高的卒中及其他血管事件的复发风险(5%~11.7%严。双联抗血小板治疗,包括氯吡格雷和阿司匹林,是减少卒中复发的有效治疗策略Magic Group的专家小组(http://magicproject.org/)最近在The BMJ中发表了一个强烈的快速推荐建议,即对于轻型缺血性卒中和TIA患者应在症状出现24小时内开始双联抗血小板治疗,并持续10~21天3。

关于缺血性卒中后女性妊娠以及针对不育、避孕和绝经期进行激素治疗的共识文件

已有报道妊娠与缺血性卒中风险增高相关，妊娠期间发生卒中是导致孕产妇死亡的主要原因之一。Kuklina等对1994年至1995年与2006年至2007年的住院数据进行的比较显示，孕妇在产前发生任何类型卒中的风险增高47％（从0．15次／1000次分娩～0．22次／1000次分娩），在产后发生任何卒中的风险增高83％（从0．12次／1000次分娩～0．22次／1000次分娩）。

Clopidogrel with aspirin in High- risk patients with Acute Non- disabling Cerebrovascular Events II (CHANCE-2): rationale and design of a multicentre randomised trial

Background In patients with a minor ischaemic stroke or transient ischaemic attack(TIA),separate trials have shown that dual antiplatelet therapy with clopidogrel plus aspirin(clopidogrel-aspirin)or ticagrelor plus aspirin(ticagrelor-aspirin)are more effective than aspirin alone in stroke secondary prevention.However,these two sets of combination have not been directly compared.Since clopidogrel was less effective in stroke patients who were CYP2C19 loss-of function(LOF)allele carriers,whether ticagrelor-aspirin is clinically superior to clopidogrel-aspirin in this subgroup of patients with stroke is unclear.Aim To describe the rationale and design considerations of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events(CHANCE-2)trial.Design CHANCE-2 is a randomised,double-blind,double-dummy,placebo-controlled,multicentre trial that compares two dual antiplatelet strategies for minor stroke or TIA patients who are CYP2C19 LOF allele carriers:ticagrelor(180 mg loading dose on day 1 followed by 90 mg twice daily on days 2-90)or clopidogrel(300 mg loading dose on day 1 followed by 75 mg daily on days 2-90),plus open-label aspirin with a dose of 75-300 mg on day 1 followed by 75 mg daily on day 2-21.All will be followed for 1 year.Study outcomes The primary efficacy outcome is any stroke(ischaemic or haemorrhagic)within 3 months and the primary safety outcome is any severe or moderate bleeding event within 3 months.Discussion The CHANCE-2 trial will evaluate whether ticagrelor-aspirin is superior to clopidogrel-aspirin for minor stroke or TIA patients who are CYP2C19 LOF allele carriers.

Remote platelet function testing using P-selectin expression in patients with recent cerebral ischaemia on clopidogrel

Background Antiplatelet agents reduce recurrence after cerebral ischaemia but are not effective in all patients,in part because of treatment resistance.The primary aim was to assess the proportion of patients who are insensitive to clopidogrel.The secondary aim was to assess the association between insensitivity to clopidogrel and recurrent cerebrovascular events.Methods Following written informed consent,independent patients with a recent non-cardioembolic ischaemic stroke or transient ischaemic attack,and taking clopidogrel,were enrolled.Platelet function was assessed with remote measurement of surface expression of P-selectin(CD62P)using commercial kits sensitive to aspirin or clopidogrel.Participants’general practitioners provided details on recurrent vascular events at least 90 days later.Data are mean(SD)and median[IQR].Resistance was defined as:aspirin median fluorescence(MF)>500 units,clopidogrel MF>860 units.Non-parametric descriptors and tests were used.Results 63 patients were recruited:mean age 64(13.7)years,women 47%.At baseline,59(95%)patients were taking clopidogrel alone with 3(5%)on combined clopidogrel and aspirin.Assessment of platelet surface P-selectin revealed:aspirin test 528[317,834],>50054.8%;clopidogrel test 429[303,656],>86011.3%.No participants on aspirin and clopidogrel showed aspirin resistance.Thirteen(20.6%)patients had a recurrent cerebrovascular event;those with an ischaemic stroke had a non-significantly higher baseline P-selectin using the clopidogrel test as compared with those with no recurrence:626[380,801]versus 406[265,609],p=0.08.Conclusions Remote measurement of platelet function assessed using the platelet surface expression of P-selectin is feasible.11%of patients taking clopidogrel showed resistance.No significant associations were noted between clopidogrel resistance and recurrent ischaemic events.

Clinical management of cerebral small vessel disease:a call for a holistic approach

Cerebral small vessel disease(SVD)is a common global brain disease that causes cognitive impairment,ischemic or hemorrhagic stroke,problems with mobility,and neuropsychiatric symptoms.The brain damage,seen as focal white and deep grey matter lesions on brain magnetic resonance imaging(MRI)or computed tomography(CT),typically accumulates"covertly"and may reach an advanced state before being detected incidentally on brain scanning or causing symptoms.Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation,perhaps explaining a lack of awareness,until recently,of the full range and complexity of SVD.In this review,we discuss the varied clinical presentations,established and emerging risk factors,relationship to SVD features on MRI or CT,and the current state of knowledge on the effectiveness of a wide range of pharmacological and lifestyle interventions.The core message is that effective assessment and clinical management of patients with SVD,as well as future advances in diagnosis,care,and treatment,will require a more"joined-up"’approach.This approach should integrate clinical expertise in stroke neurology,cognitive,and physical dysfunctions.It requires more clinical trials in order to improve pharmacological interventions,lifestyle and dietary modifications.A deeper understanding of the pathophysiology of SVD is required to steer the identification of novel interventions.An essential prerequisite to accelerating clinical trials is to improve the consistency,and standardization of clinical,cognitive and neuroimaging endpoints.