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.

Thrombolytic therapies for ischemic stroke: Triumphs and future challenges.

Acute stroke therapy has significantly evolved over the last two decades. The two main advances have been the approval of intravenous chemical thrombolysis in 1995, and the approval of intra-arterial mechanical thrombectomy in 2015. This has led to significant improvement of functional outcomes in a disease known to be the first cause of disability worldwide. Subsequent studies have focused on identifying pre-treatment predictors of good treatment candidates, by developing biochemical and imaging biomarkers. Different doses and agents of thrombolysis are also being tested. In this review article, we explain the fundamentals of stroke therapy focusing on the time, recanalization and collateral perfusion factors. We then review recent advances in stroke thrombolysis, the most significant of which is the recent trials on a novel rtPA agent, tenecteplase, and approval of endovascular treatment as a standard of care. Looking ahead, defining the benefits and limitations of bridging chemical with mechanical thrombolysis is a key area of current interest. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

Short- and Long-Term Reduction of Door-to-Needle Time in Thrombolysis for Acute Stroke.

BACKGROUND: More timely administration of tissue plasminogen activator (alteplase) for patients with acute ischemic stroke yields greater clinical benefits. We implemented door-to-needle (DTN) time reduction strategies at our center and evaluated their short- and long-term effects on in-hospital treatment delays and clinical outcomes. METHODS: Strategies, including stroke team prenotification, direct computed tomography transfer, not routinely waiting for laboratory results and alteplase delivery on the computed tomography table, were implemented in June 2013. We included all thrombolysed patients admitted directly to our hospital between January 2012 and March 2015. In-hospital delays and symptomatic intracerebral hemorrhage rates were compared between patients pre- and postmodification, and the latter period was divided into early (first 6 months) and late (beyond 6 months) phases to assess the durability of our modifications. RESULTS: Forty-eight individuals were treated premodification compared with 58 postmodification. The median DTN time was reduced from 75 to 46 minutes (p<0.0001). The median DTN time in the early and late postmodification phases was not significantly different (41 vs 46 minutes, p=0.4085). There was no significant difference in rates of symptomatic intracerebral hemorrhage (4.2 vs 1.7%, p=0.361) or stroke mimics (2.1 ves 5.2%, p=0.625) Conclusions: We were able to decrease our DTN time for acute stroke thrombolysis by implementing relatively simple modifications and these improvements persisted over time.

A novel neural substrate for the transformation of olfactory inputs into motor output.

It is widely recognized that animals respond to odors by generating or modulating specific motor behaviors. These reactions are important for daily activities, reproduction, and survival. In the sea lamprey, mating occurs after ovulated females are attracted to spawning sites by male sex pheromones. The ubiquity and reliability of olfactory-motor behavioral responses in vertebrates suggest tight coupling between the olfactory system and brain areas controlling movements. However, the circuitry and the underlying cellular neural mechanisms remain largely unknown. Using lamprey brain preparations, and electrophysiology, calcium imaging, and tract tracing experiments, we describe the neural substrate responsible for transforming an olfactory input into a locomotor output. We found that olfactory stimulation with naturally occurring odors and pheromones induced large excitatory responses in reticulospinal cells, the command neurons for locomotion. We have also identified the anatomy and physiology of this circuit. The olfactory input was relayed in the medial part of the olfactory bulb, in the posterior tuberculum, in the mesencephalic locomotor region, to finally reach reticulospinal cells in the hindbrain. Activation of this olfactory-motor pathway generated rhythmic ventral root discharges and swimming movements. Our study bridges the gap between behavior and cellular neural mechanisms in vertebrates, identifying a specific subsystem within the CNS, dedicated to producing motor responses to olfactory inputs.