Glyceryl trinitrate for treating hyperacute stroke: the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) feasibility randomised controlled trial

Glyceryl trinitrate for treating hyperacute stroke: the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) feasibility randomised controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Glyceryl trinitrate for treating hyperacute stroke: the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) feasibility randomised controlled trial Lisa J Woodhouse, Iris Mhlanga, Amanda Buck, Lucy Gray, Amanda Hedstrom, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7494203/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background High blood pressure is associated with a poor outcome after stroke. Trials of transdermal glyceryl trinitrate (GTN), a nitric oxide donor, have suggested that treatment between 3 and 5 hours might improve functional outcome. Methods We randomly assigned hospitalised patients with an acute ischaemic or haemorrhagic stroke to 2 days of transdermal glyceryl trinitrate (GTN, 5 mg/day) or sham, started between 3 and 5 hours after onset. The primary feasibility outcome was recruitment rate; proof of concept was assessed by central observers blinded to treatment assignment at 90 days using the modified Rankin Scale (mRS). Data are number (%), median [interquartile range] or mean (standard deviation). Comparisons by adjusted multiple linear regression. Findings 39 of an intended 120 participants were recruited; common exclusions were presentation >5 hours of onset or out of researcher working hours, no eligible symptoms/signs or an unclear onset time. Mean age 72 (13) years, female 41%, blood pressure 161.8(18.4)/80.8(14.9) mmHg, time from onset at baseline 216 [186, 251] minutes. The fall in blood pressure over 24 hours did not differ between GTN versus sham. Headache was more common with GTN but there was no difference in serious adverse events. mRS at 3 months did not differ between the groups. Interpretation Recruitment limitations prevented demonstration of feasibility for patients in the time window of 3-5 hours post ictus. GTN appeared safe and showed some evidence of proof-of-concept. A multicentre trial needs to further test this hypothesis. Registration ISRCTN17654248 Date: 31/3/2021 Clinical Pharmacology Neurology Internal Medicine Acute stroke blood pressure glyceryl trinitrate nitroglycerin randomised controlled trial Figures Figure 1 Figure 2 INTRODUCTION High blood pressure (BP) is present in 60% of patients with acute ischaemic stroke (AIS) or acute intracerebral haemorrhage (ICH) [ 1 ] and is associated with a worse outcome manifest as increased early recurrence or death and later death and dependency.[ 2 – 4 ] Lowering BP acutely after AIS might improve outcome providing that cerebral perfusion is not reduced in the presence of dysfunctional cerebral autoregulation. BP should not be lowered if already in the normal or low range since a U-shaped relationship exists between BP and outcome, i.e. low BP is also associated with poor outcome.[ 5 ] Lowering BP in ICH is associated with reduced haematoma expansion. Nitric oxide (NO) donors are candidate treatments for acute stroke through multiple potentially beneficial effects: NO is a vasodilator and so lowers BP and might improve cerebral perfusion; modulates endothelial, smooth muscle cell, platelet and leucocyte neuronal function; modulates neuronal function and is neuroprotective; and inhibits apoptosis. In preclinical studies of AIS, early administration of NO donors reduced infarct lesion size and improved regional cerebral blood flow and functional outcome.[ 6 – 8 ] Four small phase-2 trials of transdermal glyceryl trinitrate (GTN, also known as nitroglycerin [NTG], a NO donor) reported that GTN lowered systemic and 24-hour BP; did not alter platelet activity, middle cerebral artery blood flow velocity or regional cerebral blood flow; improved aortic compliance; could be given to patients with dysphagia; and was safe in patients with acute stroke.[ 9 – 12 ] When started within 4 hours of stroke onset, GTN was associated with improved functional outcome.[ 12 ] Three phase-3 randomised controlled trials of GTN have been reported. The large hospital-based ENOS trial recruited 4011 patients and had a recruitment time window of 48 hours. Although the trial was neutral overall,[ 13 ] the subgroup of participants treated within 6 hours of stroke onset appeared to benefit.[ 14 ] An individual patient data meta-analysis found that GTN appeared to be beneficial for both AIS and ICH when treatment was started within 6 hours.[ 15 ] Hence, a large pre-hospital ambulance-based trial, RIGHT-2, recruited 1149 patients with probable stroke within 4 hours (median 71 minutes). This trial was neutral overall [ 16 ] although patients with ICH (when treated within 2 hours) and AIS (when treated within one hour) appeared to fare worse whilst those with a stroke mimic had a better outcome.[ 17 , 18 ] Another prehospital trial, MR ASAP, randomised 325 patients up to 3 hours after stroke onset (median ~ 62 minutes) and was also neutral overall;[ 19 ] nevertheless, it too suggested outcome was worse in ICH with GTN. Taking the results together suggests that early but not too early treatment might be better, i.e. after 2 but before 6 hours. We report here the findings of the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) randomised controlled trial, the objective of which was to assess the feasibility, safety and proof of concept when GTN was administered between 3 and 5 hours after stroke onset. METHODS Trial design ENOS-2 was a prospective randomised sham-controlled blinded-endpoint parallel-group single-centre feasibility and proof-of-concept trial. In brief, patients with an acute stroke were randomised equally to two days of transdermal glyceryl trinitrate (GTN) or a sham patch. The trial broadly followed the design of ENOS [13] but without assessment of stopping versus continuing pre-stroke antihypertensive drugs. Patients Patients admitted with a clinical stroke syndrome due to ischaemia or haemorrhage to Nottingham University Hospitals NHS Trust, a comprehensive stroke centre, were eligible for the trial if they were: aged 18 or over; had a stroke syndrome comprising limb weakness, dysphasia, neglect or hemianopia; had systolic BP > 120 mmHg; and could be treated between 3 and 5 hours after onset. The diagnosis of ischaemic or haemorrhagic stroke was confirmed with computed tomography (CT) or magnetic resonance imaging (MRI) done before, or soon after, enrolment using standard techniques; the scan had to show acute ICH, AIS or be normal. Key exclusion criteria included: preceding severe dependency (modified Rankin scale, mRS 4 or 5); plasma glucose <3 mmol/l; coma (Glasgow Coma Scale < 8); witnessed seizure at presentation; known life expectancy <6 months; pure sensory symptoms; a condition mimicking stroke; other cause of intracranial haemorrhage; known allergy to GTN patch or sham dressing; planned for palliative care; recent use of a phosphodiesterase5-inhibitor; or previous enrolment in ENOS-2. Co-enrolment was allowed with mutually agreed trials: MAPS-2 (ISTRCTN40512746), OPTIMIST (clinicaltrials.com NCT03734640) and TICH-3 (ISRCTN97695350). Randomisation and masking Written informed consent was obtained from each patient, or from a relative or close friend if the patient lacked capacity, prior to enrolment and in accordance with UK regulations. Investigators entered baseline and follow-up data into a database via a secure Web-based randomisation system (https://stroke.nottingham.ac.uk/enos-2/live/enos-2_login.php). Data were checked to confirm the patient’s eligibility in real time, and the computer system then assigned a participant, with allocation 1:1, to treatment with GTN or sham. Treatment assignment comprised stratification on stroke type (IS, ICH) and minimisation on key prognostic baseline variables: age (>=72 years), severity (NIHSS>=10/42), time from onset to randomisation (>=4 hours), systolic blood pressure (>=160 mmHg) and candidate for or received reperfusion therapy (“no”); minimisation included a random element in 5% of patients. Minimisation were used to ensure that the groups were balanced for prognostic factors, and the random element reduced predictability. The randomisation algorithm then presented a treatment allocation as either ‘GTN’ or ‘No GTN’; GTN/sham were prescribed via the hospital system. Treatment Treatment was started immediately after randomisation, given daily for two days and consisted of a GTN transdermal patch (Transiderm, 5 mg) or a non-matching sham dressing (DuoDERM hydrocolloid, Convatec) with both covered by a gauze dressing to conceal allocation. The patch/dressing and gauze were changed daily (07.00-09.00 hours) with rotation of the site of placement on the shoulders or back. The dose of GTN was not adjusted during treatment and patches were left on for 24 hours, i.e. there was no overnight GTN-free period.[13] Study agents could be stopped if the patient withdrew consent, for safety reasons, or if unacceptable adverse events developed. Non-trial nitrates and other antihypertensive agents could not be given during the 2-day treatment period unless deemed necessary by the local investigator. Randomised treatment was given in addition to standard care; thrombolysis and/or mechanical thrombectomy were permitted in patients with AIS as per the admitting physician’s plan. Systematic use of antihypertensive agents (all patients, after 2 days), and oral antithrombotic and lipid lowering agents (patients with AIS) were recommended for secondary prevention. Assessments Demographic and clinical characteristics were recorded on-line during enrolment. The severity of the stroke was assessed with the National Institutes of Health stroke scale (NIHSS, range from 0 to 42, with higher scores indicating a more severe neurologic deficit) [20] at baseline, 2 days and discharge. BP was measured using a validated automated monitor as used routinely at the site. The final diagnosis was confirmed at the time of discharge/in-hospital death. The site was asked to provide a trained member of their research staff who was unaware of treatment assignment to perform post-randomisation in-hospital assessments. CT and MRI scans were evaluated using the routine hospital report as read by hospital neuroradiologists who were blinded to treatment; a natural language programme was used to confirm interpretation of the report. Investigator-reported serious adverse events, including cause-specific deaths, were validated by the Chief Investigator who were blinded to treatment assignment. Patients who did not receive their assigned treatment or who did not adhere to the protocol were followed up in full. Final follow-up was performed centrally at 90 days by telephone from the coordinating centre, blinded to treatment allocation. If the patient could not be contacted, a questionnaire covering the same outcome measures was sent by post. Outcome measures The primary outcomes were: feasibility assessed as recruitment of 120 participants (100 with AIS, 20 with ICH); mechanistic assessed as BP and heart rate; and clinical assessed as functional outcome using the modified Rankin Scale (mRS) at 90 days after enrolment.[21] Scores on the mRS range from 0 to 6, with a score of 0 indicating no symptoms, 5 severe dependency, and 6 death. Pre-specified secondary clinical outcomes included disability (Barthel index, BI [22]); cognition (telephone interview for cognition scale-modified, TICS-M [23]); mood (short Zung Depression Score, ZDS [24]); health-related quality of life (EuroQol-5 dimensions-5 levels, EQ-5D-5L, from which health utility status [HUS] using UK weightings was calculated, and EuroQoL-visual analogue scale, EQ-VAS); at 90 days. These outcomes were measured by central observers blinded to treatment assignment. At discharge from initial hospitalisation, duration of stay and discharge destination (to institution or home) were recorded. The safety outcomes of interest were serious adverse events (SAEs) up to day 2 (i.e., 48 hours after 1 st patch applied), fatal SAEs to day 90 and all-cause case fatality. Study oversight The trial was conceived and designed by the grant applicants, and they wrote the protocol (available at https://stroke.nottingham.ac.uk/enos-2/, last version 4 dated 1 March 2024). The study was approved by the Northwest – Greater Manchester South Research Ethics Committee / UK Health Research Authority (20/NW/0246, 30 June 2020), the Medicines & Healthcare products Regulatory Agency (CTA 03057/0072/001-0001, 24 August 2020) and was adopted by the UK NIHR Clinical Research Network. The trial was funded by a grant from the Nottingham University Hospitals Charity (CRF-BATH-NOV 2019), sponsored by the University of Nottingham and registered: ISRCTN17654248 (31 March 2021), EudraCT 2020-001304, IRAS 281728, WHO U1111-1259-7057. The trial was overseen by a Trial Steering Committee (which included 3 independent members) and conducted by the Trial Management Committee based at the coordinating centre in Nottingham. An independent Data Monitoring Committee reviewed unblinded data approximately annually. There was no commercial support for the trial. Study data were monitored and analysed by the ENOS-2 Coordinating Centre. Analysis, interpretation, and report writing were performed independent of the funders and sponsor. The corresponding author wrote the first draft of the manuscript, with input from the writing committee, all of whom approved the decision to submit the manuscript for publication. The corresponding author and statisticians (LJW, IM) had full access to all the data in the study; additionally, the corresponding author had final responsibility for the decision to submit for publication and is the guarantor for the study. Statistical analyses Since ENOS-2 was a feasibility study, there was no formal sample size calculation. However, recruitment of 100 patients with AIS and 20 with ICH would provide sufficient information on feasibility, safety and proof of concept (PoC). With a sample size of 100 and assuming alpha = 0.05, power 0.80 and mRS distribution as in ENOS-Early,[14] an adjusted common odds ratio of 0.51 for mRS would be detectable in PoC analyses. Statistical analyses of the effect of the treatments on clinical outcomes were planned to be analysed using adjusted binary logistic regression, Cox proportional hazards regression (for time to events, e.g. death), ordinal logistic regression and multiple linear regression, with adjustment for the randomisation factors used in stratification and minimisation.[25] The mRS would be reported as a common odds ratio with 95% confidence intervals and calculated using ordinal logistic regression. For sensitivity purposes, the primary analyses were also to be analysed unadjusted, and as a binary outcome (death or dependency, mRS >2). We would assess the heterogeneity of the treatment effects on the primary outcome in pre-specified subgroups by adding an interaction term to an unadjusted ordinal logistic regression model. Death was to be analysed using Kaplan-Meier and Cox regression models. A global outcome assessing original data from the mRS, BI, TCS-M, EQ-5D-5L, death and SAEs was to be analysed using the Wei-Lachin test.[26] Since outcomes such as mRS, EQ-5D-HUS and BI include death (scores of 6, 0 and -5 respectively) and in case treatment was associated with asymmetric effects on death and other outcome measures (e.g. more death and less impairment), an extreme value for death would be added to the other outcome scales: EQ-VAS -1, t-MMSE -1, SSS -1, TICS-M -1, ZDS 102.5, DSRS 13. The nominal level of significance for all analyses was P<0.05 since no interim analysis were to be performed. No adjustments were to be made for multiplicity of testing. Data would be shown as number (%), median [interquartile range] or mean (standard deviation). As a feasibility trial, no interim analyses or efficacy/futility stopping rules were set. Due to the paucity of recruited participants, the analyses specified in the SAP were restricted. First, tabulations were abbreviated to avoid reporting an excess number of variables. Second, unadjusted rather than adjusted analyses (using the stratification and minimisation variables) were performed to avoid failure of regression convergence and statistical over-fitting. Third, we used Fisher’s Exact test to analyse binary variables where one group had zero/very low numbers of events. Last, analyses in subgroups were not performed. Analyses were performed with SAS software (SAS Institute, Cary, North Carolina USA, version 9.4) according to the intention-to-treat principle. RESULTS Study patients Between September 2021 and June 2024, 39 patients were included (GTN 21, no GTN 18) at 1 UK site (Figure 1). Two interruptions to recruitment occurred due to lack of investigational drugs (Supplemental Figure 1). Eight protocol amendments were made (Supplemental Table 1). The trial ceased when the last batch of GTN patches went out of date. More than 1,400 patients were excluded (Supplemental Table 2). Seven consultant stroke physicians, two registrars and two allied health professionals on the trial log recruited the participants, with two of these recruiting more than 50% (Supplemental Figure 2). Baseline characteristics were well balanced between the treatment groups at baseline (Table 1). The mean (standard deviation) age was 72.3 (13.2) years, females 16 (41.0%), median [IQR] symptom onset to randomisation 216 [186-251] minutes (27, 69.2% recruited within 4 hours of onset), and NIHSS score 9.1 (6.3). The final diagnosis was AIS 33 (84.6%), ICH 1 (2.6%), transient ischaemic stroke (TIA) 4 (10.3%) and functional mimic 1 (2.6%). Consent was provided by 24 (61.5%) participants and proxy assent by 13 (33.3%) relatives or close friends 8 (20.5%) (Supplemental Table 3); emergency waiver of consent was used in 2 (5.1%) participants. A majority of neuroimaging was normal 21 (53.8%) at baseline with the remaining scans showing ischaemic 16 (41.0%) or haemorrhagic 1 (2.6%) changes (Supplemental Table 4). Evidence of previous stroke, atrophy and/or white matter disease was present in a minority of participants. Feasibility Altogether, 39 (32.5%) patients were recruited of an intended 120 (Table 2). The trial struggled to recruit for multiple reasons, these including factors internal to the trial design and protocol such as a significant number of participants who presented >5 hours after onset and those with no eligible symptoms or unknown/unclear time of onset (Supplemental Table 2). External non-protocol-related factors included lack of IMP on two occasions, presentation out-of-hours when no research staff were present and an unwillingness by some medical staff to have the trial offered to their patients due to perceived safety concerns, especially prior to potential mechanical thrombectomy (although no such concerns were identified by the DMC). Adherence Adherence with GTN versus no GTN was good with 37 (94.9%) participants receiving their first treatment and 33 (84.6%) both patches/dressings as randomised (Supplemental Table 5). There were no differences in the use of secondary antihypertensive drugs over the first two days between the two groups (Supplemental Table 6). Blood pressure The mean BP at baseline was 161.8/80.8 mmHg and fell in both GTN and no GTN groups over the 2 days of treatment (Supplementary Table 7). However, following the first dose of treatment, BP fell more with the first treatment in the sham group than in the GTN group; difference in means 17.2 (95% CI 1.2-33.3) / 5.8 (95% CI -1.37-12.9) mmHg with Sham vs 13.2 (1.4-24.9) / 0.31 (-10.0-10.6) mmHg with GTN. Nevertheless, BP did not differ at day 1 between the groups. The frequency of clinical hypotension (4 cases each, all reported as SAEs) and clinical hypertension (GTN 1, sham 2) did not differ by day 2 (Table 3). Baseline heart rate started at 81.9 bpm. In both groups, heart rate fell then increased over the first day although the initial fall was less in the control group (p=0.052) (Supplementary Table 6). Clinical outcomes There were no significant differences in death, clinical neurological deterioration, recurrent stroke, symptomatic haemorrhage or swallowing impairment at day 2 (Table 3). NIHSS at day 2 was non-significantly lower GTN 4.1 (4.2) vs sham 10.5 (13.7), p=0.053. Hospital length of stay and death in hospital or not discharged home did not differ between GTN and sham. By day 90, there were no statistical differences in dependence (mRS, Figure 2), death, disability (BI), quality of life (EQ-5D-5L, EQ-VAS) or mood (ZDS) (Table 3). Nevertheless, less cognitive impairment, measured using the TICS-M (p=0.020) and verbal fluency (animal naming) (p=0.058), was seen with GTN. Serious adverse events Although the number of participants with one or more SAEs did not differ with eight in each group (Table 3) there were less SAEs in the GTN group (9) than the sham group (15) (Table 4). The majority occurred during treatment and four in each group were considered to be possibly, probably or definitely related to treatment. No fatal SAEs were considered to be associated with treatment. One death occurred in the GTN group and was related to sepsis; the sham group had three deaths related to the nervous system and one to the respiratory system (Table 4). DISCUSSION ENOS-2 assessed the effect of GTN vs sham in patients with acute stroke within a narrow time window defined by apparent safety concerns with GTN when given before 2 hours of stroke onset [ 16 , 17 , 27 ] and futility beyond 6 hours.[ 13 , 15 ] The trial found that feasibility was challenged by multiple recruitment causes, some internal to the trial design and some external, such that only 39 of 120 planned participants were recruited. However, GTN appeared safe with tendencies to fewer deaths and SAEs and less cognitive impairment. External factors potentially relate to issues at a single centre with lack of equipoise by some clinicians. Hence, it cannot necessarily be concluded that a further study is not warranted particularly if future testing was done across several sites. A multicentre design would have been more robust but was not feasible due to the limited funding available. Such testing is remains desirable since the present data are still compatible with the positive findings seen for treatment in the range 3–5 hours after onset (Supplemental Fig. 2).[ 12 – 15 ] The findings that GTN did not lower BP are surprising for a vasodilator and not easily explained since all previous GTN trials have found that it lowered BP; chance due to the limited sample size may explain this, i.e. type II error. Nevertheless, GTN did raise heart rate as would be expected for a mixed venous and arterial dilator. The present trial has several strengths. First, it was randomised in design and used a sham treatment in contrast to earlier GTN trials. Second, the trial was a pragmatic test of real-world approaches to BP management since recruitment could be started in the Emergency Department prior to neuroimaging. Third, participants could have stroke of varying characteristics: ischaemic or haemorrhagic; severe or mild; cortical or lacunar; and anterior or posterior circulation. Fourth, outcomes were measured centrally masked to treatment assignment by observers who were not involved with clinical care. Last, transdermal administration of a drug in acute stroke is advantageous since it can be started immediately, is not confounded by dysphagia which limits the immediate use of oral treatment, does not need intravenous access and so does not need intensive monitoring, and can be stopped and re-started according to clinical need. Nevertheless, there are several limitations present. First, the final trial size was much smaller at 39 than the intended 120 participants. Some of the explanations are unrelated to the protocol and might be resolved in a multicentre design. One concern that GTN might be unsafe in patients proceeding to mechanical thrombectomy cannot be assessed due to the limited number (5) of these procedures (Supplemental Table 6). Second, the trial recruited from one site only and so is not generalisable to other sites or countries. Third, a key limitation was the narrow time-window of 3–5 hours after stroke onset although this was deliberate on the basis of previous data. Fourth, some patients assigned to GTN did not receive it for the protocolised 2 days of treatment. And fifth, some outcomes (cognition, mood) could not be measured in all participants at day 90 so further limiting the power of some statistical analyses. In conclusion, feasibility was not demonstrated and, surprisingly, GTN did not appear to lower BP. Nevertheless, GTN was safe and point estimates for treatment effects were all in a direction supporting benefit. A meta-analysis of the three trials that have examined the effect of GTN on mRS (ENOS-1/2, RIGHT-2) in the time window of 3–5 hours suggests efficacy: mean difference − 0.45 (95% CI -0.91, 0.02), p = 0.06 with no heterogeneity (Supplemental Fig. 3). Since the results support, potentially, the use of GTN in hyperacute stroke, a multicentre trial testing GTN in the time window of 3–5 hours is now warranted. Abbreviations BP blood pressure EQ-VAS European quality of life-visual analogue scale GTN glyceryl trinitrate HUS health utility status mRS modified Rankin scale NIHSS National Institutes of Health Stroke Scale PICH primary intracerebral haemorrhage RAAS renin-angiotensin-aldosterone system SSS Scandinavian Stroke Scale TICS-M modified-Telephone Interview for Cognition Scale t-MMSE telephone Mini-Mental State Examination Declarations Data availability The dataset generated during the current study are not currently publicly available due their integration into an update of our individual patient data metaanalysis. They will be shared with the VISTA Collaboration:[1] https://www.virtualtrialsarchives.org PMB is Stroke Association Professor of Stroke Medicine and is an emeritus NIHR Senior Investigator; he was chief investigator of ENOS, RIGHT and RIGHT-2. He has received honoraria from CoMind, DiaMedica and Phagenesis and holds stock options in DiaMedica. The remaining authors have no declarations. Acknowledgements We thank the research staff in Nottingham for their support and the Nottingham University Hospitals NHS Trust Charity which was the primary funder. We also thank Professor Pip Logan for access to her NIHR Senior Investigator award to facilitate NIHR eligibility and access to research coordinators. ENOS-2 acknowledges the support of the UK National Institute for Health and Care Research (NIHR) for support through the clinical research network. Author contributions Conceptualisation: Philip Bath, Nikola Sprigg, Timothy England, Lisa Woodhouse, Kailash Krishnan Methodology - Study coordinators: Amanda Buck, Lucy Gray, Amanda Hedstrom, Camille Hutchinson Analysis: Lisa J Woodhouse, Iris Mhlanga Writing – original draft preparation: Philip Bath Writing – review and editing: Philip Bath, Nikola Sprigg, Timothy England, Lisa Woodhouse, Kailash Krishnan, Iris Mhlanga, Tiffany Hamilton, Diane Havard Funding acquisition: Philip Bath, Nikola Sprigg, Timothy England, Lisa Woodhouse, Kailash Krishnan Resources: Tiffany Hamilton, Diane Havard Supervision: Philip Bath, Kailash Krishnan Data availability The dataset generated during the current study are not currently publicly available due their integration into an update of our individual patient data metaanalysis. They will be shared with the VISTA Collaboration. References Leonardi-Bee J, Bath PMW, Phillips SJ, Sandercock PAG, for the IST Collaborative Group. 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Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824). Stroke. 2013;44(11):3120-8. DOI: 10.1161/STROKEAHA.113.001301 Enos Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. Lancet. 2015;385(9968):617-28. DOI: 10.1016/S0140-6736(14)61121-1 Woodhouse L, Scutt P, Krishnan K, Berge E, Gommans J, Ntaios G, et al. Effect of hyperacute administration (within 6 hours) of transdermal glyceryl trinitrate, a nitric oxide donor, on outcome after stroke: subgroup analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Stroke. 2015;46:3194-201. DOI: Bath PM, Woodhouse L, Krishnan K, Anderson C, Berge E, Ford GA, et al. Effect of Treatment Delay, Stroke Type, and Thrombolysis on the Effect of Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome after Acute Stroke: A Systematic Review and Meta-Analysis of Individual Patient from Randomised Trials. Stroke Res Treat. 2016;2016:9706720. DOI: 10.1155/2016/9706720 Right-2 Investigators. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. Lancet. 2019;393(10175):1009-20. DOI: 10.1016/S0140-6736(19)30194-1 Bath PM, Woodhouse LJ, Krishnan K, Appleton JP, Anderson CS, Berge E, et al. Prehospital Transdermal Glyceryl Trinitrate for Ultra-Acute Intracerebral Hemorrhage: Data From the RIGHT-2 Trial. Stroke. 2019;50(11):3064-71. DOI: 10.1161/STROKEAHA.119.026389 Tunnage B, Woodhouse LJ, Dixon M, Anderson C, Ankolekar S, Appleton J, et al. Pre-hospital transdermal glyceryl trinitrate in patients with stroke mimics: data from the RIGHT-2 randomised-controlled ambulance trial. BMC emergency medicine. 2022;22(1):2. DOI: 10.1186/s12873-021-00560-x van den Berg SA, Uniken Venema SM, Reinink H, Hofmeijer J, Schonewille WJ, Miedema I, et al. Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial. Lancet Neurol. 2022;21(11):971-81. DOI: 10.1016/S1474-4422(22)00333-7 Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke. 1994;25(11):2220-6. DOI: 10.1161/01.str.25.11.2220 Lees KR, Bath PMW, Schellinger PD, Kerr DM, Fulton R, Hacke W, et al. Contemporary outcome measures in acute stroke research: choice of primary outcome measure Stroke 2012;43(4):1163-70. DOI: Sulter G, Steen C, de Keyser J, 1540. Use of the Barthel Undex and modified Rankin Scale in acute stroke trials. Stroke. 1999;30:1538-41. DOI: Desmond DW, Tatemichi TK, Hanzawa L. The telephone interview for cognitive status (TICS): Reliability and validity in a stroke sample. International Journal of Geriatric Psychiatry. 1994;9:803-07. DOI: Zung WWK. A self-rating depression scale. Arch Gen Psychiatry. 1965;12:63-70. DOI: Weir CJ, Lees KR. Comparison of stratification and adaptive methods for treatment allocation in an acute stroke clinical trial. StatMed. 2003;22:705-26. DOI: Lachin JM. Applications of the Wei-Lachin multivariate one-sided test for multiple outcomes on possibly different scales. PLoS One. 2014;9(10):e108784. DOI: 10.1371/journal.pone.0108784 Appleton JP, Woodhouse LJ, Anderson CS, Ankolekar S, Cala L, Dixon M, et al. Prehospital transdermal glyceryl trinitrate for ultra-acute ischaemic stroke: data from the RIGHT-2 randomised sham-controlled ambulance trial. Stroke Vasc Neurol. 2024;9(1):38-49. DOI: 10.1136/svn-2022-001634 Everton LF, Benfield JK, Hedstrom A, Wilkinson G, Michou E, England TJ, et al. Psychometric assessment and validation of the dysphagia severity rating scale in stroke patients. Sci Rep. 2020;10(1):7268. DOI: 10.1038/s41598-020-64208-9 de Jager CA, Budge MM, Clarke R. Utility of TICS-M for the assessment of cognitive function in older adults. Int J Geriatr Psychiatry. 2003;18(4):318-24. DOI: 10.1002/gps.830 Tables Table 1. Baseline characteristics of the patients: glyceryl trinitrate versus no glyceryl trinitrate Data are number (%), median [interquartile range] or mean (standard deviation). Characteristic N All GTN Sham Number of patients 39 21 18 Age (years) † 39 72.3 (13.2) 71.0 (11.5) 73.7 (15.1) Sex, female (%) 39 16 (41.0) 9 (42.9) 7 (39.9) Ethnicity Asian 39 2 (5.1) 2 (9.5) 0 (0.0) White 39 37 (94.9) 19 (90.5) 18 (100.0) Time to randomisation (min) † 39 216 [186, 251] 218 [192, 264] 196 [186, 245] 0 (%) 39 0.0 [0.0, 1.0] 0.0 [0.0, 1.0] 1.0 [0.0, 1.0] Medical history (%) Treated hypertension 39 24 (61.5) 11 (52.4) 13 (72.2) ACE-Inhibitor 39 13 (33.3) 4 (19.0) 9 (50.0) Angiotensin-II receptor antagonist 39 5 (12.8) 3 (14.3) 2 (11.1) Alpha-blocker 39 2 (5.1) 1 (4.8) 1 (5.6) Beta Blocker 39 8 (20.5) 4 (19.0) 4 (22.2) Calcium channel blocker 39 9 (23.1) 4 (19.0) 5 (27.8) Diuretic 39 4 (10.3) 2 (9.5) 2 (11.1) Renin 39 1 (2.6) 0 (0.0) 1 (5.6) Other antihypertensives 39 2 (5.1) 1 (4.8) 1 (5.6) Stroke 39 10 (25.6) 5 (23.8) 5 (27.8) Transient ischaemic attack 38 7 (18.4) 3 (15.0) 4 (22.2) Ischaemic heart disease 39 8 (20.5) 4 (19.0) 4 (22.2) Diabetes mellitus 39 9 (23.1) 6 (28.6) 3 (16.7) Hyperlipidaemia 39 15 (38.5) 8 (38.1) 7 (38.9) Smoking, current (%) 37 9 (24.3) 7 (33.3) 2 (11.1) Alcohol >21 units per week 36 3 (7.7) 2 (9.5) 1 (5.6) AF, current/previous 39 7 (17.9) 4 (19.0) 3 (16.7) COVID-19, definite/possible 39 3 (7.7) 2 (9.5) 1 (5.6) Nitrate use before stroke 39 2 (5.1) 2 (9.5) 0 (0.0) Side of lesion, right (%) 32 18 (56.3) 8 (44.4) 10 (71.4) NIHSS (/42) † 39 9.1 (6.3) 7.6 (4.2) 10.9 (7.9) GCS <15 (%) 39 11 (28.2) 5 (23.8) 6 (33.3) OCSP classification (%) Total anterior 39 11 (28.2) 5 (23.8) 6 (33.3) Partial anterior 39 18 (46.2) 9 (42.9) 9 (50.0) Lacunar 39 10 (25.6) 7 (33.3) 3 (16.7) Posterior 39 0 (0.0) 0 (0.0) 0 (0.0) Qualifying event ∑ Ischaemic stroke (%) ‡ 39 33 (84.6) 19 (90.5) 14 (77.8) Cardioembolic 33 12 (36.4) 7 (36.8) 5 (35.7) Large vessel 33 8 (24.2) 3 (15.8) 5 (35.7) Small vessel 33 6 (18.2) 4 (21.1) 2 (14.3) Other 33 9 (27.3) 6 (31.6) 3 (21.4) Not determined 33 1 (3.0) 0 (0.0) 1 (7.1) Primary intracerebral haemorrhage 39 1 (2.6) 1 (4.8) 0 (0.0) Transient ischaemic attack 39 4 (10.3) 1 (4.8) 3 (16.7) Stroke mimic 39 1 (2.6) 0 (0.0) 1 (5.6) ƒ AF: atrial fibrillation; BP: blood pressure; bpm: beats per minute; GCS: Glasgow Coma Scale; ICH: intracerebral haemorrhage; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; OCSP: Oxfordshire Community Stroke Project classification. Data are number (%), median [interquartile range], or mean (standard deviation). Percentages exclude missing values from denominators. Unused antihypertensive drug classes are not shown. In a post hoc analysis, the NIHSS did not differ between GTN and sham: -3.3 (95% CI -7.32, 0.72), p=0.11. † Minimisation variable ‡ Stratification variable ƒ Functional neurological disorder ¶ Sum may exceed 100% because of mixed aetiology. ∑ Qualifying event is determined by investigator by discharge. Table 2. Feasibility measures. Data are number (%). Measure Metric Achieved (%) Recruitment Overall 39/120 (32.5) Target patients 100 with ischaemia 37/100 (37.0) 20 with ICH 1/20 (5.0) Primary Retention of enrolees at Day 90 (follow-up) >70/120 (58.3) 38/39 (97.4) Treatment compliance/ adherence Received GTN/sham All 2 days treatment 33/39 (84.6) First day treatment 37/39 (94.9) Co-enrolment MAPS-2 3 OPTIMIST 1 TICH-3 1 5/39 (12.8) Table 3. Outcomes at days 2 and 90: glyceryl trinitrate versus no glyceryl trinitrate. Data are number of patients (%), median [interquartile range], or mean (standard deviation) score. Comparison by Fisher’s exact test, Mann-Whitney U-test or unadjusted cox proportional hazards, logistic regression, linear regression, shown as odds ratio (OR, with 95% confidence intervals), hazard ratio (HR), difference in medians (DIM), percentage difference (PD) or mean difference (MD). Outcome N All GTN Sham DIM/HR/MD/PD/OR (95% CI) 2p Participants 39 39 21 18 Day 2 (or discharge) Death, all cause (%) 39 1 (2.6) 0 (0.0) 1 (5.6) -5.56 (-16.14, 5.03) 0.46 § Clinical neurological deterioration (%) ‡ 39 2 (5.1) 0 (0.0) 2 (11.1) -11.11 (-25.63, 3.41) 0.21 § Recurrent stroke (%) ‡ 39 1 (2.6) 1 (4.8) 0 (0.0) 4.76 (-4.35, 13.87) 1.00 § Symptomatic ICH (%) ‡ 39 1 (2.6) 0 (0.0) 1 (5.6) -5.56 (-16.14, 5.03) 0.46 § Clinical hypotension (%) ‡ 39 8 (20.5) 4 (19.0) 4 (22.2) -3.17 (-28.69, 22.34) 1.00 § Clinical hypertension (%) ‡ 39 3 (7.7) 1 (4.8) 2 (11.1) -6.35 (-23.49, 10.79) 0.59 § Headache (%) ‡ 39 7 (17.9) 6 (28.6) 1 (5.6) 23.02 (0.99, 45.05) 0.098 § NIHSS (/43) 33 7.0 (10.1) 4.1 (4.2) 10.5 (13.7) -6.36 (-12.79, 0.08) 0.053 Dysphagia severity rating scale (/13) 39 2.4 (4.2) 2.0 (3.7) 3.0 (4.9) -1.00 (-3.66, 1.66) 0.46 Discharge data Hospital stay after randomisation (days) 39 5.0 [1.0, 13.0] 7.0 [1.0, 20.0] 4.0 [1.0, 10.0] 3.00 (-6.31, 12.31) 0.39 Death or not discharged home (%) 39 7 (17.9) 2 (9.5) 5 (27.8) 0.27 (0.05, 1.63) 0.15 Day 90 modified Rankin Scale (/6) 38 2.9 (1.8) 2.8 (1.7) 3.0 (1.8) -0.20 (-1.30, 0.90) 0.72 Death (%) 39 5 (12.8) 1 (4.8) 4 (22.2) 0.21 (0.02, 1.92) 0.17 Barthel Index (/100) 38 72.0 (38.8) 71.8 (35.8) 72.2 (43.0) -0.47 (-24.88, 23.93) 0.97 t-MMSE score (/22) 31 16.1 (7.8) 18.2 (5.7) 14.2 (9.2) 4.01 (-1.23, 9.25) 0.13 TICS-M score (/39) 31 20.2 (10.6) 24.3 (8.5) 16.3 (11.0) 8.02 (1.27, 14.78) 0.020 Verbal fluency (animal naming) 32 14.9 (9.6) 18.1 (8.5) 12.1 (9.8) 6.01 (-0.20, 12.21) 0.058 EQ-5D-5L 38 0.5 (0.3) 0.5 (0.4) 0.5 (0.3) 0.02 (-0.20, 0.24) 0.85 EQ-visual analogue scale 37 56.6 (29.5) 62.2 (26.7) 50.8 (31.9) 11.43 (-6.96, 29.82) 0.22 Zung depression scale 32 57.3 (23.3) 50.8 (20.6) 62.9 (24.7) -12.11 (-27.47, 3.26) 0.12 Participants with >=1 SAE (%) 39 16 (41.0) 8 (38.1) 8 (44.4) 0.77 (0.21, 2.77) 0.69 Global outcome 31 -0.12 (-0.38, 0.14) 0.37 BI: Barthel Index; DIM: difference in medians; EQ: EuroQol; HR: hazard ratio; ICH: intracranial haemorrhage; MD: mean difference; mRS: modified Rankin Scale; NIHSS: National Institutes of Health stroke scale; Neuro. det.: neurological deterioration; OR: odds ratio; t-MMSE: Modified telephone Mini-Mental State Examination; SAE: serious adverse event; TICS-M: Modified Telephone Interview for Cognitive Status; VAS: Visual Analogue Scale; ZDS: Zung Depression Scale. § Percentage difference and Fisher’s exact test Definitions : ‡ Clinical events determined by the investigator: recurrent stroke, sICH, hypotension, hypertension National Institutes Health stroke scale (NIHSS): 0 (normal neurological status) to 42 (coma with quadriplegia), 43 (death) [ 20 ] Dysphagia severity rating scale: 0 (normal oral intake), 12 (nil by mouth), 13 (death) [28] Barthel Index: -5 (death) to 0 (severe disability) to 100 (no disability) [22] Modified telephone Mini-Mental State Examination (t-MMSE): -1 (death), 0 (severe dementia) to 18 (normal). Modified Telephone Interview for Cognitive Status (TICS-M): -1 (death, 0 (severe dementia) to 37 (normal).[29] Verbal fluency (number of animals named in one minute): -1 (death), 0 (none named) to infinity. Health utility status (HUS, derived from European Quality of Life-5 dimensions, EQ-5D): -0.5 (very poor quality of life, 0 (death) to 1.0 (perfect quality of life) European Quality of Life-Visual Analogue Scale (EQ-VAS): -1 (death), 0 (very poor) to 100 (excellent) Zung Depression Scale (ZDS): 0 (normal), 100 (severe depression) to 102.5 (death) [24] Global outcome: continuous - mRS, BI, TICS-M, EQ-5D; binary - death, SAEs Table 4. Serious adverse events by treatment group and relationship. Data are number (%). Comparisons by binary logistic regression. All Fatal All GTN Sham OR (95% CI) p All GTN Sham OR (95% CI) p Participants 39 21 18 39 21 18 Number of SAEs 24 9 15 5 1 4 Treatment relationship Before 0 (0.0) 0 (0.0) 0 (0.0) - - 0 (0.0) 0 (0.0) 0 (0.0) - - During 22 (91.7) 8 (88.9) 14 (93.3) - 0.71 3 (60.0) 0 (0.0) 3 (75.0) - - After 2 (8.3) 1 (11.1) 1 (6.7) - 0.71 2 (40.0) 1 (100.0) 1 (25.0) - 1.00 Relationship to treatment 0.59 - Not related 2 (8.3) 1 (11.1) 1 (6.7) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Improbable 14 (58.3) 4 (44.4) 10 (66.7) - - 5 (100.0) 1 (100.0) 4 (100.0) - - Possible 6 (25.0) 3 (33.3) 3 (20.0) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Probable 1 (4.2) 0 (0.0) 1 (6.7) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Definite 1 (4.2) 1 (11.1) 0 (0.0) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Organ Cardiovascular 8 (20.5) 4 (19.0) 4 (22.2) 0.82 (0.17, 3.90) 0.81 0 (0.0) 0 (0.0) 0 (0.0) - - Nervous system 4 (10.3) 1 (4.8) 3 (16.7) 0.25 (0.02, 2.65) 0.25 3 (7.7) 0 (0.0) 3 (16.7) - - Respiratory 5 (12.8) 1 (4.8) 4 (22.2) 0.18 (0.02, 1.74) 0.14 1 (2.6) 0 (0.0) 1 (5.6) - - Gastrointestinal 2 (5.1) 1 (4.8) 1 (5.6) 0.85 (0.05, 14.64) 0.91 0 (0.0) 0 (0.0) 0 (0.0) - - Genitourinary 1 (2.6) 0 (0.0) 1 (5.6) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Haematological/Immunological 0 (0.0) 0 (0.0) 0 (0.0) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Metabolic/Endocrine 0 (0.0) 0 (0.0) 0 (0.0) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Musculoskeletal/Cutaneous 1 (2.6) 0 (0.0) 1 (5.6) - - 0 (0.0) 0 (0.0) 0 (0.0) - - Miscellaneous 3 (7.7) 2 (9.5) 1 (5.6) 1.79 (0.15, 21.54) 0.65 1 (2.6) 1 (4.8) 0 (0.0) - - Any SAE 16 (41.0) 8 (38.1) 8 (44.4) 0.77 (0.21, 2.77) 0.69 5 (12.8) 1 (4.8) 4 (22.2) 0.18 (0.02, 1.74) 0.14 Miscellaneous SAEs: tongue haematoma, coffee ground vomiting, fall Additional Declarations The authors declare potential competing interests as follows: PMB is Stroke Association Professor of Stroke Medicine and is an emeritus NIHR Senior Investigator; he was chief investigator of ENOS, RIGHT and RIGHT-2. He has received honoraria from CoMind, DiaMedica and Phagenesis and holds stock options in DiaMedica. The remaining authors have no declarations. Supplementary Files ENOS2Main20250818Supplemental.docx ENOS-2 Main 20250818 Supplemental information Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7494203","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507840551,"identity":"d1f89cf5-848d-4b65-9132-dfcd6b1acbfe","order_by":0,"name":"Lisa J Woodhouse","email":"","orcid":"https://orcid.org/0000-0002-4472-1999","institution":"University of Nottingham","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"J","lastName":"Woodhouse","suffix":""},{"id":507840553,"identity":"d413c293-173e-4367-a675-3b8aa5f3e349","order_by":1,"name":"Iris 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Nottingham","correspondingAuthor":true,"prefix":"","firstName":"Philip","middleName":"","lastName":"Bath","suffix":""}],"badges":[],"createdAt":"2025-08-30 09:11:48","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7494203/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7494203/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90884622,"identity":"651cf2e3-3748-4796-8019-476f17e75602","added_by":"auto","created_at":"2025-09-09 10:00:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":149423,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram, enrolment and follow-up.\u003c/p\u003e\n\u003cp\u003eGTN: glyceryl trinitrate. Data are number (%).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7494203/v1/4f6a8d32a3e121b40a53960f.png"},{"id":90882595,"identity":"256057c4-8703-4575-8ec5-f38829b0103a","added_by":"auto","created_at":"2025-09-09 09:52:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33542,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of modified Rankin Scale scores at 90 days: glyceryl trinitrate versus sham.\u003c/p\u003e\n\u003cp\u003eComparison of GTN vs sham by unadjusted multiple linear regression: difference in means -0.20 (-1.30, 0.90) p=0.72.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7494203/v1/fc58141aba3f72b417c1c27c.png"},{"id":90886953,"identity":"a0b02b7b-61d1-465f-bf08-a13e378d6699","added_by":"auto","created_at":"2025-09-09 10:16:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1204032,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7494203/v1/ed9755d0-e132-4b75-838d-3c70d41b617e.pdf"},{"id":90882598,"identity":"4d81f78b-c27a-4c69-ad2b-cd9bae7c78ed","added_by":"auto","created_at":"2025-09-09 09:52:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":482184,"visible":true,"origin":"","legend":"\u003cp\u003eENOS-2 Main 20250818 Supplemental information\u003c/p\u003e","description":"","filename":"ENOS2Main20250818Supplemental.docx","url":"https://assets-eu.researchsquare.com/files/rs-7494203/v1/2738d424a8ababa477e62430.docx"}],"financialInterests":"The authors declare potential competing interests as follows: PMB is Stroke Association Professor of Stroke Medicine and is an emeritus NIHR Senior Investigator; he was chief investigator of ENOS, RIGHT and RIGHT-2. He has received honoraria from CoMind, DiaMedica and Phagenesis and holds stock options in DiaMedica. The remaining authors have no declarations.","formattedTitle":"\u003cp\u003eGlyceryl trinitrate for treating hyperacute stroke: the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) feasibility randomised controlled trial\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHigh blood pressure (BP) is present in 60% of patients with acute ischaemic stroke (AIS) or acute intracerebral haemorrhage (ICH) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and is associated with a worse outcome manifest as increased early recurrence or death and later death and dependency.[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Lowering BP acutely after AIS might improve outcome providing that cerebral perfusion is not reduced in the presence of dysfunctional cerebral autoregulation. BP should not be lowered if already in the normal or low range since a U-shaped relationship exists between BP and outcome, i.e. low BP is also associated with poor outcome.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Lowering BP in ICH is associated with reduced haematoma expansion.\u003c/p\u003e\u003cp\u003eNitric oxide (NO) donors are candidate treatments for acute stroke through multiple potentially beneficial effects: NO is a vasodilator and so lowers BP and might improve cerebral perfusion; modulates endothelial, smooth muscle cell, platelet and leucocyte neuronal function; modulates neuronal function and is neuroprotective; and inhibits apoptosis. In preclinical studies of AIS, early administration of NO donors reduced infarct lesion size and improved regional cerebral blood flow and functional outcome.[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Four small phase-2 trials of transdermal glyceryl trinitrate (GTN, also known as nitroglycerin [NTG], a NO donor) reported that GTN lowered systemic and 24-hour BP; did not alter platelet activity, middle cerebral artery blood flow velocity or regional cerebral blood flow; improved aortic compliance; could be given to patients with dysphagia; and was safe in patients with acute stroke.[\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] When started within 4 hours of stroke onset, GTN was associated with improved functional outcome.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThree phase-3 randomised controlled trials of GTN have been reported. The large hospital-based ENOS trial recruited 4011 patients and had a recruitment time window of 48 hours. Although the trial was neutral overall,[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] the subgroup of participants treated within 6 hours of stroke onset appeared to benefit.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] An individual patient data meta-analysis found that GTN appeared to be beneficial for both AIS and ICH when treatment was started within 6 hours.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Hence, a large pre-hospital ambulance-based trial, RIGHT-2, recruited 1149 patients with probable stroke within 4 hours (median 71 minutes). This trial was neutral overall [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] although patients with ICH (when treated within 2 hours) and AIS (when treated within one hour) appeared to fare worse whilst those with a stroke mimic had a better outcome.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] Another prehospital trial, MR ASAP, randomised 325 patients up to 3 hours after stroke onset (median\u0026thinsp;~\u0026thinsp;62 minutes) and was also neutral overall;[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] nevertheless, it too suggested outcome was worse in ICH with GTN. Taking the results together suggests that early but not too early treatment might be better, i.e. after 2 but before 6 hours.\u003c/p\u003e\u003cp\u003eWe report here the findings of the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) randomised controlled trial, the objective of which was to assess the feasibility, safety and proof of concept when GTN was administered between 3 and 5 hours after stroke onset.\u003c/p\u003e"},{"header":"METHODS","content":"\u003ch2\u003eTrial design\u003c/h2\u003e\n\u003cp\u003eENOS-2 was a prospective randomised sham-controlled blinded-endpoint parallel-group single-centre feasibility and proof-of-concept trial. In brief, patients with an acute stroke were randomised equally to two days of transdermal glyceryl trinitrate (GTN) or a sham patch. The trial broadly followed the design of ENOS [13] but without assessment of stopping versus continuing pre-stroke antihypertensive drugs.\u003c/p\u003e\n\u003ch2\u003ePatients\u003c/h2\u003e\n\u003cp\u003ePatients admitted with a clinical stroke syndrome due to ischaemia or haemorrhage to Nottingham University Hospitals NHS Trust, a comprehensive stroke centre, were eligible for the trial if they were: aged 18 or over; had a stroke syndrome comprising limb weakness, dysphasia, neglect or hemianopia; had systolic BP \u003cu\u003e\u0026gt;\u003c/u\u003e120 mmHg; and could be treated between 3 and 5 hours after onset. The diagnosis of ischaemic or haemorrhagic stroke was confirmed with computed tomography (CT) or magnetic resonance imaging (MRI) done before, or soon after, enrolment using standard techniques; the scan had to show acute ICH, AIS or be normal.\u003c/p\u003e\n\u003cp\u003eKey exclusion criteria included: preceding severe dependency (modified Rankin scale, mRS 4 or 5); plasma glucose \u0026lt;3 mmol/l; coma (Glasgow Coma Scale \u003cu\u003e\u0026lt;\u003c/u\u003e8); witnessed seizure at presentation; known life expectancy \u0026lt;6 months; pure sensory symptoms; a condition mimicking stroke; other cause of intracranial haemorrhage; known allergy to GTN patch or sham dressing; planned for palliative care; recent use of a phosphodiesterase5-inhibitor; or previous enrolment in ENOS-2.\u003c/p\u003e\n\u003cp\u003eCo-enrolment was allowed with mutually agreed trials: MAPS-2 (ISTRCTN40512746), OPTIMIST (clinicaltrials.com NCT03734640) and TICH-3 (ISRCTN97695350).\u003c/p\u003e\n\u003ch2\u003eRandomisation and masking\u003c/h2\u003e\n\u003cp\u003eWritten informed consent was obtained from each patient, or from a relative or close friend if the patient lacked capacity, prior to enrolment and in accordance with UK regulations. Investigators entered baseline and follow-up data into a database via a secure Web-based randomisation system (https://stroke.nottingham.ac.uk/enos-2/live/enos-2_login.php). Data were checked to confirm the patient\u0026rsquo;s eligibility in real time, and the computer system then assigned a participant, with allocation 1:1, to treatment with GTN or sham. Treatment assignment comprised stratification on stroke type (IS, ICH) and minimisation on key prognostic baseline variables: age (\u0026gt;=72 years), severity (NIHSS\u0026gt;=10/42), time from onset to randomisation (\u0026gt;=4 hours), systolic blood pressure (\u0026gt;=160 mmHg) and candidate for or received reperfusion therapy (\u0026ldquo;no\u0026rdquo;); minimisation included a random element in 5% of patients. Minimisation were used to ensure that the groups were balanced for prognostic factors, and the random element reduced predictability. The randomisation algorithm then presented a treatment allocation as either \u0026lsquo;GTN\u0026rsquo; or \u0026lsquo;No GTN\u0026rsquo;; GTN/sham were prescribed via the hospital system.\u003c/p\u003e\n\u003ch2\u003eTreatment\u003c/h2\u003e\n\u003cp\u003eTreatment was started immediately after randomisation, given daily for two days and consisted of a GTN transdermal patch (Transiderm, 5 mg) or a non-matching sham dressing (DuoDERM hydrocolloid, Convatec) with both covered by a gauze dressing to conceal allocation. The patch/dressing and gauze were changed daily (07.00-09.00 hours) with rotation of the site of placement on the shoulders or back. The dose of GTN was not adjusted during treatment and patches were left on for 24 hours, i.e. there was no overnight GTN-free period.[13]\u003c/p\u003e\n\u003cp\u003eStudy agents could be stopped if the patient withdrew consent, for safety reasons, or if unacceptable adverse events developed. Non-trial nitrates and other antihypertensive agents could not be given during the 2-day treatment period unless deemed necessary by the local investigator. Randomised treatment was given in addition to standard care; thrombolysis and/or mechanical thrombectomy were permitted in patients with AIS as per the admitting physician\u0026rsquo;s plan. Systematic use of antihypertensive agents (all patients, after 2 days), and oral antithrombotic and lipid lowering agents (patients with AIS) were recommended for secondary prevention.\u003c/p\u003e\n\u003ch2\u003eAssessments\u003c/h2\u003e\n\u003cp\u003eDemographic and clinical characteristics were recorded on-line during enrolment. The severity of the stroke was assessed with the National Institutes of Health stroke scale (NIHSS, range from 0 to 42, with higher scores indicating a more severe neurologic deficit) [20] at baseline, 2 days and discharge. BP was measured using a validated automated monitor as used routinely at the site. The final diagnosis was confirmed at the time of discharge/in-hospital death. The site was asked to provide a trained member of their research staff who was unaware of treatment assignment to perform post-randomisation in-hospital assessments. CT and MRI scans were evaluated using the routine hospital report as read by hospital neuroradiologists who were blinded to treatment; a natural language programme was used to confirm interpretation of the report. Investigator-reported serious adverse events, including cause-specific deaths, were validated by the Chief Investigator who were blinded to treatment assignment. Patients who did not receive their assigned treatment or who did not adhere to the protocol were followed up in full. Final follow-up was performed centrally at 90 days by telephone from the coordinating centre, blinded to treatment allocation. If the patient could not be contacted, a questionnaire covering the same outcome measures was sent by post.\u003c/p\u003e\n\u003ch2\u003eOutcome measures\u003c/h2\u003e\n\u003cp\u003eThe primary outcomes were: feasibility assessed as recruitment of 120 participants (100 with AIS, 20 with ICH); mechanistic assessed as BP and heart rate; and clinical assessed as functional outcome using the modified Rankin Scale (mRS) at 90 days after enrolment.[21] Scores on the mRS range from 0 to 6, with a score of 0 indicating no symptoms, 5 severe dependency, and 6 death. Pre-specified secondary clinical outcomes included disability (Barthel index, BI [22]); cognition (telephone interview for cognition scale-modified, TICS-M [23]); mood (short Zung Depression Score, ZDS [24]); health-related quality of life (EuroQol-5 dimensions-5 levels, EQ-5D-5L, from which health utility status [HUS] using UK weightings was calculated, and EuroQoL-visual analogue scale, EQ-VAS); at 90 days. These outcomes were measured by central observers blinded to treatment assignment. At discharge from initial hospitalisation, duration of stay and discharge destination (to institution or home) were recorded.\u003c/p\u003e\n\u003cp\u003eThe safety outcomes of interest were serious adverse events (SAEs) up to day 2 (i.e., 48 hours after 1\u003csup\u003est\u003c/sup\u003e patch applied), fatal SAEs to day 90 and all-cause case fatality.\u003c/p\u003e\n\u003ch2\u003eStudy oversight\u003c/h2\u003e\n\u003cp\u003eThe trial was conceived and designed by the grant applicants, and they wrote the protocol (available at https://stroke.nottingham.ac.uk/enos-2/, last version 4 dated 1 March 2024). The study was approved by the Northwest \u0026ndash; Greater Manchester South Research Ethics Committee / UK Health Research Authority (20/NW/0246, 30 June 2020), the Medicines \u0026amp; Healthcare products Regulatory Agency (CTA 03057/0072/001-0001, 24 August 2020) and was adopted by the UK NIHR Clinical Research Network. The trial was funded by a grant from the Nottingham University Hospitals Charity (CRF-BATH-NOV 2019), sponsored by the University of Nottingham and registered: ISRCTN17654248 (31 March 2021), EudraCT 2020-001304, IRAS 281728, WHO U1111-1259-7057. The trial was overseen by a Trial Steering Committee (which included 3 independent members) and conducted by the Trial Management Committee based at the coordinating centre in Nottingham. An independent Data Monitoring Committee reviewed unblinded data approximately annually. There was no commercial support for the trial. Study data were monitored and analysed by the ENOS-2 Coordinating Centre. Analysis, interpretation, and report writing were performed independent of the funders and sponsor. The corresponding author wrote the first draft of the manuscript, with input from the writing committee, all of whom approved the decision to submit the manuscript for publication. The corresponding author and statisticians (LJW, IM) had full access to all the data in the study; additionally, the corresponding author had final responsibility for the decision to submit for publication and is the guarantor for the study.\u003c/p\u003e\n\u003ch2\u003eStatistical analyses\u003c/h2\u003e\n\u003cp\u003eSince ENOS-2 was a feasibility study, there was no formal sample size calculation. However, recruitment of 100 patients with AIS and 20 with ICH would provide sufficient information on feasibility, safety and proof of concept (PoC). With a sample size of 100 and assuming alpha = 0.05, power 0.80 and mRS distribution as in ENOS-Early,[14] an adjusted common odds ratio of 0.51 for mRS would be detectable in PoC analyses.\u003c/p\u003e\n\u003cp\u003eStatistical analyses of the effect of the treatments on clinical outcomes were planned to be analysed using adjusted binary logistic regression, Cox proportional hazards regression (for time to events, e.g. death), ordinal logistic regression and multiple linear regression, with adjustment for the randomisation factors used in stratification and minimisation.[25] The mRS would be reported as a common odds ratio with 95% confidence intervals and calculated using ordinal logistic regression. For sensitivity purposes, the primary analyses were also to be analysed unadjusted, and as a binary outcome (death or dependency, mRS \u0026gt;2). We would assess the heterogeneity of the treatment effects on the primary outcome in pre-specified subgroups by adding an interaction term to an unadjusted ordinal logistic regression model. Death was to be analysed using Kaplan-Meier and Cox regression models. A global outcome assessing original data from the mRS, BI, TCS-M, EQ-5D-5L, death and SAEs was to be analysed using the Wei-Lachin test.[26] Since outcomes such as mRS, EQ-5D-HUS and BI include death (scores of 6, 0 and -5 respectively) and in case treatment was associated with asymmetric effects on death and other outcome measures (e.g. more death and less impairment), an extreme value for death would be added to the other outcome scales: EQ-VAS -1, t-MMSE -1, SSS -1, TICS-M -1, ZDS 102.5, DSRS 13. The nominal level of significance for all analyses was P\u0026lt;0.05 since no interim analysis were to be performed. No adjustments were to be made for multiplicity of testing. Data would be shown as number (%), median [interquartile range] or mean (standard deviation). As a feasibility trial, no interim analyses or efficacy/futility stopping rules were set.\u003c/p\u003e\n\u003cp\u003eDue to the paucity of recruited participants, the analyses specified in the SAP were restricted. First, tabulations were abbreviated to avoid reporting an excess number of variables. Second, unadjusted rather than adjusted analyses (using the stratification and minimisation variables) were performed to avoid failure of regression convergence and statistical over-fitting. Third, we used Fisher\u0026rsquo;s Exact test to analyse binary variables where one group had zero/very low numbers of events. Last, analyses in subgroups were not performed. Analyses were performed with SAS software (SAS Institute, Cary, North Carolina USA, version 9.4) according to the intention-to-treat principle.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003ch2\u003eStudy patients\u003c/h2\u003e\n\u003cp\u003eBetween September 2021 and June 2024, 39 patients were included (GTN 21, no GTN 18) at 1 UK site (Figure 1). Two interruptions to recruitment occurred due to lack of investigational drugs (Supplemental Figure 1). Eight protocol amendments were made (Supplemental Table 1). The trial ceased when the last batch of GTN patches went out of date. More than 1,400 patients were excluded (Supplemental Table 2).\u003c/p\u003e\n\u003cp\u003eSeven consultant stroke physicians, two registrars and two allied health professionals on the trial log recruited the participants, with two of these recruiting more than 50% (Supplemental Figure 2). Baseline characteristics were well balanced between the treatment groups at baseline (Table 1). The mean (standard deviation) age was 72.3 (13.2) years, females 16 (41.0%), median [IQR] symptom onset to randomisation 216 [186-251] minutes (27, 69.2% recruited within 4 hours of onset), and NIHSS score 9.1 (6.3). The final diagnosis was AIS 33 (84.6%), ICH 1 (2.6%), transient ischaemic stroke (TIA) 4 (10.3%) and functional mimic 1 (2.6%). Consent was provided by 24 (61.5%) participants and proxy assent by 13 (33.3%) relatives or close friends 8 (20.5%) (Supplemental Table 3); emergency waiver of consent was used in 2 (5.1%) participants.\u003c/p\u003e\n\u003cp\u003eA majority of neuroimaging was normal 21 (53.8%) at baseline with the remaining scans showing ischaemic 16 (41.0%) or haemorrhagic 1 (2.6%) changes (Supplemental Table 4). Evidence of previous stroke, atrophy and/or white matter disease was present in a minority of participants.\u003c/p\u003e\n\u003ch2\u003eFeasibility\u003c/h2\u003e\n\u003cp\u003eAltogether, 39 (32.5%) patients were recruited of an intended 120 (Table 2). The trial struggled to recruit for multiple reasons, these including factors internal to the trial design and protocol such as a significant number of participants who presented \u0026gt;5 hours after onset and those with no eligible symptoms or unknown/unclear time of onset (Supplemental Table 2). External non-protocol-related factors included lack of IMP on two occasions, presentation out-of-hours when no research staff were present and an unwillingness by some medical staff to have the trial offered to their patients due to perceived safety concerns, especially prior to potential mechanical thrombectomy (although no such concerns were identified by the DMC).\u003c/p\u003e\n\u003ch2\u003eAdherence\u003c/h2\u003e\n\u003cp\u003eAdherence with GTN versus no GTN was good with 37 (94.9%) participants receiving their first treatment and 33 (84.6%) both patches/dressings as randomised (Supplemental Table 5). There were no differences in the use of secondary antihypertensive drugs over the first two days between the two groups (Supplemental Table 6).\u003c/p\u003e\n\u003ch2\u003eBlood pressure\u003c/h2\u003e\n\u003cp\u003eThe mean BP at baseline was 161.8/80.8 mmHg and fell in both GTN and no GTN groups over the 2 days of treatment (Supplementary Table 7). However, following the first dose of treatment, BP fell more with the first treatment in the sham group than in the GTN group; difference in means 17.2 (95% CI 1.2-33.3) / 5.8 (95% CI -1.37-12.9) mmHg with Sham vs 13.2 (1.4-24.9) / 0.31 (-10.0-10.6) mmHg with GTN. Nevertheless, BP did not differ at day 1 between the groups. The frequency of clinical hypotension (4 cases each, all reported as SAEs) and clinical hypertension (GTN 1, sham 2) did not differ by day 2 (Table 3). Baseline heart rate started at 81.9 bpm. In both groups, heart rate fell then increased over the first day although the initial fall was less in the control group (p=0.052) (Supplementary Table 6).\u003c/p\u003e\n\u003ch2\u003eClinical outcomes\u003c/h2\u003e\n\u003cp\u003eThere were no significant differences in death, clinical neurological deterioration, recurrent stroke, symptomatic haemorrhage or swallowing impairment at day 2 (Table 3). NIHSS at day 2 was non-significantly lower GTN 4.1 (4.2) vs sham 10.5 (13.7), p=0.053. Hospital length of stay and death in hospital or not discharged home did not differ between GTN and sham.\u003c/p\u003e\n\u003cp\u003eBy day 90, there were no statistical differences in dependence (mRS, Figure 2), death, disability (BI), quality of life (EQ-5D-5L, EQ-VAS) or mood (ZDS) (Table 3). Nevertheless, less cognitive impairment, measured using the TICS-M (p=0.020) and verbal fluency (animal naming) (p=0.058), was seen with GTN.\u003c/p\u003e\n\u003ch2\u003eSerious adverse events\u003c/h2\u003e\n\u003cp\u003eAlthough the number of participants with one or more SAEs did not differ with eight in each group (Table 3) there were less SAEs in the GTN group (9) than the sham group (15) (Table 4). The majority occurred during treatment and four in each group were considered to be possibly, probably or definitely related to treatment. No fatal SAEs were considered to be associated with treatment. One death occurred in the GTN group and was related to sepsis; the sham group had three deaths related to the nervous system and one to the respiratory system (Table 4).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eENOS-2 assessed the effect of GTN vs sham in patients with acute stroke within a narrow time window defined by apparent safety concerns with GTN when given before 2 hours of stroke onset [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and futility beyond 6 hours.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] The trial found that feasibility was challenged by multiple recruitment causes, some internal to the trial design and some external, such that only 39 of 120 planned participants were recruited. However, GTN appeared safe with tendencies to fewer deaths and SAEs and less cognitive impairment.\u003c/p\u003e\u003cp\u003eExternal factors potentially relate to issues at a single centre with lack of equipoise by some clinicians. Hence, it cannot necessarily be concluded that a further study is not warranted particularly if future testing was done across several sites. A multicentre design would have been more robust but was not feasible due to the limited funding available. Such testing is remains desirable since the present data are still compatible with the positive findings seen for treatment in the range 3\u0026ndash;5 hours after onset (Supplemental Fig.\u0026nbsp;2).[\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe findings that GTN did not lower BP are surprising for a vasodilator and not easily explained since all previous GTN trials have found that it lowered BP; chance due to the limited sample size may explain this, i.e. type II error. Nevertheless, GTN did raise heart rate as would be expected for a mixed venous and arterial dilator.\u003c/p\u003e\u003cp\u003eThe present trial has several strengths. First, it was randomised in design and used a sham treatment in contrast to earlier GTN trials. Second, the trial was a pragmatic test of real-world approaches to BP management since recruitment could be started in the Emergency Department prior to neuroimaging. Third, participants could have stroke of varying characteristics: ischaemic or haemorrhagic; severe or mild; cortical or lacunar; and anterior or posterior circulation. Fourth, outcomes were measured centrally masked to treatment assignment by observers who were not involved with clinical care. Last, transdermal administration of a drug in acute stroke is advantageous since it can be started immediately, is not confounded by dysphagia which limits the immediate use of oral treatment, does not need intravenous access and so does not need intensive monitoring, and can be stopped and re-started according to clinical need.\u003c/p\u003e\u003cp\u003eNevertheless, there are several limitations present. First, the final trial size was much smaller at 39 than the intended 120 participants. Some of the explanations are unrelated to the protocol and might be resolved in a multicentre design. One concern that GTN might be unsafe in patients proceeding to mechanical thrombectomy cannot be assessed due to the limited number (5) of these procedures (Supplemental Table\u0026nbsp;6). Second, the trial recruited from one site only and so is not generalisable to other sites or countries. Third, a key limitation was the narrow time-window of 3\u0026ndash;5 hours after stroke onset although this was deliberate on the basis of previous data. Fourth, some patients assigned to GTN did not receive it for the protocolised 2 days of treatment. And fifth, some outcomes (cognition, mood) could not be measured in all participants at day 90 so further limiting the power of some statistical analyses.\u003c/p\u003e\u003cp\u003eIn conclusion, feasibility was not demonstrated and, surprisingly, GTN did not appear to lower BP. Nevertheless, GTN was safe and point estimates for treatment effects were all in a direction supporting benefit. A meta-analysis of the three trials that have examined the effect of GTN on mRS (ENOS-1/2, RIGHT-2) in the time window of 3\u0026ndash;5 hours suggests efficacy: mean difference \u0026minus;\u0026thinsp;0.45 (95% CI -0.91, 0.02), p\u0026thinsp;=\u0026thinsp;0.06 with no heterogeneity (Supplemental Fig.\u0026nbsp;3). Since the results support, potentially, the use of GTN in hyperacute stroke, a multicentre trial testing GTN in the time window of 3\u0026ndash;5 hours is now warranted.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBP blood pressure\u003c/p\u003e\n\u003cp\u003eEQ-VAS European quality of life-visual analogue scale\u003c/p\u003e\n\u003cp\u003eGTN glyceryl trinitrate\u003c/p\u003e\n\u003cp\u003eHUS health utility status\u003c/p\u003e\n\u003cp\u003emRS modified Rankin scale\u003c/p\u003e\n\u003cp\u003eNIHSS National Institutes of Health Stroke Scale\u003c/p\u003e\n\u003cp\u003ePICH primary intracerebral haemorrhage\u003c/p\u003e\n\u003cp\u003eRAAS renin-angiotensin-aldosterone system\u003c/p\u003e\n\u003cp\u003eSSS Scandinavian Stroke Scale\u003c/p\u003e\n\u003cp\u003eTICS-M modified-Telephone Interview for Cognition Scale\u003c/p\u003e\n\u003cp\u003et-MMSE telephone Mini-Mental State Examination\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cspan\u003eData availability The dataset generated during the current study are not currently publicly available due their integration into an update of our individual patient data metaanalysis. They will be shared with the VISTA Collaboration:[1] https://www.virtualtrialsarchives.org\u003c/span\u003e\u003c/p\u003e\u003cp\u003ePMB is Stroke Association Professor of Stroke Medicine and is an emeritus NIHR Senior Investigator; he was chief investigator of ENOS, RIGHT and RIGHT-2. He has received honoraria from CoMind, DiaMedica and Phagenesis and holds stock options in DiaMedica. The remaining authors have no declarations.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eWe thank the research staff in Nottingham for their support and the Nottingham University Hospitals NHS Trust Charity which was the primary funder. We also thank Professor Pip Logan for access to her NIHR Senior Investigator award to facilitate NIHR eligibility and access to research coordinators. ENOS-2 acknowledges the support of the UK National Institute for Health and Care Research (NIHR) for support through the clinical research network.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eAuthor contributions\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eConceptualisation: Philip Bath, Nikola Sprigg, Timothy England, Lisa Woodhouse, Kailash Krishnan\u003c/p\u003e\n\u003cp\u003eMethodology - Study coordinators: Amanda Buck, Lucy Gray, Amanda Hedstrom, Camille Hutchinson\u003c/p\u003e\n\u003cp\u003eAnalysis: Lisa J Woodhouse, Iris Mhlanga\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; original draft preparation: Philip Bath\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; review and editing: Philip Bath, Nikola Sprigg, Timothy England, Lisa Woodhouse, Kailash Krishnan, Iris Mhlanga, Tiffany Hamilton, Diane Havard\u003c/p\u003e\n\u003cp\u003eFunding acquisition: Philip Bath, Nikola Sprigg, Timothy England, Lisa Woodhouse, Kailash Krishnan\u003c/p\u003e\n\u003cp\u003eResources: Tiffany Hamilton, Diane Havard\u003c/p\u003e\n\u003cp\u003eSupervision: Philip Bath, Kailash Krishnan\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eData availability\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eThe dataset generated during the current study are not currently publicly available due their integration into an update of our individual patient data metaanalysis. They will be shared with the VISTA Collaboration.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLeonardi-Bee J, Bath PMW, Phillips SJ, Sandercock PAG, for the IST Collaborative Group. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke. 2002;33:1315-20. DOI, http://www.strokeaha.org\u003c/li\u003e\n\u003cli\u003eVemmos KN, Tsivgoulis G, Spengos K, Zakopoulos N, Synetos A, Manios E, et al. U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med. 2004;255(2):257-65. DOI: 10.1046/j.1365-2796.2003.01291.x\u003c/li\u003e\n\u003cli\u003eMulder M, Ergezen S, Lingsma HF, Berkhemer OA, Fransen PSS, Beumer D, et al. Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). Stroke. 2017;48(7):1869-76. DOI: 10.1161/STROKEAHA.116.016225\u003c/li\u003e\n\u003cli\u003eMaier B, Gory B, Taylor G, Labreuche J, Blanc R, Obadia M, et al. Mortality and Disability According to Baseline Blood Pressure in Acute Ischemic Stroke Patients Treated by Thrombectomy: A Collaborative Pooled Analysis. J Am Heart Assoc. 2017;6(10). DOI: 10.1161/JAHA.117.006484\u003c/li\u003e\n\u003cli\u003eGeeganage C, Bath PMW. Relationship between therapeutic changes in blood pressure and outcomes in acute stroke. A metaregression. Hypertension 2009;54:775-81. DOI: \u003cu\u003e10.1161/hypertensionaha.109.133538\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eWillmot M, Murphy S, Leonardi-Bee J, Bath P. Systematic review of nitric oxide donors and L-arginine in experimental stroke: effects on infarct size and cerebral blood flow. CerebrovascDis. 2003;16(3):S3 66 (abstract). DOI: \u003c/li\u003e\n\u003cli\u003eManiskas ME, Roberts JM, Trueman R, Learoyd AE, Gorman A, Fraser JF, et al. Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke. J Neurointerv Surg. 2018;10(1):29-33. DOI: 10.1136/neurintsurg-2016-012793\u003c/li\u003e\n\u003cli\u003eSorby-Adams AJ, Learoyd AE, Bath PM, Burrows F, Farr TD, Leonard AV, et al. Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021;41(12):3248-59. DOI: 10.1177/0271678X211018901\u003c/li\u003e\n\u003cli\u003eBath PMW, Pathansali R, Iddenden R, Bath FJ. The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. Cerebrovasc Dis. 2001;11:265-72. DOI: \u003c/li\u003e\n\u003cli\u003eRashid P, Weaver C, Leonardi-Bee J, Bath F, Fletcher S, Bath P. The effects of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure, cerebral and cardiac hemodynamics, and plasma nitric oxide levels in acute stroke. J Stroke Cerebrovasc Dis. 2003;12(3):143-51. DOI: 10.1016/S1052-3057(03)00037-5\u003c/li\u003e\n\u003cli\u003eWillmot M, Ghadami A, Whysall B, Clarke W, Wardlaw J, Bath PM. Transdermal glyceryl trinitrate lowers blood pressure and maintains cerebral blood flow in recent stroke. Hypertension. 2006;47:1209-15. DOI: \u003c/li\u003e\n\u003cli\u003eAnkolekar S, Fuller M, Cross I, Renton C, Cox P, Sprigg N, et al. Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824). Stroke. 2013;44(11):3120-8. DOI: 10.1161/STROKEAHA.113.001301\u003c/li\u003e\n\u003cli\u003eEnos Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. Lancet. 2015;385(9968):617-28. DOI: 10.1016/S0140-6736(14)61121-1\u003c/li\u003e\n\u003cli\u003eWoodhouse L, Scutt P, Krishnan K, Berge E, Gommans J, Ntaios G, et al. Effect of hyperacute administration (within 6 hours) of transdermal glyceryl trinitrate, a nitric oxide donor, on outcome after stroke: subgroup analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Stroke. 2015;46:3194-201. DOI: \u003c/li\u003e\n\u003cli\u003eBath PM, Woodhouse L, Krishnan K, Anderson C, Berge E, Ford GA, et al. Effect of Treatment Delay, Stroke Type, and Thrombolysis on the Effect of Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome after Acute Stroke: A Systematic Review and Meta-Analysis of Individual Patient from Randomised Trials. Stroke Res Treat. 2016;2016:9706720. DOI: 10.1155/2016/9706720\u003c/li\u003e\n\u003cli\u003eRight-2 Investigators. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. Lancet. 2019;393(10175):1009-20. DOI: 10.1016/S0140-6736(19)30194-1\u003c/li\u003e\n\u003cli\u003eBath PM, Woodhouse LJ, Krishnan K, Appleton JP, Anderson CS, Berge E, et al. Prehospital Transdermal Glyceryl Trinitrate for Ultra-Acute Intracerebral Hemorrhage: Data From the RIGHT-2 Trial. Stroke. 2019;50(11):3064-71. DOI: 10.1161/STROKEAHA.119.026389\u003c/li\u003e\n\u003cli\u003eTunnage B, Woodhouse LJ, Dixon M, Anderson C, Ankolekar S, Appleton J, et al. Pre-hospital transdermal glyceryl trinitrate in patients with stroke mimics: data from the RIGHT-2 randomised-controlled ambulance trial. BMC emergency medicine. 2022;22(1):2. DOI: 10.1186/s12873-021-00560-x\u003c/li\u003e\n\u003cli\u003evan den Berg SA, Uniken Venema SM, Reinink H, Hofmeijer J, Schonewille WJ, Miedema I, et al. Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial. Lancet Neurol. 2022;21(11):971-81. DOI: 10.1016/S1474-4422(22)00333-7\u003c/li\u003e\n\u003cli\u003eLyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke. 1994;25(11):2220-6. DOI: 10.1161/01.str.25.11.2220\u003c/li\u003e\n\u003cli\u003eLees KR, Bath PMW, Schellinger PD, Kerr DM, Fulton R, Hacke W, et al. Contemporary outcome measures in acute stroke research: choice of primary outcome measure Stroke 2012;43(4):1163-70. DOI: \u003c/li\u003e\n\u003cli\u003eSulter G, Steen C, de Keyser J, 1540. Use of the Barthel Undex and modified Rankin Scale in acute stroke trials. Stroke. 1999;30:1538-41. DOI: \u003c/li\u003e\n\u003cli\u003eDesmond DW, Tatemichi TK, Hanzawa L. The telephone interview for cognitive status (TICS): Reliability and validity in a stroke sample. International Journal of Geriatric Psychiatry. 1994;9:803-07. DOI: \u003c/li\u003e\n\u003cli\u003eZung WWK. A self-rating depression scale. Arch Gen Psychiatry. 1965;12:63-70. DOI: \u003c/li\u003e\n\u003cli\u003eWeir CJ, Lees KR. Comparison of stratification and adaptive methods for treatment allocation in an acute stroke clinical trial. StatMed. 2003;22:705-26. DOI: \u003c/li\u003e\n\u003cli\u003eLachin JM. Applications of the Wei-Lachin multivariate one-sided test for multiple outcomes on possibly different scales. PLoS One. 2014;9(10):e108784. DOI: 10.1371/journal.pone.0108784\u003c/li\u003e\n\u003cli\u003eAppleton JP, Woodhouse LJ, Anderson CS, Ankolekar S, Cala L, Dixon M, et al. Prehospital transdermal glyceryl trinitrate for ultra-acute ischaemic stroke: data from the RIGHT-2 randomised sham-controlled ambulance trial. Stroke Vasc Neurol. 2024;9(1):38-49. DOI: 10.1136/svn-2022-001634\u003c/li\u003e\n\u003cli\u003eEverton LF, Benfield JK, Hedstrom A, Wilkinson G, Michou E, England TJ, et al. Psychometric assessment and validation of the dysphagia severity rating scale in stroke patients. Sci Rep. 2020;10(1):7268. DOI: 10.1038/s41598-020-64208-9\u003c/li\u003e\n\u003cli\u003ede Jager CA, Budge MM, Clarke R. Utility of TICS-M for the assessment of cognitive function in older adults. Int J Geriatr Psychiatry. 2003;18(4):318-24. DOI: 10.1002/gps.830\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Baseline characteristics of the patients: glyceryl trinitrate versus no glyceryl trinitrate\u003c/p\u003e\n\u003cp\u003eData are number (%), median [interquartile range] or mean (standard deviation).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSham\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge (years) \u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72.3 (13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71.0 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e73.7 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSex, female (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (39.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEthnicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;White\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e37 (94.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19 (90.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTime to randomisation (min) \u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e216 [186, 251]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e218 [192, 264]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e196 [186, 245]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026lt;4 hours/240 minutes (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27 (69.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13 (72.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCandidate for reperfusion \u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e22 (56.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (61.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePre-morbid mRS \u0026gt;0 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0 [0.0, 1.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0 [0.0, 1.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.0 [0.0, 1.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMedical history (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Treated hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24 (61.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13 (72.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; ACE-Inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Angiotensin-II receptor antagonist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Alpha-blocker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Beta Blocker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Calcium channel blocker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (23.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Diuretic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Renin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Other antihypertensives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Transient ischaemic attack\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Ischaemic heart disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Diabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (23.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Hyperlipidaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15 (38.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (38.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Smoking, current (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (24.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Alcohol \u0026gt;21 units per week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;AF, current/previous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;COVID-19, definite/possible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNitrate use before stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSide of lesion, right (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNIHSS (/42) \u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9.1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.6 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10.9 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGCS \u0026lt;15 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (28.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (23.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (33.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOCSP classification (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Total anterior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (28.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Partial anterior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Lacunar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Posterior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQualifying event \u0026sum;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIschaemic stroke (%) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33 (84.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19 (90.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Cardioembolic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (36.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Large vessel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Small vessel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Not determined\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePrimary intracerebral haemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTransient ischaemic attack\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStroke mimic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6) \u0026fnof;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAF: atrial fibrillation; BP: blood pressure; bpm: beats per minute; GCS: Glasgow Coma Scale; ICH: intracerebral haemorrhage; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; OCSP: Oxfordshire Community Stroke Project classification.\u003c/p\u003e\n\u003cp\u003eData are number (%), median [interquartile range], or mean (standard deviation).\u003c/p\u003e\n\u003cp\u003ePercentages exclude missing values from denominators. Unused antihypertensive drug classes are not shown. In a post hoc analysis, the NIHSS did not differ between GTN and sham: -3.3 (95% CI -7.32, 0.72), p=0.11.\u003c/p\u003e\n\u003cp\u003e\u0026dagger; Minimisation variable\u003c/p\u003e\n\u003cp\u003e\u0026Dagger; Stratification variable\u003c/p\u003e\n\u003cp\u003e\u0026fnof; Functional neurological disorder\u003c/p\u003e\n\u003cp\u003e\u0026para; Sum may exceed 100% because of mixed aetiology.\u003c/p\u003e\n\u003cp\u003e\u0026sum; Qualifying event is determined by investigator by discharge.\u003c/p\u003e\n\u003cp\u003eTable 2. Feasibility measures.\u003c/p\u003e\n\u003cp\u003eData are number (%).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMeasure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMetric\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAchieved (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eRecruitment\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39/120 (32.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTarget patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100 with ischaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e37/100 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 with ICH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1/20 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePrimary\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRetention of enrolees at Day 90 (follow-up)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;70/120 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38/39 (97.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreatment compliance/ adherence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eReceived GTN/sham\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAll 2 days treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33/39 (84.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFirst day treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e37/39 (94.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eCo-enrolment\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMAPS-2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 3\u003c/p\u003e\n \u003cp\u003eOPTIMIST \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003cp\u003eTICH-3 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5/39 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3. Outcomes at days 2 and 90: glyceryl trinitrate versus no glyceryl trinitrate.\u003c/p\u003e\n\u003cp\u003eData are number of patients (%), median [interquartile range], or mean (standard deviation) score. Comparison by Fisher\u0026rsquo;s exact test, Mann-Whitney U-test or unadjusted cox proportional hazards, logistic regression, linear regression, shown as odds ratio (OR, with 95% confidence intervals), hazard ratio (HR), difference in medians (DIM), percentage difference (PD) or mean difference (MD).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSham\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDIM/HR/MD/PD/OR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2p\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eParticipants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eDay 2 (or discharge)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDeath, all cause (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-5.56 (-16.14, 5.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.46 \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eClinical neurological deterioration (%) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-11.11 (-25.63, 3.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.21 \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRecurrent stroke (%) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.76 (-4.35, 13.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.00 \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSymptomatic ICH (%) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-5.56 (-16.14, 5.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.46 \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eClinical hypotension (%) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-3.17 (-28.69, 22.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eClinical hypertension (%) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-6.35 (-23.49, 10.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.59 \u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHeadache\u0026nbsp;(%) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23.02 (0.99, 45.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.098\u0026nbsp;\u0026sect;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNIHSS (/43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.0 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.1 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10.5 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-6.36 (-12.79, 0.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDysphagia severity rating scale (/13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.4 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.0 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.0 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-1.00 (-3.66, 1.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eDischarge data\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHospital stay after randomisation (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.0 [1.0, 13.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.0 [1.0, 20.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.0 [1.0, 10.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.00 (-6.31, 12.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDeath or not discharged home (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.27 (0.05, 1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eDay 90\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003emodified Rankin Scale (/6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.9 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.8 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.0 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.20 (-1.30, 0.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDeath (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.21 (0.02, 1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBarthel Index (/100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72.0 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71.8 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72.2 (43.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.47 (-24.88, 23.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003et-MMSE score (/22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16.1 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18.2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14.2 (9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.01 (-1.23, 9.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTICS-M score (/39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20.2 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24.3 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16.3 (11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8.02 (1.27, 14.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVerbal fluency (animal naming)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14.9 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18.1 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.1 (9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.01 (-0.20, 12.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEQ-5D-5L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.5 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.5 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.5 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.02 (-0.20, 0.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEQ-visual analogue scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e56.6 (29.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e62.2 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e50.8 (31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11.43 (-6.96, 29.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eZung depression scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e57.3 (23.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e50.8 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e62.9 (24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-12.11 (-27.47, 3.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eParticipants with \u0026gt;=1 SAE (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.77 (0.21, 2.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGlobal outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.12 (-0.38, 0.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBI: Barthel Index; DIM: difference in medians; EQ: EuroQol; HR: hazard ratio; ICH: intracranial haemorrhage; MD: mean difference; mRS: modified Rankin Scale; NIHSS: National Institutes of Health stroke scale; Neuro. det.: neurological deterioration; OR: odds ratio; t-MMSE: Modified telephone Mini-Mental State Examination; SAE: serious adverse event; TICS-M: Modified Telephone Interview for Cognitive Status; VAS: Visual Analogue Scale; ZDS: Zung Depression Scale.\u003c/p\u003e\n\u003cp\u003e\u0026sect; Percentage difference and Fisher\u0026rsquo;s exact test\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDefinitions\u003c/em\u003e:\u003c/p\u003e\n\u003cp\u003e\u0026Dagger; Clinical events determined by the investigator: recurrent stroke, sICH, hypotension, hypertension\u003c/p\u003e\n\u003cp\u003eNational Institutes Health stroke scale (NIHSS): 0 (normal neurological status) to 42 (coma with quadriplegia), 43 (death) \u003cstrong\u003e[\u003c/strong\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDysphagia severity rating scale: 0 (normal oral intake), 12 (nil by mouth), 13 (death) [28]\u003c/p\u003e\n\u003cp\u003eBarthel Index: -5 (death) to 0 (severe disability) to 100 (no disability) [22]\u003c/p\u003e\n\u003cp\u003eModified telephone Mini-Mental State Examination (t-MMSE): -1 (death), 0 (severe dementia) to 18 (normal).\u003c/p\u003e\n\u003cp\u003eModified Telephone Interview for Cognitive Status (TICS-M): -1 (death, 0 (severe dementia) to 37 (normal).[29]\u003c/p\u003e\n\u003cp\u003eVerbal fluency (number of animals named in one minute): -1 (death), 0 (none named) to infinity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHealth utility status (HUS, derived from European Quality of Life-5 dimensions, EQ-5D): -0.5 (very poor quality of life, 0 (death) to 1.0 (perfect quality of life)\u003c/p\u003e\n\u003cp\u003eEuropean Quality of Life-Visual Analogue Scale (EQ-VAS): -1 (death), 0 (very poor) to 100 (excellent)\u003c/p\u003e\n\u003cp\u003eZung Depression Scale (ZDS): 0 (normal), 100 (severe depression) to 102.5 (death) [24]\u003c/p\u003e\n\u003cp\u003eGlobal outcome: continuous - mRS, BI, TICS-M, EQ-5D; binary - death, SAEs\u003c/p\u003e\n\u003cp\u003eTable 4. Serious adverse events by treatment group and relationship.\u003c/p\u003e\n\u003cp\u003eData are number (%). Comparisons by binary logistic regression.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFatal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSham\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSham\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eParticipants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of SAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreatment relationship\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBefore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDuring\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e22 (91.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (88.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (93.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAfter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRelationship to treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNot related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eImprobable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDefinite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOrgan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCardiovascular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.82 (0.17, 3.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNervous system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.25 (0.02, 2.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRespiratory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.18 (0.02, 1.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.85 (0.05, 14.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGenitourinary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHaematological/Immunological\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMetabolic/Endocrine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMusculoskeletal/Cutaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMiscellaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.79 (0.15, 21.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny SAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.77 (0.21, 2.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.18 (0.02, 1.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMiscellaneous SAEs: tongue haematoma, coffee ground vomiting, fall\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"5a602737-185e-471c-9ffc-65b17d7018ec","identifier":"10.13039/100011330","name":"Nottingham University Hospitals NHS Trust","awardNumber":"CRF-BATH-NOV 2019","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Nottingham","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acute stroke, blood pressure, glyceryl trinitrate, nitroglycerin, randomised controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-7494203/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7494203/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHigh blood pressure is associated with a poor outcome after stroke. Trials of transdermal glyceryl trinitrate (GTN), a nitric oxide donor, have suggested that treatment between 3 and 5 hours might improve functional outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe randomly assigned hospitalised patients with an acute ischaemic or haemorrhagic stroke to 2 days of transdermal glyceryl trinitrate (GTN, 5 mg/day) or sham, started between 3 and 5 hours after onset. The primary feasibility outcome was recruitment rate; proof of concept was assessed by central observers blinded to treatment assignment at 90 days using the modified Rankin Scale (mRS). Data are number (%), median [interquartile range] or mean (standard deviation). Comparisons by adjusted multiple linear regression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e39 of an intended 120 participants were recruited; common exclusions were presentation \u0026gt;5 hours of onset or out of researcher working hours, no eligible symptoms/signs or an unclear onset time. Mean age 72 (13) years, female 41%, blood pressure 161.8(18.4)/80.8(14.9) mmHg, time from onset at baseline 216 [186, 251] minutes. The fall in blood pressure over 24 hours did not differ between GTN versus sham. Headache was more common with GTN but there was no difference in serious adverse events. mRS at 3 months did not differ between the groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecruitment limitations prevented demonstration of feasibility for patients in the time window of 3-5 hours post ictus. GTN appeared safe and showed some evidence of proof-of-concept. A multicentre trial needs to further test this hypothesis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eISRCTN17654248\u003c/p\u003e\n\u003cp\u003eDate: 31/3/2021\u003c/p\u003e","manuscriptTitle":"Glyceryl trinitrate for treating hyperacute stroke: the Efficacy of Nitric Oxide in Stroke-2 (ENOS-2) feasibility randomised controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 09:52:41","doi":"10.21203/rs.3.rs-7494203/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4fa5da03-53d0-40ed-9146-336e1715fc57","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54235959,"name":"Clinical Pharmacology"},{"id":54235960,"name":"Neurology"},{"id":54235961,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2025-09-09T09:52:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-09 09:52:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7494203","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7494203","identity":"rs-7494203","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}