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Abstract Background and aims Uncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date. Methods INTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP]

Abstract Endothelial progenitor cells (EPCs), expressing markers for stemness (CD34), immaturity (CD133) and endothelial maturity (KDR), may determine the extent of post-stroke vascular repair. Given the prevalence of stroke in elderly, this study explored whether variations in plasmatic availability of certain EPC subtypes could predict the severity and outcome of disease in older patients. Blood samples were collected from eighty-one consented patients (≥ 65 years) at admission and days 7, 30 and 90 post-stroke. EPCs were counted with flow cytometry. Stroke severity and outcome were assessed using the National Institutes of Health Stroke Scale, Barthel Index and modified Rankin Scale. The levels of key elements known to affect EPC characteristics were measured by ELISA. Diminished total antioxidant capacity and CD34 + KDR + and CD133 + KDR + counts in early phases of stroke were associated with disease severity and worse functional outcome at day 90 post-stroke. Baseline levels of angiogenic agent PDGF-BB, but not VEGF, positively correlated with CD34 + KDR + numbers at day 90. Baseline LDL-cholesterol levels were inversely correlated with CD34 + KDR+, CD133 + KDR + and CD34 + CD133 + KDR + numbers at day 90. Close correlation between baseline CD34 + KDR + and CD133 + KDR + counts and the outcome of stroke proposes these particular EPC subtypes as potential prognostic markers for ischaemic stroke.

Abstract 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 .

Abstract Objective Software developed using artificial intelligence may automatically identify arterial occlusion and provide collateral vessel scoring on CT angiography (CTA) performed acutely for ischemic stroke. We aimed to assess the diagnostic accuracy of e‐CTA by Brainomix™ Ltd by large‐scale independent testing using expert reading as the reference standard. Methods We identified a large clinically representative sample of baseline CTA from 6 studies that recruited patients with acute stroke symptoms involving any arterial territory. We compared e‐CTA results with masked expert interpretation of the same scans for the presence and location of laterality‐matched arterial occlusion and/or abnormal collateral score combined into a single measure of arterial abnormality. We tested the diagnostic accuracy of e‐CTA for identifying any arterial abnormality (and in a sensitivity analysis compliant with the manufacturer's guidance that software only be used to assess the anterior circulation). Results We include CTA from 668 patients (50% female; median: age 71 years, NIHSS 9, 2.3 h from stroke onset). Experts identified arterial occlusion in 365 patients (55%); most (343, 94%) involved the anterior circulation. Software successfully processed 545/668 (82%) CTAs. The sensitivity, specificity and diagnostic accuracy of e‐CTA for detecting arterial abnormality were each 72% (95% CI = 66–77%). Diagnostic accuracy was non‐significantly improved in a sensitivity analysis excluding occlusions from outside the anterior circulation (76%, 95% CI = 72–80%). Interpretation Compared to experts, the diagnostic accuracy of e‐CTA for identifying acute arterial abnormality was 72–76%. Users of e‐CTA should be competent in CTA interpretation to ensure all potential thrombectomy candidates are identified.

Introduction: Cognitive decline and mood disorders are two major concerns of people affected by stroke. The extent to which cognition and mood relate to or are independent of stroke severity and post-stroke dependency are unclear. We examined the associations between stroke severity, global measures of cognition, mood and dependency up to 14-weeks post-stroke in a large national study of neurocognitive complications of stroke up to two years, the Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) study. Methods: R4VaD recruited patients with stroke of all subtypes and severities and collected clinical, cognitive and mood data at baseline (within six-weeks post-stroke), subacutely (6+/-2 weeks later; ie. maximum 14-weeks post-stroke) and 1 and 2 years. We measured baseline stroke severity (National Institute of Health Stroke Scale, NIHSS), pre-stroke and 14-week dependency (Modified Rankin Scale, mRS), cognition (Montreal Cognitive Assessment, MoCA; Modified Telephone Interview for Cognitive Status, TICS-m), and mood (Zung depression scale; Patient Health Questionnaire, PHQ; General Anxiety Disorder scale, GAD-7). We analysed baseline and 14-week cognition and mood using linear models with log-transformed NIHSS, adjusted for mRS, age, sex, education, hypertension, diabetes and smoking. Results: We recruited 2441 participants (mean age=68.2 SD=13.5; 40% female; median NIHSS=2.0, IQR=0-4, range=0-24; median stroke onset to recruitment=6 days, IQR=3-13; median time to follow-up=6.6 weeks, IQR=6.0-7.9). Table 1 shows baseline and subacute cognition and mood scores. At baseline higher NIHSS associated with lower cognition (MoCA: β= -0.22, p

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.

IntroductionCerebral microbleeds (CMBs) are associated with white matter damage, and various neurodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility-weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate automated detection of CMBs would help to determine quantitative imaging biomarkers (e.g., CMB count) on large datasets. In this work, we propose a fully automated, deep learning-based, 3-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g., GRE/SWI/QSM) for their accurate detections.MethodsIn our method, the first step consists of an initial candidate detection step that detects CMBs with high sensitivity. In the second step, candidate discrimination step is performed using a knowledge distillation framework, with a multi-tasking teacher network that guides the student network to classify CMB and non-CMB instances in an offline manner. Finally, a morphological clean-up step further reduces false positives using anatomical constraints. We used four datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics.ResultsOn cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) of over 90% with an average of 80 % with different modalities. The python implementation of the proposed method is openly available.

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.

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.

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 .

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 p170 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.

Abstract Background Early pre-hospital initiation of blood pressure (BP) lowering could improve outcomes for patients with acute stroke, by reducing hematoma expansion in intracerebral hemorrhage (ICH), and time to reperfusion treatment and risk of intracranial hemorrhage in ischemic stroke (IS). We present the design of the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4). Methods A multi-center, ambulance-delivered, prospective, randomized, open-label, blinded endpoint (PROBE) assessed trial of pre-hospital BP lowering in 3116 hypertensive patients with suspected acute stroke at 50+ sites in China. Patients are randomized through a mobile phone digital system to intensive BP lowering to a target systolic BP of

Abstract Background Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. Methods Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan’s multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. Results Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. Conclusions Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Endogenous fibrinolysis might lead to hematoma progression in spontaneous intracerebral hemorrhage (ICH). We studied plasma biomarkers of fibrinolysis and hemostasis in twenty-two patients with ICH and nine healthy controls (HC) in a single-center study. Patients with ICH had significantly higher D-dimer and plasmin-alpha-2-antiplasmin complexes compared to HC. At baseline, patients with hematoma progression had higher urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) and lower plasminogen levels, compared to those with no progression. 24-hour and day-7 matrix metalloproteinase-9 (MMP-9) was significantly increased in patients with hematoma progression.

Ischemic stroke is a devastating, life altering event which can severely reduce patient quality of life. Despite years of research there have been minimal therapeutic advances. Endothelial progenitor cells (EPCs), stem cells involved in both vasculogenesis and angiogenesis, may be a potential therapeutic target. After a stroke, EPCs migrate to the site of ischemic injury to repair cerebrovascular damage, and their numbers and functional capacity may determine patients’ outcome. This study aims to determine whether the number of circulating EPCs and their functional aspects may be used as biomarkers to identify the type (cortical or lacunar) and/or severity of ischemic stroke. The study will also investigate if there are any differences in these characteristics between healthy volunteers over and under 65 years of age. 100 stroke patients (50 lacunar and 50 cortical strokes) will be recruited in this prospective, observational case-controlled study. Blood samples will be taken from stroke patients at baseline (within 48 hours of stroke) and days 7, 30 and 90. EPCs will be counted with flow cytometry. The plasma levels of pro- and anti-angiogenic factors and inflammatory cytokines will also be determined. Outgrowth endothelial cells will be cultured to be used in tube formation, migration and proliferation functional assays. Primary outcome is disability or dependence on day 90 after stroke, assessed by the modified Rankin Scale. Secondary outcomes are changes in circulating EPC numbers and/or functional capacity between patient and healthy volunteers, between patient subgroups and between elderly and young healthy volunteers. Recruitment started in February 2017, 167 participants have been recruited. Recruitment will end in November 2019. West Midlands - Coventry & Warwickshire Research Ethics Committee approved this study (REC number: 16/WM/0304) on September 8, 2016. Protocol version: 2.0. The Bayraktutan Dunhill Medical Trust EPC Study was registered in ClinicalTrials.gov (NCT02980354) on November 15, 2016. This study will determine whether the number of EPCs can be used as a prognostic or diagnostic marker for ischemic strokes and is a step towards discovering if transplantation of EPCs may aid patient recovery.

Summary: Background: It is not known whether to continue or temporarily stop existing antihypertensive drugs in patients with acute stroke. Methods: We performed a prospective subgroup analysis of patients enrolled into the Efficacy of Nitric Oxide in Stroke (ENOS) trial who were randomised to continue vs stop prior antihypertensive therapy within 12 h of stroke onset. The primary outcome was functional outcome, assessed with the modified Rankin Scale at 90 days by observers blinded to treatment assignment, and analysed with ordinal logistic regression. Findings: Of 4011 patients recruited into ENOS from 2001 to 2014, 2097 patients were randomised to continue vs stop prior antihypertensive treatment, and 384 (18.3%, continue 185, stop 199) were enrolled within 12 h of ictus: mean (SD) age 71.8 (11.8) years, female 193 (50.3%), ischaemic stroke 342 (89.1%) and total anterior circulation syndrome 114 (29.7%). As compared with stopping, continuing treatment within 12 h of onset lowered blood pressure by 15.5/9.6 mmHg (p

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g., blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g., the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline's generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (within-dataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.

Background: Lacunar stroke, a frequent clinical manifestation of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression. Methods: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25 mg bd, cilostazol 100 mg bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology, vascular function, and neuroimaging. LACI-1 was powered (80%, alpha 0.05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546. Findings: LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) females, mean age 66 (SD 11, range 40–85) years, onset-randomisation 203 (range 6–920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6.4, 95%CI 1.2–11.7, p = 0.02), platelet count higher (MD 35.7, 95%CI 2.8, 68.7, p = 0.03) and white matter hyperintensities reduced more (Chi-square p = 0.007) with cilostazol versus no cilostazol. Interpretation: Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified. Funding: Alzheimer's Society (AS-PG-14-033). Keywords: Lacunar stroke, Small vessel disease, Randomised controlled trial, Cilostazol, Isosorbide mononitrate, Endothelium, Blood–brain barrier, White matter hyperintensities, Cerebrovascular reactivity

Abstract Background For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet therapy modifies the risks of recurrent ICH, major haemorrhagic events, major occlusive vascular events, or a composite of all major vascular events compared to avoiding antiplatelet therapy. Methods/design The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, parallel group, open, assessor-blind, randomised trial comparing starting versus avoiding antiplatelet therapy for adults surviving antithrombotic-associated ICH. Recruitment began on 22 May 2013 and ended on 31 May 2018. Follow-up ended on 30 November 2018. This update to the protocol describes the statistical analysis plan (version 1.7, finalised on 25 January 2019). Database lock and un-blinding occurred on 29 January 2019, after which the un-masked trial statistician conducted the final analyses according to this statistical analysis plan. Discussion Final results of RESTART will be analysed and disseminated in May 2019. Trial registration ISRCTN registry 71907627. Prospectively registered on 25 April 2013.

Background: Central adjudication of stroke type is commonly implemented in large multicentre clinical trials. We investigated the effect of central adjudication of diagnosis of stroke type at trial entry in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Methods: ENOS recruited patients with acute ischaemic or haemorrhagic stroke, and diagnostic adjudication was carried out using cranial scans. For this study, diagnoses made by local site clinicians were compared with those by central, masked adjudicators using kappa statistics. The trial primary analysis and subgroup analysis by stroke type were re-analysed using stroke diagnosis made by local clinicians, and simulations were used to assess the impact of increased non-differential misclassification and subgroup effects. Results: Agreement on stroke type (Ischaemic, Intracerebral Haemorrhage, Unknown stroke type, No-stroke) was high (κ = 0.92). Adjudication of stroke type had no impact on the primary outcome or subgroup analysis by stroke type. With misclassification increased to 10 times the level observed in ENOS and a simulated subgroup effect present, adjudication would have affected trial conclusions. Conclusions: Stroke type at trial entry was diagnosed accurately by local clinicians in ENOS. Adjudication of stroke type by central adjudicators had no measurable effect on trial conclusions. Diagnostic adjudication may be important if diagnosis is complex and a treatment-diagnosis interaction is expected. Keywords: Adjudication, Diagnosis, Clinical trial, Stroke

Background Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. Methods and Results This is an exploratory analysis of the TICH‐2 (Tranexamic Acid in Intracerebral Hemorrhage‐2) double‐blind, randomized, placebo‐controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre‐ICH antiplatelet therapy, and 24‐hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre‐ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no‐antiplatelet group. Pre‐ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01–1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32–1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25–2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62–0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41–0.91) with no significant interaction between pre‐ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Conclusions Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.

Background: Thrombolysis, with or without thrombectomy, for acute ischaemic stroke is associated with an increased risk of intracranial bleeding. We assessed whether treatment with glyceryl trinitrate (GTN), a nitric oxide donor, may influence the associated bleeding risk.Methods: We searched for completed randomized controlled trials of GTN vs. no GTN in acute ischaemic stroke with data on reperfusion treatments (thrombolysis and/or thrombectomy). The primary efficacy outcome was functional status as assessed by the modified Rankin Scale (mRS) at day 90; the primary safety outcome was intracranial bleeding. Secondary safety outcomes included symptomatic intracranial hemorrhage and haemorrhagic transformation of infarction. Individual patient data were pooled and meta-analysis performed using ordinal or binary logistic regression with adjustment for trial and prognostic variables both overall and in those randomized within 6 h of symptom onset.Results: Three trials met the eligibility criteria. Of 715 patients with ischaemic stroke who underwent thrombolysis (709, >99%) or thrombectomy (24, 3.4%), 357 (49.9%) received GTN and 358 (50.1%) received no GTN. Overall, there was no difference in the distribution of the mRS at day 90 between GTN vs. no GTN (OR 0.94, 95% CI 0.72–1.23; p = 0.65); similarly, there was no difference in intracranial hemorrhage rates between treatment groups (OR 0.90, 95% CI 0.43–1.89; p = 0.77). In those randomized to GTN vs. no GTN within 6 h of symptom onset, there were numerically fewer bleeding events, but these analyses did not reach statistical significance.Conclusions: In ischaemic stroke patients treated predominantly with thrombolysis, transdermal GTN was safe, but did not influence functional outcome at 90 days.

Background: A transient ischaemic attack (TIA) and minor stroke are medical emergencies and often a warning sign of future strokes if remain untreated. Few studies have investigated the long-term psychosocial effects of TIA and minor stroke. Secondary prevention and medical management are often the primary focus with limited access offered for further psychosocial support. Psychoeducational interventions can provide education and advice to people with physical health conditions and, with suitable tailoring, could be appropriate for people after TIA and minor stroke. This study aims to develop a group psychoeducational intervention for people after TIA and minor stroke and to test whether it is acceptable and feasible. Methods: This mixed-methodology study involves two phases: Phase 1) A qualitative study to determine the content of a suitable intervention; Phase 2) A single-centre feasibility randomised controlled trial to evaluate the acceptability of this intervention. The overall study has ethical approval. Stroke survivors have been involved in designing and monitoring the trial. The aim is to recruit 30-40 participants from a Stroke/TIA Service, within 6 months following their diagnosis. Participants will be randomly allocated to either the usual care control group or the intervention group (psychoeducational programme). The programme will consist of six group sessions based on providing education, psychological and social support. The primary outcomes will relate to the feasibility aims of the study. Outcomes will be collected at 3 and 6 months to assess mood, quality of life, knowledge and satisfaction, and resource use. Discussion: There is a need to develop and evaluate effective interventions that enhance the education provided to people after TIA and minor stroke and to promote their psychosocial wellbeing. Findings will indicate the acceptability of the intervention and parameters needed to conduct a definitive trial. Registration: ClinicalTrials.gov ID NCT02550392; registered on 15 September 2015; status: completed.

Background: Artificial intelligence-based software may automatically detect ischaemic stroke lesions and provide an Alberta Stroke Program Early CT score (ASPECTS) on CT, and identify arterial occlusion and provide a collateral score on CTA. Large-scale independent testing will inform clinical use, but is lacking. We aim to test e-ASPECTS and e-CTA (Brainomix, Oxford UK) using CT scans obtained from a range of clinical studies. Methods: Using prospectively collected baseline CT and CTA scans from 10 national/international clinical stroke trials or registries (total >6600 patients), we will select a large clinically representative sample for testing e-ASPECTS and e-CTA compared to previously acquired independent expert human interpretation (reference standard). Our primary aims are to test agreement between software-derived and masked human expert ASPECTS, and the diagnostic accuracy of e-ASPECTS for identifying all causes of stroke symptoms using follow-up imaging and final clinical opinion as diagnostic ground truth. Our secondary aims are to test when and why e-ASPECTS is more or less accurate, or succeeds/fails to produce results, agreement between e-CTA and human expert CTA interpretation, and repeatability of e-ASPECTS/e-CTA results. All testing will be conducted on an intention-to-analyse basis. We will assess agreement between software and expert-human ratings and test the diagnostic accuracy of software. Conclusions: RITeS will provide comprehensive, robust and representative testing of e-ASPECTS and e-CTA against the current gold-standard, expert-human interpretation.

Background Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may protect the brain from ischemic reperfusion injury. Methods and Results We performed a phase IIb blinded dose‐escalation sham‐controlled trial in patients with hyperacute stroke, randomized 1:1 to receive RIC (four 5‐minute cycles) or sham to the nonparetic upper limb, in 3 blocks of increasing dose, starting within 6 hours of ictus. The primary outcome was trial feasibility (recruitment, attrition). Secondary outcomes included adherence, tolerability, safety (serious adverse events), plasma biomarkers at days 1 and 4 (S100‐ß protein, matrix metalloproteinase‐9, and neuron‐specific enolase), and functional outcome. Sixty participants were recruited from 2 centers (3 per month) with no loss to follow‐up: time to randomization 4 hours 5 minutes (SD 72 minutes), age 72 years (12), men 60%, blood pressure 154/80 mm Hg (25/12), National Institutes of Health Stroke Scale 8.4 (6.9), and 55% thrombolyzed. RIC was well tolerated with adherence not differing between RIC and sham, falling in both groups on day 3 (P=0.001, repeated measures ANOVA) because of discharge or transfer. S100ß increased in the sham group (mean rise 111 pg/mL [302], P=0.041, repeated measures ANCOVA) but not the RIC group. There were no differences in matrix metalloproteinase‐9, neuron‐specific enolase, number with serious adverse events (RIC 10 versus sham 10, P=0.81), deaths (2 versus 4, P=0.36), or modified Rankin Scale score (2 [interquartile range 1–4], 2 [interquartile range, 1–3]; P=0.85). Conclusions RIC in hyperacute stroke is feasible when given twice daily for 2 days and appears safe in a small population with hyperacute stroke. A larger phase III trial is warranted. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02779712.

Abstract Objective We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants’ spot sign status. Results Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients. Trial registration ISRCTN93732214 (http://www.isrctn.com)

Abstract Background For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs. Methods/design The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study). Discussion Final results of RESTART will be analysed and disseminated in 2019. Trial registration ISRCTN71907627 (www.isrctn.com/ISRCTN71907627). Prospectively registered on 25 April 2013.

Objective We report on: (1) the proportion of patients with known atrial fibrillation (AF); and (2) demographic, clinical or radiological differences between patients with known AF (and not treated) and patients with newly diagnosed AF, in a cohort of patients who presented with ischaemic stroke or transient ischaemic attack (TIA) not previously treated with anticoagulation.Design We reviewed cross-sectional baseline demographic and clinical data from a prospective observational cohort study, (CROMIS-2).Setting Patients were recruited from 79 hospital stroke centres throughout the UK and one centre in the Netherlands.Participants Patients were eligible if they were adults who presented with ischaemic stroke or TIA and AF and had not been previously treated with oral anticoagulation.Main outcome measures Proportion of patients with known AF before index ischaemic stroke or TIA from a cohort of patients who have not been previously treated with oral anticoagulation. Secondary analysis includes the comparison of CHA2DS2-VASc and HAS-BLED scores and other demographics and risk factors between those with newly diagnosed AF and those with previously known AF.Results Of 1470 patients included in the analysis (mean age 76 years (SD 10)), 622 (42%) were female; 999 (68%) patients had newly diagnosed AF and 471 (32%) patients had known AF. Of the 471 patients with known AF, 68% had a strong indication for anticoagulation and 89% should have been considered for anticoagulation based upon CHA2DS2-VASc score. Patients with known AF were more likely to have a prior history of dementia (4% vs 2%, p=0.02) and had higher HAS-BLED scores (median 3 vs 2). CHA2DS2-VASc, other risk factors and demographics were similar.Conclusions About 1/3 of patients who present with stroke and have AF who have not been treated with oral anticoagulation have previously known AF. Of these patients, at least 68% were not adequately treated with oral anticoagulation.Trial registration number NCT02513316.

Background: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. Objective: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). Design: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. Setting: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). Participants: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset. Exclusion criteria: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. Conclusions: Tranexamic acid did not affect a patient’s functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. Future work: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed. Trial registration: Current Controlled Trials ISRCTN93732214. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.

Background: Cilostazol and isosorbide mononitrate (ISMN) are candidate treatments for cerebral small vessel disease and lacunar ischaemic stroke. As both drugs may influence hemoglobin and platelet count, and hemodynamics, we sought to assess their effects in the lacunar intervention-1 (LACI-1) trial.Methods: Fifty-seven lacunar ischaemic stroke patients were randomized to immediate ISMN, cilostazol, or their combination for 9 weeks in addition to guideline stroke prevention. A fourth group received both drugs with a delayed start. Full blood count, platelet function, peripheral blood pressure (BP), heart rate and central hemodynamics (Augmentation index, Buckberg index) were measured at baseline, and weeks 3 and 8. Differences were assessed by multiple linear regression adjusted for baseline and key prognostic variables. Registration ISRCTN 12580546.Results: At week 8, platelet count was higher with cilostazol vs. no cilostazol (mean difference, MD 35.73, 95% confidence intervals, 95% CI 2.81–68.66, p = 0.033), but no significant differences were noted for hemoglobin levels or platelet function. At week 8, BP did not differ between the treatment groups, whilst heart rate was higher in those taking cilostazol vs. no cilostazol (MD 6.42, 95% CI 1.17–11.68, p = 0.017). Buckberg index (subendocardial perfusion) was lower in those randomized to cilostazol vs. no cilostazol and in those randomized to both drugs vs. either drug. Whilst ISMN significantly increased unadjusted augmentation index (arterial stiffness, MD 21.19, 95% CI 9.08–33.31, p = 0.001), in isolation both drugs non-significantly reduced augmentation index adjusted for heart rate.Conclusions: Cilostazol increased heart rate and platelet count, and reduced Buckberg index, whilst both drugs may individually reduce arterial stiffness adjusted for heart rate. Neither drug had clinically significant effects on hemoglobin or platelet function over 8 weeks. Further assessment of the safety and efficacy of these medications following lacunar ischaemic stroke is warranted.

Abstract Introduction: The Anti-fibrinolytics Trialists Collaboration aims to increase knowledge about the effectiveness and safety of anti-fibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of anti-fibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42019128260). We will conduct an individual patient data meta-analysis of randomised controlled trials with 500 patients or more assessing the effects of anti-fibrinolytics in acute intracranial haemorrhage. The primary outcomes will be 1) death from stroke or head injury within 30 days of randomisation, and 2) death from stroke or head injury, or dependency within 90 days of randomisation. The primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of anti-fibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of anti-fibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of anti-fibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.

Background There is concern that blood pressure (BP) lowering in acute stroke may compromise cerebral perfusion and worsen outcome in the presence of carotid stenosis. We assessed the effect of glyceryl trinitrate (GTN) in patients with carotid stenosis using data from the Efficacy of Nitric Oxide in Stroke (ENOS) Trial.Methods ENOS randomised 4011 patients with acute stroke and raised systolic BP (140–220 mm Hg) to transdermal GTN or no GTN within 48 hours of onset. Those on prestroke antihypertensives were also randomised to stop or continue their medication for 7 days. The primary outcome was the modified Rankin Scale (mRS) at day 90. Ipsilateral carotid stenosis was split:

Abstract Rationale Aside from blood pressure lowering, treatment options for intracerebral haemorrhage remain limited and a proportion of patients will undergo early haematoma expansion with resultant significant morbidity and mortality. Tranexamic acid (TXA), an anti-fibrinolytic drug, has been shown to significantly reduce mortality in patients, who are bleeding following trauma, when given rapidly. TICH-2 is testing whether TXA is effective at improving outcome in spontaneous intracerebral haemorrhage (SICH). Methods and design TICH-2 is a pragmatic, phase III, prospective, double-blind, randomised placebo-controlled trial. Two thousand adult (aged ≥ 18 years) patients with an acute SICH, within 8 h of stroke onset, will be randomised to receive TXA or the placebo control. The primary outcome is ordinal shift of modified Rankin Scale score at day 90. Analyses will be performed using intention-to-treat. Results This paper and its attached appendices describe the statistical analysis plan (SAP) for the trial and were developed and published prior to database lock and unblinding to treatment allocation. The SAP includes details of analyses to be undertaken and unpopulated tables which will be reported in the primary and key secondary publications. The database will be locked in early 2018, ready for publication of the results later in the same year. Discussion The SAP details the analyses that will be done to avoid bias arising from prior knowledge of the study findings. The trial will determine whether TXA can improve outcome after SICH, which currently has no definitive therapy. Trial registration ISRCTN registry, ID: ISRCTN93732214 . Registered on 17 January 2013.

Background: Two antiplatelet agents are better than one for preventing recurrent stroke after acute ischaemic stroke or transient ischaemic attack (TIA). Therefore, intensive treatment with three agents might be better still, providing it does not cause undue bleeding. Objective: To compare the safety and efficacy of intensive therapy with guideline antiplatelet therapy for acute ischaemic stroke and TIA. Design: International prospective randomised open-label blinded end-point parallel-group superiority clinical trial. Setting: Acute hospitals at 106 sites in four countries. Participants: Patients > 50 years of age with acute non-cardioembolic ischaemic stroke or TIA within 48 hours of ictus (stroke). Interventions: Participants were allocated at random by computer to 1 month of intensive (combined aspirin, clopidogrel and dipyridamole) or guideline (combined aspirin and dipyridamole, or clopidogrel alone) antiplatelet agents, and followed for 90 days. Main outcome measures: The primary outcome was the incidence and severity of any recurrent stroke (ischaemic, haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days by blinded telephone follow-up. Analysis using ordinal logistic regression was by intention to treat. Other outcomes included bleeding and its severity, death, myocardial infarction (MI), disability, mood, cognition and quality of life. Results: The trial was stopped early on the recommendation of the Data Monitoring Committee after recruitment of 3096 participants (intensive, n = 1556; guideline, n = 1540) from 106 hospitals in four countries between April 2009 and March 2016. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy in 3070 (99.2%) participants with data [93 vs. 105 stroke/TIA events; adjusted common odds ratio 0.90, 95% confidence interval (CI) 0.67 to 1.20; p = 0.47]. Major (encompassing fatal) bleeding was increased with intensive as compared with guideline therapy [39 vs. 17 participants; adjusted hazard ratio (aHR) 2.23, 95% CI 1.25 to 3.96; p = 0.006]. There were no differences between the treatment groups in all-cause mortality, or the composite of death, stroke, MI and major bleeding (aHR 1.02, 95% CI 0.77 to 1.35; p = 0.88). Limitations: Patients and investigators were not blinded to treatment. The comparator group comprised two guideline strategies because of changes in national guidelines during the trial. The trial was stopped early, thereby reducing its statistical power. Conclusions: The use of three antiplatelet agents is associated with increased bleeding without any significant reduction in recurrence of stroke or TIA. Future work: The safety and efficacy of dual antiplatelet therapy (combined aspirin and clopidogrel) versus aspirin remains to be defined. Further research is required on identifying individual patient response to antiplatelets, and the relationship between response and the subsequent risks of vascular recurrent events and bleeding complications. Trial registration: Current Controlled Trials ISRCTN47823388. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 48. See the NIHR Journal Library website for further project information. The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) vanguard phase was funded by the British Heart Foundation (grant PG/08/083/25779, from 1 April 2009 to 30 September 2012) and indirect funding was provided by the Stroke Association through its funding of the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. There was no commercial support for the trial and antiplatelet drugs were sourced locally at each site. The trial was sponsored by the University of Nottingham.

Introduction: The Antifibrinolytic Trialists Collaboration aims to increase knowledge about the effectiveness and safety of antifibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of antifibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42016052155). We will conduct an individual patient data meta-analysis of randomised controlled trials with 1000 patients or more assessing the effects of antifibrinolytics in acute intracranial haemorrhage. We will assess the effect on two co-primary outcomes: 1) Death in hospital within 30 days of randomisation, and 2) Death or dependency at final follow-up within 90 days of randomisation. The co-primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of antifibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of antifibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of antifibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.

Background and purposeCentral adjudication of serious adverse events (SAEs) can be undertaken in clinical trials, especially for open-label studies where outcome assessment may be at risk of bias. This study explored the effect of central adjudication of SAEs on the safety results of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial.MethodsENOS assigned patients with acute stroke at random to receive either transdermal glyceryl trinitrate (GTN) or no GTN and to Stop or Continue previous antihypertensive treatment. SAEs were reported by local investigators who were not blinded to treatment allocation. Central adjudicators, blinded to treatment allocation, reviewed the investigators reports and used evidence available to confirm or re-categorise the classification of event, likely causality, diagnosis and expectedness of event.ResultsOf 4011 patients enrolled in ENOS, 1473 SAEs were reported by local investigators; this was reduced to 1444 after the review by adjudicators, with 29 re-classified as not an SAE. There was fair agreement between investigators and adjudicators regarding likely causality, with 808 agreements and 644 disagreements (56% crude agreement, weighted kappa, κ = 0.31). Agreement increased upon dichotomisation of the causality categories, with 1432 agreements and 20 disagreements (99% crude agreement, kappa = 0.54). Repeating the main trial safety analysis with investigator reported events showed that adjudication had no effect on the main trial safety conclusions.ConclusionsIn a large trial, with many SAEs reported, central adjudication of these events did not affect trial conclusions. This suggests that adjudication of SAEs in a clinical trial where the intervention already has a well-established safety profile may not be necessary. Potential efficiency savings (financial, logistical) can be made through not adjudicating SAEs.

Introduction: The Antifibrinolytic Trialists Collaboration aims to increase knowledge about the effectiveness and safety of antifibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of antifibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42016052155). We will conduct an individual patient data meta-analysis of randomised controlled trials with 1000 patients or more assessing the effects of antifibrinolytics in acute intracranial haemorrhage. We will assess the effect on two co-primary outcomes: 1) death in hospital at end of trial follow-up, and 2) death in hospital or dependency at end of trial follow-up. The co-primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of antifibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of antifibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of antifibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.

BackgroundPregnant women may have an increased risk of stroke compared with nonpregnant women of similar age, but the magnitude and the timing of such risk are unclear. We examined the risk of a first stroke event in women of childbearing age and compared the risk during pregnancy and in the early postpartum period with the background risk outside these periods. Methods and ResultsWe conducted an open cohort study of 2 046 048 women aged 15 to 49 years between April 1, 1997, and March 31, 2014, using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care records in England. Risk of first stroke was assessed by calculating the incidence rate of stroke in antepartum, peripartum (2 days before until 1 day after delivery), and early (first 6 weeks) and late (second 6 weeks) postpartum periods compared with nonpregnant time using a Poisson regression model with adjustment for maternal age, socioeconomic group, and calendar time. A total of 2511 women had a first stroke. The incidence rate of stroke was 25.0 per 100 000 person‐years (95% CI 24.0–26.0) in nonpregnant time. The rate was lower antepartum (10.7 per 100 000 person‐years, 95% CI 7.6–15.1) but 9‐fold higher peripartum (161.1 per 100 000 person‐years, 95% CI 80.6–322.1) and 3‐fold higher early postpartum (47.1 per 100 000 person‐years, 95% CI 31.3–70.9). Rates of ischemic and hemorrhagic stroke both increased peripartum and early postpartum. ConclusionsAlthough the absolute risk of first stroke is low in women of childbearing age, healthcare professionals should be aware of a considerable increase in relative risk during the peripartum and early postpartum periods.

Background. The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation. Methods. Platelet function, assessed by remotely measured surface expression of P-selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values. Results. The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2–408.4) (2p

BACKGROUND:Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. METHODS:In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125-170 mmHg were assigned randomly to at least 6 months of intensive (target SBP

Background. Nitric oxide (NO) donors are a candidate treatment for acute stroke and two trials have suggested that they might improve outcome if administered within 4–6 hours of stroke onset. We assessed the safety and efficacy of NO donors using individual patient data (IPD) from completed trials. Methods. Randomised controlled trials of NO donors in patients with acute or subacute stroke were identified and IPD sought from the trialists. The effect of NO donor versus control on functional outcome was assessed using the modified Rankin scale (mRS) and death, by time to randomisation. Secondary outcomes included measures of disability, mood, and quality of life. Results. Five trials (4,197 participants) were identified, all involving glyceryl trinitrate (GTN). Compared with control, GTN lowered blood pressure by 7.4/3.3 mmHg. At day 90, GTN did not alter any clinical measures. However, in 312 patients randomised within 6 hours of stroke onset, GTN was associated with beneficial shifts in the mRS (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.34–0.78) and reduced death (OR 0.32, 95% CI 0.14–0.78). Conclusions. NO donors do not alter outcome in patients with recent stroke. However, when administered within 6 hours, NO donors might improve outcomes in both ischaemic and haemorrhagic stroke.

BACKGROUND:Granulocyte-colony stimulating factor (G-CSF) mobilises endogenous haematopoietic stem cells and enhances recovery in experimental stroke. Recovery may also be dependent on an enriched environment and physical activity. G-CSF may have the potential to enhance recovery when used in combination with physiotherapy, in patients with disability late after stroke. METHODS:A pilot 2 x 2 factorial randomised (1:1) placebo-controlled trial of G-CSF (double-blind), and/or a 6 week course of physiotherapy, in 60 participants with disability (mRS >1), at least 3 months after stroke. Primary outcome was feasibility, acceptability and tolerability. Secondary outcomes included death, dependency, motor function and quality of life measured 90 and 365 days after enrolment. RESULTS:Recruitment to the trial was feasible and acceptable; of 118 screened patients, 92 were eligible and 32 declined to participate. 60 patients were recruited between November 2011 and July 2013. All participants received some allocated treatment. Although 29 out of 30 participants received all 5 G-CSF/placebo injections, only 7 of 30 participants received all 18 therapy sessions. G-CSF was well tolerated but associated with a tendency to more adverse events than placebo (16 vs 10 patients, p = 0.12) and serious adverse events (SAE) (9 vs 3, p = 0.10). On average, patients received 14 (out of 18 planned) therapy sessions, interquartile range [12, 17]. Only a minority (23%) of participants completed all physiotherapy sessions, a large proportion of sessions (114 of 540, 21%) were cancelled due to patient (94, 17%) and therapist factors (20, 4%). No significant differences in functional outcomes were detected in either the G-CSF or physiotherapy group at day 90 or 365. CONCLUSIONS:Delivery of G-CSF is feasible in chronic stroke. However, the study failed to demonstrate feasibility for delivering additional physiotherapy sessions late after stroke therefore a definitive study using this trial design is not supported. Future work should occur earlier after stroke, alongside on-going clinical rehabilitation. TRIAL REGISTRATION:ISRCTN.com ISRCTN16714730.

Background. Assessing poststroke cognitive impairment is complex. A subscale of the NIHSS, the Cog-4, has been proposed as a quick test of “cognitive impairment.” but a study of its properties in a larger dataset is lacking. Methods. Data from 9,147 patients with acute stroke from the VISTA archive was used to generate Cog-4 scores. The statistical properties of Cog-4, its relationship with baseline clinical characteristics, and other functional outcome measures at day 90 were assessed. Results. Mean age of patients was 69.2 years and 45.8%, were females. Day-90 Cog-4 was highly positively skewed (skewness 0.926). Patients with left hemispheric stroke had higher day-90 Cog-4 score (P

Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.

Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke.A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p

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 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

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], >500 54.8%; clopidogrel test 429 [303, 656], >860 11.3%. 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.