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.

Evaluating artificial intelligence software for delineating hemorrhage extent on CT brain imaging in stroke: AI delineation of ICH on CT.

BACKGROUND: The extent and distribution of intracranial hemorrhage (ICH) directly affects clinical management. Artificial intelligence (AI) software can detect and may delineate ICH extent on brain CT. We evaluated e-ASPECTS software (Brainomix Ltd.) performance for ICH delineation. METHODS: We qualitatively assessed software delineation of ICH on CT using patients from six stroke trials. We assessed hemorrhage delineation in five compartments: lobar, deep, posterior fossa, intraventricular, extra-axial. We categorized delineation as excellent, good, moderate, or poor. We assessed quality of software delineation with number of affected compartments in univariate analysis (Kruskall-Wallis test) and ICH location using logistic regression (dependent variable: dichotomous delineation categories 'excellent-good' versus 'moderate-poor'), and report odds ratios (OR) and 95 % confidence intervals (95 %CI). RESULTS: From 651 patients with ICH (median age 75 years, 53 % male), we included 628 with assessable CTs. Software delineation of ICH extent was 'excellent' in 189/628 (30 %), 'good' in 255/628 (41 %), 'moderate' in 127/628 (20 %), and 'poor' in 57/628 cases (9 %). The quality of software delineation of ICH was better when fewer compartments were affected (Z = 3.61-6.27; p = 0.0063). Software delineation of ICH extent was more likely to be 'excellent-good' quality when lobar alone (OR = 1.56, 95 %CI = 0.97-2.53) but 'moderate-poor' with any intraventricular (OR = 0.56, 95 %CI = 0.39-0.81, p = 0.002) or any extra-axial (OR = 0.41, 95 %CI = 0.27-0.62, p<0.001) extension. CONCLUSIONS: Delineation of ICH extent on stroke CT scans by AI software was excellent or good in 71 % of cases but was more likely to over- or under-estimate extent when ICH was either more extensive, intraventricular, or extra-axial.

Poststroke Executive Function in Relation to White Matter Damage on Clinically Acquired CT Brain Imaging.

BACKGROUND: Executive function (EF) impairments are prevalent post stroke and are associated with white matter (WM) damage on MRI. However, less is known about the relationship between poststroke EF and WM damage on CT imaging. OBJECTIVE: To investigate the relationship between poststroke EF and WM damage associated with stroke lesions and WM hypointensities (WMHs) on clinically acquired CT imaging. METHOD: This study analyzed data from the Oxford Cognitive Screening Program, which recruited individuals aged ≥18 years with a confirmed stroke from an acute stroke unit. The individuals completed a follow-up assessment 6 months post stroke. We included individuals with a CT scan showing a visible stroke who completed follow-up EF assessment using the Oxford Cognitive Screen-Plus rule-finding task. We manually delineated stroke lesions and quantified then dichotomized WM damage caused by the stroke using the HCP-842 atlas. We visually rated then dichotomized WMHs using the Age-Related White Matter Changes Scale. RESULTS: Among 87 stroke survivors (M age = 73.60 ± 11.75; 41 female; 61 ischemic stroke), multivariable linear regression showed that stroke damage to the medial lemniscus ( B = -8.86, P < 0.001) and the presence of WMHs ( B = -5.42, P = 0.005) were associated with poorer EF 6 months post stroke after adjusting for covariates including age and education. CONCLUSION: Poorer EF was associated with WM damage caused by stroke lesions and WMHs on CT. These results confirm the importance of WM integrity for EF post stroke and demonstrate the prognostic utility of CT-derived imaging markers for poststroke cognitive outcomes.

Understanding the performance and reliability of NLP tools: a comparison of four NLP tools predicting stroke phenotypes in radiology reports.

Background: Natural language processing (NLP) has the potential to automate the reading of radiology reports, but there is a need to demonstrate that NLP methods are adaptable and reliable for use in real-world clinical applications. Methods: We tested the F1 score, precision, and recall to compare NLP tools on a cohort from a study on delirium using images and radiology reports from NHS Fife and a population-based cohort (Generation Scotland) that spans multiple National Health Service health boards. We compared four off-the-shelf rule-based and neural NLP tools (namely, EdIE-R, ALARM+, ESPRESSO, and Sem-EHR) and reported on their performance for three cerebrovascular phenotypes, namely, ischaemic stroke, small vessel disease (SVD), and atrophy. Clinical experts from the EdIE-R team defined phenotypes using labelling techniques developed in the development of EdIE-R, in conjunction with an expert researcher who read underlying images. Results: EdIE-R obtained the highest F1 score in both cohorts for ischaemic stroke, ≥93%, followed by ALARM+, ≥87%. The F1 score of ESPRESSO was ≥74%, whilst that of Sem-EHR is ≥66%, although ESPRESSO had the highest precision in both cohorts, 90% and 98%. For F1 scores for SVD, EdIE-R scored ≥98% and ALARM+ ≥90%. ESPRESSO scored lowest with ≥77% and Sem-EHR ≥81%. In NHS Fife, F1 scores for atrophy by EdIE-R and ALARM+ were 99%, dropping in Generation Scotland to 96% for EdIE-R and 91% for ALARM+. Sem-EHR performed lowest for atrophy at 89% in NHS Fife and 73% in Generation Scotland. When comparing NLP tool output with brain image reads using F1 scores, ALARM+ scored 80%, outperforming EdIE-R at 66% in ischaemic stroke. For SVD, EdIE-R performed best, scoring 84%, with Sem-EHR 82%. For atrophy, EdIE-R and both ALARM+ versions were comparable at 80%. Conclusions: The four NLP tools show varying F1 (and precision/recall) scores across all three phenotypes, although more apparent for ischaemic stroke. If NLP tools are to be used in clinical settings, this cannot be performed "out of the box." It is essential to understand the context of their development to assess whether they are suitable for the task at hand or whether further training, re-training, or modification is required to adapt tools to the target task.

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.

Accuracy of artificial intelligence software for CT angiography in stroke.

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

Baseline brain imaging signs in patients with ischaemic stroke by the presence of atrial fibrillation: the ENCHANTED trial.

BACKGROUND: We aimed to assess the association of atrial fibrillation (AF) on outcomes in a post hoc analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) and how this association is modified by baseline imaging features. METHODS: Inverse probability of treatment weight was used to remove baseline imbalances between those with and without AF. The primary outcome was the modified Rankin Scale (mRS) scores at 90 days. Secondary outcomes were symptomatic intracerebral haemorrhage (sICH), early neurological deterioration or death within 24 h, and death at 90 days. The logistic regression model was used to determine the associations. RESULTS: Of the 3285 patients included in this analysis, 636 (19%) had AF at baseline. Compared with non-AF, AF was not significantly associated with an unfavourable shift of mRS (odds ratio 1.09; 95% confidence interval, 0.96-1.24), but with sICH (2.82; 1.78-4.48; IST-3 criteria), early neurological deterioration or death within 24 h (1.31; 1.01-1.70), and death (1.42; 1.12-1.79). Among patients with acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions), AF was associated with the increased risk of all the poor outcomes (all P < 0.04 for interaction). CONCLUSIONS: We found AF increased risk of sICH, early neurological deterioration or death and death, but not unfavourable functional recovery at day 90 after thrombolysis in patients with AIS. The presence of acute ischaemic brain imaging signs at stroke presentation could be used to improve risk stratification in the presence of AF. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT01422616).

MRI for collateral assessment pre-thrombectomy and association with outcome: a systematic review and meta-analysis.

PURPOSE: Various neuroimaging methods exist to assess the collateral circulation in stroke patients but much of the evidence is based on computed tomography. Our aim was to review the evidence for using magnetic resonance imaging for collateral status evaluation pre-thrombectomy and assess the impact of these methods on functional independence. METHODS: We systematically reviewed EMBASE and MEDLINE for studies that evaluated baseline collaterals using MRI pre-thrombectomy and conducted a meta-analysis to express the relationship between good collaterals (defined variably as the presence [good] vs absence [poor] or quality [ordinal scores binarized as good-moderate vs poor] of collaterals) and functional independence (modified Rankin score mRS≤2) at 90 days. Outcome data were presented as relative risk (RR, 95% confidence interval, 95%CI). We assessed for study heterogeneity, publication bias, and conducted subgroup analyses of different MRI methods and affected arterial territories. RESULTS: From 497 studies identified, we included 24 (1957 patients) for the qualitative synthesis, and 6 (479 patients) for the metanalysis. Good pre-thrombectomy collaterals were significantly associated with favorable outcome at 90 days (RR=1.91, 95%CI=1.36-2.68], p= 0.0002) with no difference between MRI methods and affected arterial territory subgroups. There was no evidence of statistical heterogeneity (I2=25%) among studies but there was evidence of publication bias. CONCLUSION: In stroke patients treated with thrombectomy, good pre-treatment collaterals assessed using MRI are associated with double the rate of functional independence. However, we found evidence that relevant MR methods are heterogenous and under-reported. Greater standardization and clinical validation of MRI for collateral evaluation pre-thrombectomy are required.

Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial.

Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Assessing Brain Tissue Viability on Nonenhanced Computed Tomography After Ischemic Stroke.

BACKGROUND: Treatment for ischemic stroke can be offered beyond conventional time limits for patients with favorable computed tomography perfusion (CTP), but this is not universally available. We sought a threshold for brain attenuation on nonenhanced computed tomography (NECT) to differentiate CTP-defined penumbra vs core, and correlated NECT features with CTP. METHODS: We retrospectively assessed consecutive patients presenting to King Abdulaziz University Hospital with ischemic stroke (2017-2020), baseline NECT, and a visible defect on concurrent CTP. Using CTP as the reference standard, we measured the attenuation of ischemic and healthy contralateral brain on NECT to produce attenuation ratios (ischemic/normal) for penumbra and core. We used area under the receiver operating characteristic curve to estimate the optimal computed tomography (CT) attenuation ratio for penumbra. Per patient, we qualitatively assessed 8 regions within the affected cerebral hemisphere: on NECT as normal, hypoattenuating (with/out swelling), or isolated swelling and on CTP as normal, penumbra, or core. We sought associations between isolated swelling and penumbra, and between hypoattenuation and core. RESULTS: We include 142 patients (86 male), mean age 61±14 years. Median 261 minutes (interquartile range, 173-382) to NECT. We measured 206 ischemic lesions (124 penumbra, 82 core). Optimal CT attenuation ratio for identifying penumbra was >0.87, with 86% sensitivity 91% specificity (area under the receiver operating characteristic curve, 0.95 [95% CI, 0.92-0.98]; P<0.0001). We qualitatively assessed 976 cerebral regions (72 isolated swelling, 254 hypoattenuation). On NECT, isolated swelling usually corresponded to CTP penumbra (70/72, 97%), whereas visible NECT hypoattenuation was found with core (141/254, 56%) and penumbra (109/254, 43%). CTP core lesions were rarely normal on NECT (13/155, 8%). CONCLUSIONS: After ischemic stroke, brain tissue viability can be assessed using NECT. Isolated swelling is highly specific to penumbra. Visible hypoattenuation does not always represent core, nearly half of such lesions were penumbral on concurrent CTP and can be differentiated by measuring lesion attenuation.

External Validation of e-ASPECTS Software for Interpreting Brain CT in Stroke.

OBJECTIVE: The purpose of this study was to test e-ASPECTS software in patients with stroke. Marketed as a decision-support tool, e-ASPECTS may detect features of ischemia or hemorrhage on computed tomography (CT) imaging and quantify ischemic extent using Alberta Stroke Program Early CT Score (ASPECTS). METHODS: Using CT from 9 stroke studies, we compared software with masked experts. As per indications for software use, we assessed e-ASPECTS results for patients with/without middle cerebral artery (MCA) ischemia but no other cause of stroke. In an analysis outside the intended use of the software, we enriched our dataset with non-MCA ischemia, hemorrhage, and mimics to simulate a representative "front door" hospital population. With final diagnosis as the reference standard, we tested the diagnostic accuracy of e-ASPECTS for identifying stroke features (ischemia, hyperattenuated arteries, and hemorrhage) in the representative population. RESULTS: We included 4,100 patients (51% women, median age = 78 years, National Institutes of Health Stroke Scale [NIHSS] = 10, onset to scan = 2.5 hours). Final diagnosis was ischemia (78%), hemorrhage (14%), or mimic (8%). From 3,035 CTs with expert-rated ASPECTS, most (2084/3035, 69%) e-ASPECTS results were within one point of experts. In the representative population, the diagnostic accuracy of e-ASPECTS was 71% (95% confidence interval [CI] = 70-72%) for detecting ischemic features, 85% (83-86%) for hemorrhage. Software identified more false positive ischemia (12% vs 2%) and hemorrhage (14% vs <1%) than experts. INTERPRETATION: On independent testing, e-ASPECTS provided moderate agreement with experts and overcalled stroke features. Therefore, future prospective trials testing impacts of artificial intelligence (AI) software on patient care and outcome are required before widespread implementation of stroke decision-support software. ANN NEUROL 2022;92:943-957.

A daily temperature rhythm in the human brain predicts survival after brain injury.

Patients undergo interventions to achieve a 'normal' brain temperature; a parameter that remains undefined for humans. The profound sensitivity of neuronal function to temperature implies the brain should be isothermal, but observations from patients and non-human primates suggest significant spatiotemporal variation. We aimed to determine the clinical relevance of brain temperature in patients by establishing how much it varies in healthy adults. We retrospectively screened data for all patients recruited to the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High Resolution Intensive Care Unit Sub-Study. Only patients with direct brain temperature measurements and without targeted temperature management were included. To interpret patient analyses, we prospectively recruited 40 healthy adults (20 males, 20 females, 20-40 years) for brain thermometry using magnetic resonance spectroscopy. Participants were scanned in the morning, afternoon, and late evening of a single day. In patients (n = 114), brain temperature ranged from 32.6 to 42.3°C and mean brain temperature (38.5 ± 0.8°C) exceeded body temperature (37.5 ± 0.5°C, P < 0.0001). Of 100 patients eligible for brain temperature rhythm analysis, 25 displayed a daily rhythm, and the brain temperature range decreased in older patients (P = 0.018). In healthy participants, brain temperature ranged from 36.1 to 40.9°C; mean brain temperature (38.5 ± 0.4°C) exceeded oral temperature (36.0 ± 0.5°C) and was 0.36°C higher in luteal females relative to follicular females and males (P = 0.0006 and P < 0.0001, respectively). Temperature increased with age, most notably in deep brain regions (0.6°C over 20 years, P = 0.0002), and varied spatially by 2.41 ± 0.46°C with highest temperatures in the thalamus. Brain temperature varied by time of day, especially in deep regions (0.86°C, P = 0.0001), and was lowest at night. From the healthy data we built HEATWAVE-a 4D map of human brain temperature. Testing the clinical relevance of HEATWAVE in patients, we found that lack of a daily brain temperature rhythm increased the odds of death in intensive care 21-fold (P = 0.016), whilst absolute temperature maxima or minima did not predict outcome. A warmer mean brain temperature was associated with survival (P = 0.035), however, and ageing by 10 years increased the odds of death 11-fold (P = 0.0002). Human brain temperature is higher and varies more than previously assumed-by age, sex, menstrual cycle, brain region, and time of day. This has major implications for temperature monitoring and management, with daily brain temperature rhythmicity emerging as one of the strongest single predictors of survival after brain injury. We conclude that daily rhythmic brain temperature variation-not absolute brain temperature-is one way in which human brain physiology may be distinguished from pathophysiology.

Accuracy of Automated Computer-Aided Diagnosis for Stroke Imaging: A Critical Evaluation of Current Evidence.

There is increasing interest in computer applications, using artificial intelligence methodologies, to perform health care tasks previously performed by humans, particularly in medical imaging for diagnosis. In stroke, there are now commercial artificial intelligence software for use with computed tomography or MR imaging to identify acute ischemic brain tissue pathology, arterial obstruction on computed tomography angiography or as hyperattenuated arteries on computed tomography, brain hemorrhage, or size of perfusion defects. A rapid, accurate diagnosis may aid treatment decisions for individual patients and could improve outcome if it leads to effective and safe treatment; or conversely, to disaster if a delayed or incorrect diagnosis results in inappropriate treatment. Despite this potential clinical impact, diagnostic tools including artificial intelligence methods are not subjected to the same clinical evaluation standards as are mandatory for drugs. Here, we provide an evidence-based review of the pros and cons of commercially available automated methods for medical imaging diagnosis, including those based on artificial intelligence, to diagnose acute brain pathology on computed tomography or magnetic resonance imaging in patients with stroke.

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 .

Thrombolysis outcomes according to arterial characteristics of acute ischemic stroke by alteplase dose and blood pressure target.

BACKGROUND: We explored the influence of low-dose intravenous alteplase and intensive blood pressure lowering on outcomes of acute ischemic stroke according to status/location of vascular obstruction in participants of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: ENCHANTED was a multicenter, quasi-factorial, randomized trial to determine efficacy and safety of low- versus standard-dose intravenous alteplase and intensive- versus guideline-recommended blood pressure lowering in acute ischemic stroke patients. In those who had baseline computed tomography or magnetic resonance imaging angiography, the degree of vascular occlusion was grouped according to being no (NVO), medium (MVO), or large (LVO). Logistic regression models were used to determine 90-day outcomes (modified Rankin scale [mRS] shift [primary], other mRS cut-scores, intracranial hemorrhage, early neurologic deterioration, and recanalization) by vascular obstruction status/site. Heterogeneity in associations for outcomes across subgroups was estimated by adding an interaction term to the models. RESULTS: There were 940 participants: 607 in alteplase arm only, 243 in blood pressure arm only, and 90 assigned to both arms. Compared to the NVO group, functional outcome was worse in LVO (mRS shift, adjusted OR [95% CI] 2.13 [1.56-2.90]) but comparable in MVO (1.34 [0.96-1.88]) groups. There were no differences in associations of alteplase dose or blood pressure lowering and outcomes across NVO/MVO/LVO groups (mRS shift: low versus standard alteplase dose 0.84 [0.54-1.30]/0.48 [0.25-0.91]/0.99 [0.75-2.09], Pinteraction = 0.28; intensive versus standard blood pressure lowering 1.32 [0.74-2.38]/0.78 [0.31-1.94]/1.24 [0.64-2.41], Pinteraction = 0.41), except for a borderline significant difference for intensive blood pressure lowering and increased early neurologic deterioration (0.63 [0.14-2.72]/0.17 [0.02-1.47]/2.69 [0.90-8.04], Pinteraction = 0.05). CONCLUSIONS: Functional outcome by dose of alteplase or intensity of blood pressure lowering is not modified by vascular obstruction status/site according to analyses from ENCHANTED, although these results are compromised by low statistical power.Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifiers: NCT01422616.

Normal Appearing Ischaemic Brain Tissue on CT and Outcome After Intravenous Alteplase.

Background and Aims: The visibility of ischaemic brain lesions on non-enhanced CT increases with time. Obviously hypoattenuating lesions likely represent infarction. Conversely, viable ischaemic brain lesions may be non-visible on CT. We tested whether patients with normal appearing ischaemic brain tissue (NAIBT) on their initial CT are identifiable, and if NAIBT yields better outcomes with alteplase. Methods: With data from the Third International Stroke Trial (IST-3, a large randomized-controlled trial of intravenous alteplase for ischaemic stroke) we used receiver-operating characteristic analysis to find a baseline National Institutes of Health Stroke Scale (NIHSS) threshold for identifying patients who developed medium-large ischaemic lesions within 48 h. From patients with baseline CT (acquired <6 h from stroke onset), we used this NIHSS threshold for selection and tested whether favorable outcome after alteplase (6-month Oxford Handicap Score 0-2) differed between patients with NAIBT vs. with those with visible lesions on baseline CT using binary logistic regression (controlled for age, NIHSS, time from stroke onset to CT). Results: From 2,961 patients (median age 81 years, median 2.6 h from stroke onset, 1,534 [51.8%] female, 1,484 [50.1%] allocated alteplase), NIHSS>11 best identified those with medium-large ischaemic lesions (area under curve = 0.79, sensitivity = 72.3%, specificity = 71.9%). In IST-3, 1,404/2,961 (47.4%) patients had baseline CT and NIHSS>11. Of these, 745/1,404 (53.1%) had visible baseline ischaemic lesions, 659/1,404 (46.9%) did not (NAIBT). Adjusted odds ratio for favorable outcome after alteplase was 1.54 (95% confidence interval, 1.01-2.36), p = 0.045 among patients with NAIBT vs. 1.61 (0.97-2.67), p = 0.066 for patients with visible lesions, with no evidence of an alteplase-NAIBT interaction (p-value = 0.895). Conclusions: Patients with ischaemic stroke and NIHSS >11 commonly develop sizeable ischaemic brain lesions by 48 h that may not be visible within 6 h of stroke onset. Invisible ischaemic lesions may indicate tissue viability. In IST-3, patients with this clinical-radiological mismatch allocated to alteplase achieved more favorable outcome than those allocated to control.

Early decompressive hemicraniectomy in thrombolyzed acute ischemic stroke patients from the international ENCHANTED trial.

Decompressive hemicraniectomy (DHC) can improve outcomes for patients with severe forms of acute ischemic stroke (AIS), but the evidence is mainly derived from non-thrombolyzed patients. We aimed to determine the characteristics and outcomes of early DHC in thrombolyzed AIS participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Post-hoc analyses of ENCHANTED, an international, partial-factorial, open, blinded outcome-assessed, controlled trial in 4557 thrombolysis-eligible AIS patients randomized to low- versus standard-dose intravenous alteplase (Arm A, n = 2350), intensive versus guideline-recommended blood pressure control (Arm B, n = 1280), or both (Arms A + B, n = 947). Logistic regression models were used to identify baseline variables associated with DHC, with inverse probability of treatment weights employed to eliminate baseline imbalances between those with and without DHC. Logistic regression was also used to determine associations of DHC and clinical outcomes of death/disability, major disability, and death (defined by scores 2-6, 3-5, and 6, respectively, on the modified Rankin scale) at 90 days post-randomization. There were 95 (2.1%) thrombolyzed AIS patients who underwent DHC, who were significantly younger, of non-Asian ethnicity, and more likely to have had prior lipid-lowering treatment and severe neurological impairment from large vessel occlusion than other patients. DHC patients were more likely to receive other management interventions and have poor functional outcomes than non-DHC patients, with no relation to different doses of intravenous alteplase. Compared to other thrombolyzed AIS patients, those who received DHC had a poor prognosis from more severe disease despite intensive in-hospital management.

Low-Dose vs Standard-Dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial.

OBJECTIVE: To determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar acute ischemic stroke (AIS), we performed post hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose arm. METHODS: In a cohort of 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin Scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables. RESULTS: Of 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all p interaction ≥0.07). CONCLUSIONS: We found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definite/probable lacunar AIS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01422616.

Hyperdense artery sign, symptomatic infarct swelling and effect of alteplase in acute ischaemic stroke.

BACKGROUND: Alteplase improves functional outcomes of patients with acute ischaemic stroke, but its effects on symptomatic infarct swelling, an adverse complication of stroke and the influence of CT hyperdense artery sign (HAS) are unclear. This substudy of the Third International Stroke Trial aimed to investigate the association between HAS and symptomatic infarct swelling and effect of intravenous alteplase on this association. METHODS: We included stroke patients whose prerandomisation scan was non-contrast CT. Raters, masked to clinical information, assessed baseline (prerandomisation) and follow-up (24-48 hours postrandomisation) CT scans for HAS, defined as an intracranial artery appearing denser than contralateral arteries. Symptomatic infarct swelling was defined as clinically significant neurological deterioration ≤7 days after stroke with radiological evidence of midline shift, effacement of basal cisterns or uncal herniation. RESULTS: Among 2961 patients, HAS presence at baseline was associated with higher risk of symptomatic infarct swelling (OR 2.21; 95% CI 1.42 to 3.44). Alteplase increased the risk of swelling (OR 1.69; 95% CI 1.11 to 2.57), with no difference between patients with and those without baseline HAS (p=0.49). In patients with baseline HAS, alteplase reduced the proportion with HAS at follow-up (OR 0.67; 95% CI 0.50 to 0.91), where HAS disappearance was associated with reduced risk of swelling (OR 0.25, 95% CI 0.14 to 0.47). CONCLUSION: Although alteplase was associated with increased risk of symptomatic infarct swelling in patients with or without baseline HAS, it was also associated with accelerated clearance of HAS, which in return reduced swelling, providing further mechanistic insights to underpin the benefits of alteplase.