ABSTRACT Introduction Post stroke dysphagia is common, associated with poor functional outcome and lacks treatment strategies beyond behaviour therapies delivered by speech & language therapists. Here, we present the statistical analysis plan for the ongoing pharyngeal electrical stimulation for acute stroke dysphagia trial (PhEAST). PES is a candidate treatment for dysphagia present in non-ventilated stroke patients. Methods PhEAST is an investigator-initiated international prospective randomised open-label blinded-endpoint phase-4 superiority trial involving 650 participants with tube-dependent post-stroke dysphagia. Consenting patients are randomised to PES versus no PES given on top of standard care with PES given daily for 6 days. The primary outcome is the dysphagia severity rating scale (DSR.S), a measure of swallowing impairment, made at days 14 and 90 and analysed using repeated measures regression. Conclusion We present the statistical analysis plan for the main analyses based on data up to day 90 along with planned secondary analyses including presentation of baseline data, health economics, cognition and extended follow-up to 12 months.

Data regarding management of patients already on an antiplatelet when presenting with an ischaemic stroke or transient ischaemic attack (TIA) are limited. This secondary analysis of the triple antiplatelets for reducing dependency in ischaemic stroke (TARDIS) trial explored clinical outcomes across prior antiplatelet groups. TARDIS was an international prospective-randomised open-label blinded-endpoint trial assessing 30 days of triple vs. guideline antiplatelet therapy in patients with acute ischaemic stroke or TIA. The number of pre-stroke/TIA antiplatelet agents was collected pre-randomisation. The primary outcome was the combined incidence of, and dependency from, any recurrent stroke (using the modified Rankin Scale) or TIA within 90 days analysed using ordinal logistic regression with adjustment for prognostic factors. Baseline imaging features of brain frailty were adjudicated centrally by neuroimaging experts. 1080/3096 (34.9

Introduction Acute ischaemic stroke and primary intracerebral haemorrhage are complicated by oropharyngeal dysphagia in more than 50% of patients. Currently, there are no definitive treatments for post-stroke dysphagia. Pharyngeal electrical stimulation (PES) can drive long-term beneficial changes in the cortical control of swallowing with functionally relevant reorganisation of the swallowing cortex correlating with reduced dysphagia. Methods The pharyngeal electrical stimulation for acute stroke dysphagia trial (PhEAST) is an international prospective randomised open-label blinded-endpoint parallel-group phase-4 superiority effectiveness trial. 638 patients with post-stroke dysphagia and dependency on nasogastric tube feeding are being recruited within 2 to 31 days of ictus. Participants are recruited from UK and Austria and randomised to six days of optimised PES (given for 10 minutes each day) versus no PES on top of standard care. The primary outcome is the dysphagia severity rating scale (DSRS), an assessment of swallowing impairment, measured locally on day 14 and centrally at day 90 by trained observers masked to treatment and analysed using repeated measures regression analysis. Secondary outcomes include: functional oral intake scale, feeding status scale, international dysphagia diet standardisation initiative scale, presence of a feeding tube, pneumonia, antibiotic use, health-related quality of life, dependency, disability, frailty, mood, cognition, global impact and health economics at days 14, 90, 180 and 365. Safety measures include death and serious adverse events. Discussion PhEAST has recruited more than 574 participants from 45 hospitals in the UK and Austria; recruitment will complete at end October 2026. The attached Supplement summarises the protocol and follows the EQUATOR SPIRIT guideline.

BACKGROUND AND PURPOSE:Ambulance trials assessing interventions in suspected stroke patients will recruit patients with currently active symptoms that will resolve into transient ischaemic attack (TIA). The safety and efficacy of glyceryl trinitrate (GTN) in the pre-specified subgroup of patients with TIA in the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT-2) was assessed. METHODS:RIGHT-2 was a pre-hospital-initiated multicentre randomized sham-controlled blinded-endpoint trial that randomized patients with presumed ultra-acute stroke within 4 h of symptom onset to transdermal GTN or sham. Final diagnosis was determined by site investigators. The primary outcome was a shift in modified Rankin Scale (mRS) scores at 90 days analysed using ordinal logistic regression reported as adjusted common odds ratio with 95% confidence intervals (CIs). Secondary outcomes included death or dependence (mRS >2). RESULTS:In all, 109 of 1149 (9.5%) patients had a final diagnosis of TIA (GTN 57, sham 52) with mean age 73 (SD 13) years, 19 (17.4%) had pre-morbid mRS >2, and onset to randomization was 80 min (interquartile range 49, 105). GTN lowered blood pressure by 7.4/5.2 mmHg compared with sham by hospital arrival. At day 90, GTN had no effect on shift in mRS scores (common odds ratio for increased dependence 1.47, 95% CI 0.70-3.11) but was associated with increased death or dependence (mRS >2): GTN 29 (51.8%) versus sham 23 (46.9%), odds ratio 3.86 (95% CI 1.09-13.59). CONCLUSIONS:Pre-hospital ultra-acute transdermal GTN did not improve overall functional outcome in patients with investigator-diagnosed TIA compared with sham treatment.

Cerebral small vessel disease (cSVD) causes lacunar stroke (25% of ischaemic strokes), haemorrhage, dementia, physical frailty, or is ‘covert’, but has no specific treatment. Uncertainties about the design of clinical trials in cSVD, which patients to include or outcomes to assess, may have delayed progress. Based on experience in recent cSVD trials, we reviewed ways to facilitate future trials in patients with cSVD.We assessed the literature and the LACunar Intervention Trial 2 (LACI-2) for data to inform choice of Participant, Intervention, Comparator, Outcome, including clinical versus intermediary endpoints, potential interventions, effect of outcome on missing data, methods to aid retention and reduce data loss. We modelled risk of missing outcomes by baseline prognostic variables in LACI-2 using binary logistic regression.Imaging versus clinical outcomes led to larger proportions of missing data. We present reasons for and against broad versus narrow entry criteria. We identified numerous repurposable drugs with relevant modes of action to test in various cSVD subtypes. Cognitive impairment is the most common clinical outcome after lacunar ischaemic stroke but was missing more frequently than dependency, quality of life or vascular events in LACI-2. Assessing cognitive status using Diagnostic and Statistical Manual for Mental Disorders Fifth Edition can use cognitive data from multiple sources and may help reduce data losses.Trials in patients with all cSVD subtypes are urgently needed and should use broad entry criteria and clinical outcomes and focus on ways to maximise collection of cognitive outcomes to avoid missing data.

Introduction: The Tranexamic acid for IntraCerebral Haemorrhage-2 (TICH-2) trial reported no significant improvement in death and dependency at day 90 despite reductions in haematoma expansion, early neurological deterioration and early death. However, significant recovery after stroke, particularly intracerebral haemorrhage (ICH), may take more than 3 months. Here we report the participant outcomes at 1 year after stroke. Patients and methods: TICH-2 was a prospective randomised controlled trial that tested the efficacy and safety of tranexamic acid in spontaneous ICH when given within 8 h of onset. Patients with ICH on anticoagulation were excluded. Centralised blinded telephone follow up was performed for patients from the United Kingdom at 1 year. The primary outcome was modified Rankin Scale at 1 year. Secondary outcomes included Barthel index, Telephone Interview Cognitive Status-modified, EuroQoL-5D and Zung Depression Scale. This was a prespecified secondary analysis of the TICH-2 trial. Results: About 2325 patients were recruited into the trial (age 68.9 ± 13.8 years; 1301 male, 56%). About 1910 participants (82.2%) were eligible for day 365 follow up. 57 patients (3.0%) were lost to follow up. Tranexamic acid did not reduce the risk of poor functional outcome at 1 year (adjusted OR 0.91 95% CI 0.77–1.09; p = 0.302). However, Cox proportional hazard analysis revealed significant survival benefit in the tranexamic acid group (adjusted HR 0.83, 95% CI 0.70–0.99; p = 0.038). Conclusion: There was no difference in functional outcome at 1 year after ICH. Tranexamic acid may reduce mortality at 1 year without an increase in severely dependent survivors. But this should be interpreted with caution as this is a result of secondary analysis in a neutral 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 4 hours 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>2 107 (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 1 hour 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.

Background The Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial-2 (RIGHT-2) reported no overall treatment difference between glyceryl trinitrate (GTN) and sham at day 90. Here we assess participants’ outcomes 1 year after randomisation.Methods RIGHT-2 was an ambulance-based prospective randomised controlled trial where patients with presumed stroke and systolic blood pressure (BP) of >120 mm Hg received either GTN (5 mg/day) or sham patch. Centralised blinded telephone follow-up was performed at days 90 (primary endpoint) and 365 (secondary endpoint). The lead outcome was dependency assessed with the modified Rankin Scale (mRS).Results 1149 patients were recruited to RIGHT-2 between October 2015 and May 2018, and 1097 (95.5%) had outcome data recorded at day 365. At baseline, the patients were; female (48%), had a mean age of 73 (15) years, BP of 162 (25)/92 (18) mm Hg, onset to randomisation of 70 (45–115) min, diagnosis of ischaemic stroke (52%), intracerebral haemorrhage (ICH) (13%), transient ischaemic attack (TIA) (9%) and mimics (26%). There was no effect of GTN on mRS score at day 365 in participants with confirmed stroke/TIA (adjusted common odds ratio (acOR) 1.10, 95% CI 0.86 to 1.42) or in all patients. In patients randomised to GTN, mRS at day 365 tended to be worse in those with ICH (acOR 1.65, 95% CI 0.84 to 3.25) and better in those with a mimic diagnosis (acOR 0.53, 95% CI 0.33 to 0.84).Conclusion At 1 year post randomisation, dependency did not differ between GTN and sham treatment in either the target population or overall. In prespecified subgroup analyses, GTN was associated with reduced dependency in participants with a final diagnosis of mimic and a non-significant worse outcome in participants with ICH.Trial registration number ISRCTN26986053.

BackgroundTreatment for stroke is time-dependent, and ambulance services play a vital role in the early recognition, assessment and transportation of stroke patients. Innovations which begin in ambulance services to expedite delivery of treatments for stroke are developing. However, research delivery in ambulance services is novel, developing and not fully understood.AimsTo synthesise literature encompassing ambulance service-based randomised controlled interventions for acute stroke with consideration to the characteristics of the type of intervention, consent modality, time intervals and issues unique to research delivery in ambulance services.Summary of reviewOnline searches of MEDLINE, EMBASE, Web of Science, CENTRAL and WHO IRCTP databases and hand searches identified 15 eligible studies from 538. Articles were heterogeneous in nature and meta-analysis was partially available as 13 studies reported key time intervals, but terminology varied. Randomised interventions were evident across all points of contact with ambulance services: identification of stroke during the call for help, higher dispatch priority assigned to stroke, on-scene assessment and clinical interventions, direct referral to comprehensive stroke centres and definitive care delivery at scene. Consent methods ranged between informed patient, waiver and proxy modalities with country-specific variation. Challenges unique to the prehospital setting comprise the geographical distribution of ambulance resources, low recruitment rates, prolonged recruitment phases, management of investigational medicinal product and incomplete datasets.ConclusionResearch opportunities exist across all points of contact between stroke patients and ambulance services, but randomisation and consent remain novel. Early collaboration and engagement between trialists and ambulance services will alleviate some of the complexities reported.Registration numberPROSPERO 2018CRD42018075803

Acute ischemic stroke is a leading cause of death and major disability worldwide. Approximately 50% of ischemic strokes are caused by atherothrombotic occlusion of the cerebral arteries, and antiplatelets are the mainstay of secondary stroke preventative treatment. Aspirin is beneficial if given early, and short‐term treatment using aspirin and clopidogrel is increasingly used for patients with intracranial atherosclerotic disease, minor stroke, and or transient ischemic attack. However, up to 50% of patients continue to have recurrent stroke and major vascular events, which may be partly attributable to resistance to aspirin and or clopidogrel. Although the precise mechanisms are unknown, clinical and genetic factors associated with bioavailability and binding to target receptors are implicated. This narrative review begins with the concept of aspirin and clopidogrel resistance in ischemic stroke and transient ischemic attack, potential mechanisms including genetic polymorphisms, and an overview of platelet function measures and limitations. We conclude by highlighting practical issues in the management of patients with aspirin andclopidogrel resistance including the emerging interest in ticagrelor, prasugrel, and cilostazol as well as directions for future trials in transient ischemic attack and acute ischemic stroke.

The stroke advance clinical practitioner (ACP) and stroke specialist nurse (SSN) are two vitally important roles within the hyper acute stroke unit, acute stroke unit and spoke sites that provide acute stroke care for continued rehabilitation until the point of discharge. The SSN role has been developed over the past decade, whereas the ACP role is much newer. While there are similarities between the two roles, there are some core differences that allow the two roles to coexist and support one another. It is important to understand the two roles, the differences and how each will benefit from the other, as this will allow teams working within hyper acute stroke units and acute stroke units to work to their full potential, while ensuring professional and patient safety and enhancing job satisfaction and patient care.

Susac syndrome is a likely autoimmune microangiopathy affecting the brain, retina and inner ear. Due to the rarity of this condition, diagnosis and treatment can be challenging. Diagnosis is based on the presence of the clinical triad of central nervous system dysfunction, branch retinal artery occlusions and sensorineural hearing loss. Typical MRI findings of callosal and peri-callosal lesions may assist in diagnosis. Clinical course can be monophasic, polycyclic or chronic continuous. It is important to look out for red flags to attain an accurate diagnosis and follow a therapeutic algorithm based on severity of the disease and response to treatment. Patients are treated with steroids and immunosuppressive agents with a variable response. Early aggressive treatment especially in severe cases, may help in preventing relapses and morbidity/disability. This study highlights important diagnostic features and proposes a treatment algorithm based on clinical experience from management of 16 patients from 2 neuroscience centres in the UK since 2007, who were followed up over a long period of 3–15 years.

Background Tranexamic acid reduced haematoma expansion and early death, but did not improve functional outcome in the tranexamic acid for hyperacute spontaneous intracerebral haemorrhage-2 (TICH-2) trial. In a predefined subgroup, there was a statistically significant interaction between prerandomisation baseline systolic blood pressure (SBP) and the effect of tranexamic acid on functional outcome (p=0.019).Methods TICH-2 was an international prospective double-blind placebo-controlled randomised trial evaluating intravenous tranexamic acid in patients with acute spontaneous intracerebral haemorrhage (ICH). Prerandomisation baseline SBP was split into predefined ≤170 and >170 mm Hg groups. The primary outcome at day 90 was the modified Rankin Scale (mRS), a measure of dependency, analysed using ordinal logistic regression. Haematoma expansion was defined as an increase in haematoma volume of >33% or >6 mL from baseline to 24 hours. Data are OR or common OR (cOR) with 95% CIs, with significance at p<0.05.Results Of 2325 participants in TICH-2, 1152 had baseline SBP≤170 mm Hg and were older, had larger lobar haematomas and were randomised later than 1173 with baseline SBP>170 mm Hg. Tranexamic acid was associated with a favourable shift in mRS at day 90 in those with baseline SBP≤170 mm Hg (cOR 0.73, 95% CI 0.59 to 0.91, p=0.005), but not in those with baseline SBP>170 mm Hg (cOR 1.05, 95% CI 0.85 to 1.30, p=0.63). In those with baseline SBP≤170 mm Hg, tranexamic acid reduced haematoma expansion (OR 0.62, 95% CI 0.47 to 0.82, p=0.001), but not in those with baseline SBP>170 mm Hg (OR 1.02, 95% CI 0.77 to 1.35, p=0.90).Conclusions Tranexamic acid was associated with improved clinical and radiological outcomes in ICH patients with baseline SBP≤170 mm Hg. Further research is needed to establish whether certain subgroups may benefit from tranexamic acid in acute ICH.Trial registration number ISRCTN93732214.

Acute intracerebral hemorrhage is the most devastating stroke subtype and is associated with significant morbidity and mortality. Poor prognosis is associated with primary brain injury from the presenting hematoma, and despite advances in clinical trials of evacuation or reducing expansion, management is largely limited to supportive care and secondary prevention. Recent research has led to a better understanding of the pathophysiology of the cerebral edema surrounding the hematoma (perihematomal edema) and the identification of treatment targets and potential interventions. Some therapies have progressed to testing in phase 2 and 3 clinical trials, while novel agents are in development. This review focuses on the pathogenesis of perihematomal edema and its natural history and summarizes the results of potential interventions including preclinical and clinical studies. This review also lists the gaps in the current knowledge and suggests directions for future trials of perihematomal edema that could potentially change clinical practice.

Intensive antiplatelet therapy did not reduce recurrent stroke/transient ischaemic attack (TIA) events as compared with guideline treatment in the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial, but did increase the frequency and severity of bleeding. In this pre-specified analysis, we investigated predictors of bleeding and the association of bleeding with outcome. TARDIS was an international prospective randomised open-label blinded-endpoint trial in participants with ischaemic stroke or TIA within 48 h of onset. Participants were randomised to 30 days of intensive antiplatelet therapy (aspirin, clopidogrel, dipyridamole) or guideline-based therapy (either clopidogrel alone or combined aspirin and dipyridamole). Bleeding was defined using the International Society on Thrombosis and Haemostasis five-level ordered categorical scale: fatal, major, moderate, minor, none. Of 3,096 participants, bleeding severity was: fatal 0.4%, major 1.5%, moderate 1.2%, minor 11.4%, none 85.5%. Major/fatal bleeding was increased with intensive as compared with guideline therapy: 39 vs. 17 participants, adjusted hazard ratio 2.21, 95% CI 1.24–3.93, p = 0.007. Bleeding events diverged between treatment groups in the 8–35 day period but not in the 0–7 or 36–90 day epochs. In multivariate analysis more, and more severe, bleeding events were seen with increasing age, female sex, pre-morbid dependency, increased time to randomisation, prior major bleed, prior antiplatelet therapy and in those randomised to triple vs guideline antiplatelet therapy. More severe bleeding was associated with worse clinical outcomes across multiple physical, emotional and quality of life domains. Trial registration ISRCTN47823388 .

Background Half of patients who achieve successful recanalization following endovascular thrombectomy (EVT) for acute ischemic stroke experience poor functional outcome. We aim to investigate whether the use of adjunctive intra-arterial antithrombotic therapy (AAT) during EVT is safe and efficacious compared with standard therapy (ST) of EVT with or without prior intravenous thrombolysis. Methods Electronic databases were searched (PubMed/MEDLINE, Embase, Cochrane Library) from 2010 until October 2023. Data were pooled using a random-effects model and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias was assessed using ROBINS-I and ROB-2. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes were successful recanalization (modified Thrombolysis In Cerebral Infarction (TICI) 2b-3), symptomatic intracranial hemorrhage (sICH), and 90-day mortality. Results 41 randomized and non-randomized studies met the eligibility criteria. Overall, 15 316 patients were included; 3296 patients were treated with AAT during EVT and 12 020 were treated with ST alone. Compared with ST, patients treated with AAT demonstrated higher odds of functional independence (46.5% AAT vs 42.6% ST; OR 1.22, 95% CI 1.07 to 1.40, P=0.004, I2=48%) and a lower likelihood of 90-day mortality (OR 0.71, 95% CI 0.61 to 0.83, P<0.0001, I2=20%). The rates of sICH (OR 1.00, 95% CI 0.82 to 1.22,P=0.97, I2=13%) and successful recanalization (OR 1.09, 95% CI 0.84 to 1.42, P=0.52, I2=76%) were not significantly different. Conclusion The use of AAT during EVT may improve functional outcomes and reduce mortality rates compared with ST alone, without an increased risk of sICH. These findings should be interpreted with caution pending the results from ongoing phase III trials to establish the efficacy and safety of AAT during EVT.

Acute stroke is the leading cause of disability in the UK and a leading cause of mortality worldwide. The majority of patients with ischaemic stroke present with minor deficits or transient ischaemic attack (TIA), and are often first seen by patient-facing clinicians. Urgent evaluation and treatment are important as many patients are at high risk of major vascular events and death within hours to days after the index event. This narrative review summarises the evidence on four antiplatelet treatments for non-cardioembolic stroke prevention: aspirin, clopidogrel, dipyridamole and ticagrelor. Each of these drugs has a unique mechanism and has been tested as a single agent or in combination. Aspirin, when given early is beneficial and short-term treatment with aspirin and clopidogrel has been shown to be more effective in high-risk TIA / minor stroke. This review concludes by highlighting gaps in evidence, including scope for future trials that could potentially change clinical practice.

Abstract Background Prehospital stroke trials will inevitably recruit patients with non-stroke conditions, so called stroke mimics. We undertook a pre-specified analysis to determine outcomes in patients with mimics in the second Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2). Methods RIGHT-2 was a prospective, multicentre, paramedic-delivered, ambulance-based, sham-controlled, participant-and outcome-blinded, randomised-controlled trial of transdermal glyceryl trinitrate (GTN) in adults with ultra-acute presumed stroke in the UK. Final diagnosis (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic) was determined by the hospital investigator. This pre-specified subgroup analysis assessed the safety and efficacy of transdermal GTN (5 mg daily for 4 days) versus sham patch among stroke mimic patients. The primary outcome was the 7-level modified Rankin Scale (mRS) at 90 days. Results Among 1149 participants in RIGHT-2, 297 (26%) had a final diagnosis of mimic (GTN 134, sham 163). The mimic group were younger, mean age 67 (SD: 18) vs 75 (SD: 13) years, had a longer interval from symptom onset to randomisation, median 75 [95% CI: 47,126] vs 70 [95% CI:45,108] minutes, less atrial fibrillation and a lower systolic blood pressure and Face-Arm-Speech-Time tool score than the stroke group. The three most common mimic diagnoses were seizure (17%), migraine or primary headache disorder (17%) and functional disorders (14%). At 90 days, the GTN group had a better mRS score as compared to the sham group (adjusted common odds ratio 0.54; 95% confidence intervals 0.34, 0.85; p = 0.008), a difference that persisted at 365 days. There was no difference in the proportion of patients who died in hospital, were discharged to a residential care facility, or suffered a serious adverse event. Conclusions One-quarter of patients suspected by paramedics to have an ultra-acute stroke were subsequently diagnosed with a non-stroke condition. GTN was associated with unexplained improved functional outcome observed at 90 days and one year, a finding that may represent an undetected baseline imbalance, chance, or real efficacy. GTN was not associated with harm. Trial registration This trial is registered with International Standard Randomised Controlled Trials Number ISRCTN 26986053 .