Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Dural arteriovenous fistula causing reversible cognitive impairment.

A previously independent 82-year-old woman presented with 5 months of worsening confusion, mobility and cognitive decline, with deficits in orientation, language and executive function. A cerebral dural arteriovenous fistula was identified and successfully embolised, after which her cognitive ability and independence dramatically improved. Although rare, a dural arteriovenous fistula may mimic a rapidly progressive dementia, but its early recognition and treatment can completely reverse the dementia.

Pre-hospital transdermal glyceryl trinitrate in patients with stroke mimics: data from the RIGHT-2 randomised-controlled ambulance trial.

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

Characteristics and outcomes of COVID-19 associated stroke: a UK multicentre case-control study.

OBJECTIVE: We set out to determine which characteristics and outcomes of stroke are associated with COVID-19. METHODS: This case-control study included patients admitted with stroke to 13 hospitals in England and Scotland between 9 March and 5 July 2020. We collected data on 86 strokes (81 ischaemic strokes and 5 intracerebral haemorrhages) in patients with evidence of COVID-19 at the time of stroke onset (cases). They were compared with 1384 strokes (1193 ischaemic strokes and 191 intracerebral haemorrhages) in patients admitted during the same time period who never had evidence of COVID-19 (controls). In addition, the whole group of stroke admissions, including another 37 patients who appeared to have developed COVID-19 after their stroke, were included in two logistic regression analyses examining which features were independently associated with COVID-19 status and with inpatient mortality. RESULTS: Cases with ischaemic stroke were more likely than ischaemic controls to occur in Asians (18.8% vs 6.7%, p<0.0002), were more likely to involve multiple large vessel occlusions (17.9% vs 8.1%, p<0.03), were more severe (median National Institutes of Health Stroke Scale score 8 vs 5, p<0.002), were associated with higher D-dimer levels (p<0.01) and were associated with more severe disability on discharge (median modified Rankin Scale score 4 vs 3, p<0.0001) and inpatient death (19.8% vs 6.9%, p<0.0001). Recurrence of stroke during the patient's admission was rare in cases and controls (2.3% vs 1.0%, NS). CONCLUSIONS: Our data suggest that COVID-19 may be an important modifier of the onset, characteristics and outcome of acute ischaemic stroke.

Views of paramedics on their role in an out-of-hospital ambulance-based trial in ultra-acute stroke: qualitative data from the Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT).

STUDY OBJECTIVE: Optimal practices for recruiting, consenting, and randomizing patients, and delivering treatment in out-of-hospital ultra-acute stroke trials, remain unclear. We aim to identify key barriers and facilitators relevant to the design and conduct of ambulance-based stroke trials and to formulate preliminary recommendations for the design of future trials. METHODS: Using semistructured interviews, we investigated the experiences and challenges faced by paramedics who took part in a randomized controlled trial in suspected ultra-acute stroke, the Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT), in which recruitment, consent, randomization, assessment, and treatment were delivered by paramedics before hospitalization. RESULTS: We purposively selected a diversity sample of 14 of the 78 paramedics who participated in RIGHT. We identified 13 themes (7 facilitators and 6 barriers to out-of-hospital stroke research). A simple stroke diagnostic tool, use of proxy consent on behalf of patients, and straightforward trial processes were identified as the main facilitators. Recruitment became easier with each new randomization attempt. Key barriers reported were informed consent in the emergency setting, lack of institutional support for research, learning curve and rarity (each paramedic treats only a few eligible patients), and difficulty in attending training sessions. Interviewed paramedics were motivated to participate in research. CONCLUSION: Ultra-acute stroke research in the out-of-hospital environment is feasible, but important barriers need to be addressed. Proxy consent by paramedics addresses some of the difficulties with the consent process in the out-of-hospital setting.

Relationship between poststroke cognition, baseline factors, and functional outcome: data from "efficacy of nitric oxide in stroke" trial.

BACKGROUND: Poststroke cognitive impairment is common and identification of prognostic factors associated with it and its relationship with other functional outcomes may help in developing preventative strategies. METHODS: Previously independent patients with acute stroke, enrolled into the ongoing "Efficacy of Nitric Oxide in Stroke" trial, were assessed by telephone on day 90 for cognitive impairment using modified versions of "Mini Mental State Examination" (MMSE-M) and "Telephone Instrument for Cognitive Status" (TICS-M) scales and category fluency. The relationship of cognitive impairment with baseline prognostic factors and other functional outcomes at day 90 were studied. RESULTS: The analysis included 1572 patients, mean age 69 years (standard deviation, 12), and female 40%. By 90 days, 246 patients had died, and cognitive impairment was present in 38%. Increasing age, stroke severity, heart rate, and presence of cerebral atrophy on baseline neuroimaging were associated with cognitive impairment (all P < .001). Hypertension and atrial fibrillation were also associated with category fluency and MMSE-M, respectively. Cognition was significantly related to other functional outcomes, TICS-M with dependency (modified Rankin Scale, rs = -.562, P < .001); disability (Barthel Index, rs = .577, P < .001); mood (Zung Depression Score, rs = -.542, P < .001); and quality of life (Euro Quality of life-5 Descriptor, rs = .519, P < .001). CONCLUSIONS: In previously independent individuals, cognitive impairment was common 3 months after stroke and related to increasing age, stroke severity, hypertension, atrial fibrillation, and cerebral atrophy on brain scanning. Cognition was related to dependency, disability, low mood, and quality of life. Hence, treatment directed toward reducing dependency might also reduce cognitive impairment.

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

BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined 'brain frailty' markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging 'brain frailty' was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

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).

BACKGROUND AND PURPOSE: The practicalities of doing ambulance-based trials where paramedics perform all aspects of a clinical trial involving patients with ultra-acute stroke have not been assessed. METHODS: We performed a randomized controlled trial with screening, consent, randomization, and treatment performed by paramedics prior to hospitalization. Patients with probable ultra-acute stroke (<4 hours) and systolic blood pressure (SBP) >140 mm Hg were randomized to transdermal glyceryl trinitrate (GTN; 5 mg/24 hours) or none (blinding under gauze dressing) for 7 days with the first dose given by paramedics. The primary outcome was SBP at 2 hours. RESULTS: Of a planned 80 patients, 41 (25 GTN, 16 no GTN) were enrolled >22 months with median age [interquartile range] 79 [16] years; men 22 (54%); SBP 168 [46]; final diagnosis: stroke 33 (80%) and transient ischemic attack 3 (7%). Time to randomization was 55 [75] minutes. After treatment with GTN versus no GTN, SBP at 2 hours was 153 [31] versus 174 [27] mm Hg, respectively, with difference -18 [30] mm Hg (P=0.030). GTN improved functional outcome with a shift in the modified Rankin Scale by 1 [3] point (P=0.040). The rates of death, 4 (16%) versus 6 (38%; P=0.15), and serious adverse events, 14 (56%) versus 10 (63%; P=0.75), did not differ between GTN and no GTN. CONCLUSIONS: Paramedics can successfully enroll patients with ultra-acute stroke into an ambulance-based trial. GTN reduces SBP at 2 hours and seems to be safe in ultra-acute stroke. A larger trial is needed to assess whether GTN improves functional outcome. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com/ISRCTN66434824/66434824. Unique identifier: 66434824.

Effect of the neutral CLOTS 1 trial on the use of graduated compression stockings in the Efficacy of Nitric Oxide Stroke (ENOS) trial.

BACKGROUND AND PURPOSE: Current evidence suggests that the time lag from the publication of randomised clinical trial results to changes in prescribing behaviour for drugs is gradually reducing. However, the effect of results of clinical trials of devices and non-pharmacological interventions on clinical practice is less clear. METHODS: Prospective data from the ongoing international 'Efficacy of Nitric Oxide Stroke' (ENOS) trial were analysed to assess the use of graduated compression stockings (GCS) for deep vein thrombus (DVT) prophylaxis in acute stroke patients before and after publication of the large 'Clots in Legs Or sTockings after Stroke' (CLOTS-1) trial. RESULTS: Data on GCS use were available for 1971 patients with acute stroke enrolled into ENOS from February 2003 to April 2011; of these, 498 (25.3%) wore GCS. Prior to publication of CLOTS-1, GCS use was common (>50%) in the UK, Australasia and Canada but infrequent in Asia and the rest of Europe. After publication of CLOTS-1, use of GCS in the UK declined from 398/656 (61%) to 20/567 (4%) (p<0.001) but not elsewhere (eg, in Australasia (57% before publication vs 70% after publication, p=0.24, but based on small numbers). Practice change was apparent within 3 months of the study publication and was sustained thereafter. There was no change in DVT rates before and after CLOTS-1 (0.8% vs 1.0%). CONCLUSIONS: GCS use declined dramatically following the reporting of the CLOTS-1 trial. The results support the notion that a neutral trial of a device can influence clinical practice rapidly, which is important with a widely used and moderately expensive (time and finance) intervention.

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): effects on outcomes at day 365 in a randomised, sham-controlled, blinded, phase III, superiority ambulance-based trial.

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

Intensive versus Guideline Blood Pressure and Lipid Lowering in Patients with Previous Stroke: Main Results from the Pilot 'Prevention of Decline in Cognition after Stroke Trial' (PODCAST) Randomised Controlled Trial.

BACKGROUND: Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. METHODS: In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125-170 mmHg were assigned randomly to at least 6 months of intensive (target SBP <125 mmHg) or guideline (target SBP <140 mmHg) BP lowering. The subset of patients with ischaemic stroke and total cholesterol 3.0-8.0 mmol/l were also assigned randomly to intensive (target LDL-cholesterol <1.3 mmol/l) or guideline (target LDL-c <3.0 mmol/l) lipid lowering. The primary outcome was the Addenbrooke's Cognitive Examination-Revised (ACE-R). RESULTS: We enrolled 83 patients, mean age 74.0 (6.8) years, and median 4.5 months after stroke. The median follow-up was 24 months (range 1-48). Mean BP was significantly reduced with intensive compared to guideline treatment (difference -10·6/-5·5 mmHg; p<0·01), as was total/LDL-cholesterol with intensive lipid lowering compared to guideline (difference -0·54/-0·44 mmol/l; p<0·01). The ACE-R score during treatment did not differ for either treatment comparison; mean difference for BP lowering -3.6 (95% CI -9.7 to 2.4), and lipid lowering 4.4 (95% CI -2.1 to 10.9). However, intensive lipid lowering therapy was significantly associated with improved scores for ACE-R at 6 months, trail making A, modified Rankin Scale and Euro-Qol Visual Analogue Scale. There was no difference in rates of dementia or serious adverse events for either comparison. CONCLUSION: In patients with recent stroke and normal cognition, intensive BP and lipid lowering were feasible and safe, but did not alter cognition over two years. The association between intensive lipid lowering and improved scores for some secondary outcomes suggests further trials are warranted. TRIAL REGISTRATION: ISRCTN ISRCTN85562386.

The cog-4 subset of the national institutes of health stroke scale as a measure of cognition: relationship with baseline factors and functional outcome after stroke using data from the virtual international stroke trials archive.

Background. Assessing poststroke cognitive impairment is complex. A subscale of the NIHSS, the Cog-4, has been proposed as a quick test of "cognitive impairment." but a study of its properties in a larger dataset is lacking. Methods. Data from 9,147 patients with acute stroke from the VISTA archive was used to generate Cog-4 scores. The statistical properties of Cog-4, its relationship with baseline clinical characteristics, and other functional outcome measures at day 90 were assessed. Results. Mean age of patients was 69.2 years and 45.8%, were females. Day-90 Cog-4 was highly positively skewed (skewness 0.926). Patients with left hemispheric stroke had higher day-90 Cog-4 score (P < 0.001). Age, stroke severity, and previous stroke were significant predictors of Cog-4. Cog-4 was significantly correlated with dependency (modified Rankin Scale, r s = 0.512), and disability (Barthel Index, r s = -0.493). Conclusions. The Cog-4 scale at day 90 cannot be considered a useful test of cognition since it only superficially measures cognition. It is heavily dependent on the side of stroke, is inevitably associated with functional outcome (being a subset of the NIHSS), and suffers from a profound "floor" effect. Specific and validated measures are more appropriate for the assessment of poststroke cognition than Cog-4.

The influence of stroke risk factors and comorbidities on assessment of stroke therapies in humans and animals.

The main driving force behind the assessment of novel pharmacological agents in animal models of stroke is to deliver new drugs to treat the human disease rather than to increase knowledge of stroke pathophysiology. There are numerous animal models of the ischaemic process and it appears that the same processes operate in humans. Yet, despite these similarities, the drugs that appear effective in animal models have not worked in clinical trials. To date, tissue plasminogen activator is the only drug that has been successfully used at the bedside in hyperacute stroke management. Several reasons have been put forth to explain this, but the failure to consider comorbidities and risk factors common in older people is an important one. In this article, we review the impact of the risk factors most studied in animal models of acute stroke and highlight the parallels with human stroke, and, where possible, their influence on evaluation of therapeutic strategies.

Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the "Rapid Intervention with GTN in Hypertensive Stroke Trial" (RIGHT, ISRCTN66434824).

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

Clinical trials for preventing post stroke cognitive impairment.

Post stroke dementia (PSD) develops in up to 40% of patients and often co-exists with Alzheimer's disease in the elderly. Unsurprisingly, the combination of stroke and dementia is associated with considerable morbidity and mortality, and is devastating to patients and carers. Limited trial evidence suggests that lowering high blood pressure reduces the development of cognitive decline, vascular dementia and PSD, although whether this relates to the magnitude of BP reduction or specific drug classes remains unclear. Biological plausibility and/or existing studies suggest that other types of drug treatments might also be effective, including choline esterase inhibitors, lipid lowering agents, antiplatelet agents, and selective serotonin reuptake inhibitors. Preventing cognitive decline and dementia post stroke is critical and large definitive trials are now needed.