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.

Outcomes of endovascular thrombectomy for ischaemic stroke among nonagenarians with and without pre-existing dependency.

BACKGROUND: Our aim was to compare the outcomes of treatment with endovascular thrombectomy for pre-stroke dependent versus pre-stroke independent among the very elderly ≥90 years. METHODS: A retrospective cohort study was performed on 106 patients ≥90 years who underwent endovascular thrombectomy for ischaemic stroke in Western Australia between June 2016 and September 2021. Patient, stroke and procedural details along with inpatient progress and outcome at 90 days were recorded. Patients were divided into Group A (pre-stroke modified Rankin Scale 0-2) and Group B (pre-stroke modified Rankin Scale >2). Primary outcome measure was functional status at 90 days post-stroke, with favourable clinical outcome defined as a 90-day mRS category equal to the patients' respective pre-stroke mRS category. Secondary outcome measures include successful reperfusion, symptomatic intracranial haemorrhage, hospital length-of-stay, change in accommodation to an aged care facility, and mortality during admission, at 90 days and one year. RESULTS: 61 patients were allocated to Group A and 45 to Group B. There was none with pre-stroke mRS 5. Group B had more pre-existing cognitive impairment, aged care facility residents, higher median age and lower Alberta Stroke Program Early CT Score. For primary outcome measure, 38 % of patients in Group A and 49 % in Group B achieved a favourable clinical outcome. The difference was not significant (p=0.3408). For secondary outcome measures, Group B had a significantly higher 90-day mortality rate at 47 % versus 24 % in Group A (p=0.03). All other secondary outcome measures were similar between the two groups. These include the rate of successful reperfusion and symptomatic intracranial haemorrhage, hospital length-of-stay, new transition into an aged care facility, inpatient mortality rate and 1-year mortality rate. CONCLUSION: When treated with endovascular thrombectomy for ischaemic stroke, nonagenarians with pre-existing dependency achieved a rate of favourable functional outcome comparable with their independent peers, although they also had higher 90-day mortality rate.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome is a progressive, generally late-onset, neurological disorder associated with biallelic pentanucleotide expansions in Intron 2 of the RFC1 gene. The locus exhibits substantial genetic variability, with multiple pathogenic and benign pentanucleotide repeat alleles previously identified. To determine the contribution of pathogenic RFC1 expansions to neurological disease within an Australasian cohort and further investigate the heterogeneity exhibited at the locus, a combination of flanking and repeat-primed PCR was used to screen a cohort of 242 Australasian patients with neurological disease. Patients whose data indicated large gaps within expanded alleles following repeat-primed PCR, underwent targeted long-read sequencing to identify novel repeat motifs at the locus. To increase diagnostic yield, additional probes at the RFC1 repeat region were incorporated into the PathWest diagnostic laboratory targeted neurological disease gene panel to enable first-pass screening of the locus for all samples tested on the panel. Within the Australasian cohort, we detected known pathogenic biallelic expansions in 15.3% (n = 37) of patients. Thirty indicated biallelic AAGGG expansions, two had biallelic 'Maori alleles' [(AAAGG)exp(AAGGG)exp], two samples were compound heterozygous for the Maori allele and an AAGGG expansion, two samples had biallelic ACAGG expansions and one sample was compound heterozygous for the ACAGG and AAGGG expansions. Forty-five samples tested indicated the presence of biallelic expansions not known to be pathogenic. A large proportion (84%) showed complex interrupted patterns following repeat-primed PCR, suggesting that these expansions are likely to be comprised of more than one repeat motif, including previously unknown repeats. Using targeted long-read sequencing, we identified three novel repeat motifs in expanded alleles. Here, we also show that short-read sequencing can be used to reliably screen for the presence or absence of biallelic RFC1 expansions in all samples tested using the PathWest targeted neurological disease gene panel. Our results show that RFC1 pathogenic expansions make a substantial contribution to neurological disease in the Australasian population and further extend the heterogeneity of the locus. To accommodate the increased complexity, we outline a multi-step workflow utilizing both targeted short- and long-read sequencing to achieve a definitive genotype and provide accurate diagnoses for patients.

Cost-Effectiveness of Monitoring Patients Post-Stroke With Mobile ECG During the Hospital Stay.

Background The effectiveness of a nurse-led in-hospital monitoring protocol with mobile ECG (iECG) was investigated for detecting atrial fibrillation in patients post-ischemic stroke or post-transient ischemic attack. The study aimed to assess the cost-effectiveness of using iECG during the initial hospital stay compared with standard 24-hour Holter monitoring. Methods and Results A Markov microsimulation model was constructed to simulate the lifetime health outcomes and costs. The rate of atrial fibrillation detection in iECG and Holter monitoring during the in-hospital phase and characteristics of modeled population (ie, age, sex, CHA2DS2-VASc) were informed by patient-level data. Costs related to recurrent stroke, stroke management, medications (new oral anticoagulants), and rehabilitation were included. The cost-effectiveness analysis outcome was calculated as an incremental cost per quality-adjusted life-year gained. As results, monitoring patients with iECG post-stroke during the index hospitalization was associated with marginally higher costs (A$31 196) and greater benefits (6.70 quality-adjusted life-years) compared with 24-hour Holter surveillance (A$31 095 and 6.66 quality-adjusted life-years) over a 20-year time horizon, with an incremental cost-effectiveness ratio of $3013/ quality-adjusted life-years. Monitoring patients with iECG also contributed to lower recurrence of stroke and stroke-related deaths (140 recurrent strokes and 20 deaths avoided per 10 000 patients). The probabilistic sensitivity analyses suggested iECG is highly likely to be a cost-effective intervention (100% probability). Conclusions A nurse-led iECG monitoring protocol during the acute hospital stay was found to improve the rate of atrial fibrillation detection and contributed to slightly increased costs and improved health outcomes. Using iECG to monitor patients post-stroke during initial hospitalization is recommended to complement routine care.

Nurse Led Smartphone Electrographic Monitoring for Atrial Fibrillation after Ischemic Stroke: SPOT-AF.

BACKGROUND AND PURPOSE: Paroxysmal atrial fibrillation (PAF) underlying acute stroke frequently evades detection by standard practice, considered to be a combination of routine electrocardiogram (ECG) monitoring, and 24-hour Holter recordings. We hypothesized that nurse-led in-hospital intermittent monitoring approach would increase PAF detection rate. METHODS: We recruited patients hospitalised for stroke/transient ischemic attack, without history of atrial fibrillation (AF), in a prospective multi-centre observational study. Patients were monitored using a smartphone-enabled handheld ECG (iECG) during routine nursing observations, and underwent 24-hour Holter monitoring according to local practice. The primary outcome was comparison of AF detection by nurse-led iECG versus Holter monitoring in patients who received both tests: secondary outcome was oral anticoagulant commencement at 3-month following PAF detection. RESULTS: One thousand and seventy-nine patients underwent iECG monitoring: 294 had iECG and Holter monitoring. AF was detected in 25/294 (8.5%) by iECG, and 8/294 (2.8%) by 24-hour Holter recordings (P<0.001). Median duration from stroke onset to AF detection for iECG was 3 days (interquartile range [IQR], 2 to 6) compared with 7 days (IQR, 6 to 10) for Holter recordings (P=0.02). Of 25 patients with AF detected by iECG, 11 were commenced on oral anticoagulant, compared to 5/8 for Holter. AF was detected in 8.8% (69/785 patients) who underwent iECG recordings only (P=0.8 vs. those who had both iECG and 24-hour Holter). CONCLUSIONS: Nurse-led in-hospital iECG surveillance after stroke is feasible and effective and detects more PAF earlier and more frequently than routine 24-hour Holter recordings. Screening with iECG could be incorporated into routine post-stroke nursing observations to increase diagnosis of PAF, and facilitate institution of guideline-recommended anticoagulation.

Cerebral arterial gas embolism proven by computed tomography following transthoracic echocardiography using bubble contrast.

A 75 year-old male developed features of an acute stroke following bubble contrast echocardiography, which was shown on emergent computed tomography scanning to be a result of cerebral arterial gas embolism (CAGE) to the left middle cerebral artery. Ischaemic stroke symptoms have previously been reported as a rare complication of bubble contrast echocardiography. Radiologically proven CAGE from bubble contrast echocardiography had not been reported at the time this case occurred. Immediate provision of 100% oxygen and administration of hyperbaric oxygen are recommended treatments for CAGE and were associated with a substantial recovery for this patient.

Mechanical thrombectomy for anterior circulation stroke: 5-year experience in a statewide service with differences in pretreatment time metrics across two hospitals sites.

OBJECTIVE: To audit our institutional mechanical thrombectomy (MT) outcomes for acute anterior circulation stroke and examine the influence of workflow time metrics on patient outcomes. METHODS: A database of 100 MT cases was maintained throughout May 2010-February 2015 as part of a statewide service provided across two tertiary hospitals (H1 and H2). Patient demographics, stroke and procedural details, blinded angiographic outcomes, and 90-day modified Rankin Scale (mRS) scores were recorded. The following time points in stroke treatment were recorded: stroke onset, hospital presentation, CT imaging, arteriotomy, and recanalization. Statistical analysis of outcomes, predictors of outcome, and differences between the hospitals was carried out. RESULTS: Thrombolysis in Cerebral Infarction (TICI) 2b/3 reperfusion was 79%. Forty-nine per cent of patients had good clinical outcomes (mRS 0-2). In a subgroup analysis of 76 patients with premorbid mRS 0-1 and first CT performed ≤4.5 h after stroke onset, 60% had good clinical outcomes. Patient and disease characteristics were matched between the two hospitals. H1 had shorter times between hospital presentation and CT (32 vs 55 min, p=0.01), CT and arteriotomy (33 vs 69 min, p=0.00), and stroke onset and recanalization (198 vs 260 min, p=0.00). These time metrics independently predicted good clinical outcome. Median days spent at home in the first 90 days was greater at H1 (61 vs 8, p=0.04) than at H2. A greater proportion of patients treated at H1 were independent (mRS 0-2) at 90 days (54% vs 42%); however, this was not statistically significant (p=0.22). CONCLUSIONS: Outcomes similar to randomized controlled trials are attainable in 'real-world' settings. Workflow time metrics were independent predictors of clinical outcome, and differed between the two hospitals owing to site-specific organizational differences.

Delayed angiographic changes in postpartum cerebral angiopathy.

Postpartum cerebral angiopathy is a well-recognised subgroup of the reversible vasoconstriction syndromes. Increasingly described is a delay between clinical onset and angiographic changes. We report a patient who presented 19 days postpartum with severe thunderclap headaches, vertigo and a seizure. The clinical syndrome preceded evidence of extensive vasoconstriction on MRA imaging by 15 days; the changes were reversible at 3 months.

Validation of emergency and final diagnosis coding in transient ischemic attack: South Western Sydney transient ischemic attack study.

BACKGROUND: It is important to establish the validity of diagnostic coding in administrative datasets used in stroke and transient ischemic attack (TIA) research. This study examines the accuracy of emergency department (ED) TIA diagnosis and final diagnostic coding after hospital admission. METHODS: Using administrative datasets, we identified all patients with an ED TIA diagnosis (435.9; ICD-9) admitted to Liverpool Hospital from January 2003 to December 2007. ED and hospital admission records were matched and final diagnosis codes (ICD-10-AM) recorded. All records were expertly reviewed to determine coding validity. RESULTS: 570 patients were admitted with an ED TIA diagnosis. According to ICD-10-AM coding, 46% had TIA, 29% stroke and 25% TIA mimic diagnoses. Expert review determined final diagnoses of TIA in 51.4%, stroke in 26.1% and TIA mimic in 22.5% of the patients. The positive predictive value of a final TIA diagnosis (ICD-10-AM) was 88.2% when subjected to expert review. TIA mimic disorders diagnosed after admission included serious conditions. CONCLUSIONS: Half of the emergency diagnoses retained a TIA diagnosis after hospital admission. In the setting of neurological admission there were small percentage differences between coded final diagnosis for TIA, stroke and mimic and diagnoses at expert review. Admission of ED TIA cases permitted identification of TIA mimics with serious conditions requiring non-TIA management.

Decreasing presentations of seizures to emergency departments in a large Australian population.

This study was designed (1) to compare the prevalence of emergency department (ED) presentations in Western Zone Sydney South West Area Health Service (WZS) between 1998-2002 and 2003-2007 for epilepsy (including status epilepticus (SE) and convulsions), hospital admission rates, and proportion of first seizure presentations; and (2) to compare these data with those for New South Wales (NSW) and Australia-wide figures. Using health department data sets, we found 19,834 presentations to WZS EDs between 1998 and 2007 (24.85/10,000 population/year). When the periods 2003-2007 and 1998-2002 in WZS are compared, ED presentations fell by 3% (P=0.03) and hospital admissions fell by 6% (P=0.001). The prevalence of ED presentations for seizures in NSW did not change (P=0.92), but hospital admissions fell by 3% (P<0.0001). When 1999/2000-2002/2003 was compared with 2003/2004-2006/2007, the prevalence of hospital admissions in Australia fell by 1% (P=0.0002). Rates of presentation for epilepsy in WZS have fallen over the last decade. Most presentations were first seizures rather than recurrences. The reason for this is speculative, but may reflect improved levels of education and health care delivery.