Tenecteplase (TNK) is a third generation tissue plasminogen activator and is currently indicated for the thrombolytic treatment of acute myocardial infarction at a dose of 0.5mg/kg.¹ Presenting higher fibrin specificity, no evidence of neurotoxicity or effect on blood-brain barrier and much higher resistance to tissue plasminogen activator inhibitor type 1 compared to alteplase, has emphasized the potential efficacy and safety of TNK in the treatment of acute ischemic stroke as well.² Another important pharmacological property is the longer half-life of TNK, allowing for a single bolus injection and achieving a fast recanalization.³ The COVID-19 pandemic and the associated restrictions have highlighted even more the importance of this practical advantage of TNK over alteplase use, in the sense that it reduces the staff exposure to contagion.⁴

From theory to action, in 2021 and based on the results of the available randomized-controlled clinical trials (RCTs; ATTEST, Australian-TNK, and EXTEND-IA TNK trials),^5,6 the European Stroke Organisation (ESO) presented the guidelines on intravenous thrombolysis for acute ischaemic stroke, recommending that in patients with large vessel occlusion (LVO), who are candidates for mechanical thrombectomy, and for whom intravenous thrombolysis is considered before thrombectomy, TNK at a dose 0.25mg/kg is suggested over alteplase.⁷ However, the quality of the evidence used for this recommendation is graded as low. Yet, TNK use could not be supported in unselected stroke patients by the ESO guidelines,⁷ based on the analysis of available RCT data (TNK-S2B and ATTEST trials).^8,9

During the ESOC 2022, four RCTs regarding the use of TNK in acute ischemic stroke presented their results: AcT,¹⁰ NOR-TEST 2,¹¹ TASTE-A,¹² and TWIST¹³ trials. The AcT¹⁰ and the TASTE-A¹² trials evaluated TNK at a dose of 0.25mg/kg for intravenous thrombolysis in eligible, yet unselected, patients within 4.5 hours of symptom onset, at different settings. AcT was a phase 3, pragmatic, prospective, randomized, open-label, controlled, blinded endpoint, non-inferiority trial (with a non-inferiority margin of 5%), that was conducted in primary and comprehensive stroke centers in Canada.¹⁰ According to the results of the AcT trial, 36.9% of the TNK-treated patients achieved mRS 0-1 at 3 months compared to 34.8% in the alteplase-treated group. Non inferiority of TNK versus alteplase was proven (unadjusted risk difference 2.1%; 95%CI: -2.6 to 6.9%), without any safety concerns raising.

TASTE-A was a phase 2, prospective, randomized, open-label, controlled, blinded endpoint, superiority trial, that was conducted in a single mobile stroke unit in Australia and randomized acute ischemic stroke patients eligible for intravenous thrombolysis, who were otherwise unselected.¹² TNK-treated patients presented significantly smaller CT perfusion lesions (median of 12ml), as evaluated during hospital admission, versus alteplase-treated patients (median of 25ml). No difference was noted between the two arms regarding safety issues or 3-month mRS scores, including the mRS 0-1 (41.8% in the TNK group versus 40.8% in the alteplase group).

These results may potentially move forward the use of TNK at a dose of 0.25mg/kg for intravenous thrombolysis of acute stroke patients, also beyond selected patients with LVO and intended thrombectomy. More RCTs are currently ongoing and  may strengthen the evidence to use TNK  as intravenous thrombolytic treatment for acute ischemic stroke.

Conflict of interest statement

Dr. Palaiodimou reports no conflicts of interest.

References

1. Bivard A, Lin L, Parsonsb MW. Review of stroke thrombolytics. Journal of stroke. 2013;15(2):90-98.
2. Marshall RS. Progress in Intravenous Thrombolytic Therapy for Acute Stroke. JAMA neurology. 2015;72(8):928-934.
3. Gerschenfeld G, Smadja D, Turc G, et al. Functional Outcome, Recanalization, and Hemorrhage Rates After Large Vessel Occlusion Stroke Treated With Tenecteplase Before Thrombectomy. Neurology. 2021;97(22):e2173-e2184.
4. Warach SJ, Saver JL. Stroke Thrombolysis With Tenecteplase to Reduce Emergency Department Spread of Coronavirus Disease 2019 and Shortages of Alteplase. JAMA neurology. 2020;77(10):1203-1204.
5. Bivard A, Huang X, Levi CR, et al. Tenecteplase in ischemic stroke offers improved recanalization: Analysis of 2 trials. Neurology. 2017;89(1):62-67.
6. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. The New England journal of medicine. 2018;378(17):1573-1582.
7. Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. European stroke journal. 2021;6(1):I-lxii.
8. Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. The Lancet Neurology. 2015;14(4):368-376.
9. Haley EC, Jr., Thompson JL, Grotta JC, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707-711.
10. Menon BK, Swartz RH, for the AcT Investigators. Intravenous Alteplase compared to Tenecteplase in Acute Ischemic Stroke. The AcT RCT. ESOC 2022. May 4, 2022.
11. Kvistad CE, Næss H, Helleberg BH, et al. Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. The Lancet Neurology. 2022;21(6):511-519.
12. Bivard A, Zhao H, Coote S, et al. Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance (Mobile Stroke Unit-TASTE-A): protocol for a prospective randomised, open-label, blinded endpoint, phase II superiority trial of tenecteplase versus alteplase for ischaemic stroke patients presenting within 4.5 hours of symptom onset to the mobile stroke unit. BMJ open. 2022;12(4):e056573.
13. Roaldsen MB, on behalf of the TWIST Collaborators. Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST). ESOC 2022. May 6, 2022.

Did you attend the European Stroke Organisation Conference 2022?

There were over 4000 participants onsite and online from 107 countries: were you one of them? Did you attend in person or online?  I attended in person and enjoyed catching up with familiar faces for the first time in several years. I thought the conference was a great success – hats off to the organising committee and everyone else involved!

What did you think about the state of play for stroke research?

There was a wealth of cutting edge stroke research: from plenary sessions with results from breaking clinical trials, to scientific sessions covering a broad range of topics, and over a thousand e-posters. I attended the plenary sessions and several scientific sessions, including those dedicated to research about patients with intracerebral haemorrhage. Considering the challenges many have faced over the past few years, it makes the scientific progress on display all the more impressive.

What did you take away from the conference?

There were some important clinical trial results with implications for clinical practice: what will you take back to your local department that has the potential to change your practice?

I was struck by the increasing number of early-career researchers who did stellar jobs presenting their work, including in the most high-profile sessions. I attended the ESO young stroke physician and researchers committee meeting which focussed on several initiatives to promote the careers of early-career researchers from around the world (more details here: https://eso-stroke.org/about-eso/who-we-are/young-stroke-physicians-and-researchers-committee/) . The future is looking bright for the next generation of stroke researchers!

What’s on the horizon?

ESOC 2023 Munich will be here before we know it! What’s on your stroke research horizon for the coming year?

I’m excited about the upcoming ESO Edinburgh Stroke Research Workshop on 10th-12th October 2022. This fantastic 3-day course residential course set in the beautiful city of Edinburgh is aimed at early-career researchers who want to develop a research question for a PhD or MD project. There are lectures, small group sessions and several opportunities for tailored individual feedback from leading European stroke researchers. Read more and apply here: https://www.ed.ac.uk/clinical-brain-sciences/postgraduate-study/stroke-research-workshop. Don’t miss the application deadline of 15^th June 2022.

I’d love to hear your thoughts: get in touch @tom_moullaali on Twitter for more discussion!

Finally, after a long wait and great suspense due to the pandemic and the winds of war, we reached Switzerland for this fantastic Stroke Winter (or, more precisely, Spring) School in Bern!

Many of us coming from warm places confessed that one of the reasons for wanting to be there was the presence of snow in this wonderful little medieval city in the heart of Switzerland. Surprisingly, this lively place was waiting for us in its spring colours!

The theoretical part of the course was held in the “sitem-insel” building, part of the Inselspital campus, where we attended practical simulations on-site. Try to imagine all the things you would like to know about stroke, all the hidden secrets, and every tip that could help you to diagnose and treat patients in the best way possible: you will find the answers at the Stroke School in Bern.

The faculty, coming from all over the world, from Canada to Vietnam, chaired by neurologists and neuroradiologists (super-prof Gralla) put its wealth of knowledge at our disposal, going beyond the simple guidelines and indications and revealing to us the direction in which stroke research is heading.

Every morning we enjoyed lectures covering all areas of interest related to stroke: from epidemiology (women and stroke and how to organise your stroke network) to treatment (indications for IVT and EVT; treatment of intracranial stenosis and paediatric strokes) and secondary prevention (from anticoagulation to anti-aggregation). During the afternoon we were divided into small groups of neurologists and neuroradiologists. In these groups we simulated a real-life stroke pathway, from admission to choice of treatment (for neurologists), or mechanical thrombectomy on an animal model (for neuroradiologists)! A couple of hours were dedicated to students’ presentations of a challenging case in which they had been involved. The students were able to discuss their case with the other participants and two faculty members: one neurologist and one interventional radiologist. In short, nothing was left to chance or inadequately addressed. The added value of this course was the friendly atmosphere that allowed us to feel absolutely free to ask the faculty any question that was on our minds, without any kind of embarrassment.

All this happened in a very evocative setting, in which we were surrounded by beautiful mountains and even a small park with a family of bears. Each course day concluded with a social dinner, which on the last night turned into a party with a taste of Bern’s nightlife; the goal to encourage bonds between young stroke researchers from all over the world (from Honduras to Armenia) was largely satisfied!

We created a link of friendship with many colleagues, and being in Bern as a pair (neurologist and neuroradiologist) was a winning choice. The aim was to build a real “team” as in the ideal model for management of patients with acute stroke.

As well as the scientific features of the course, the organisation was perfect: hotel locations, travel passes, and social dinners were all great, making this experience unforgettable. It was a pleasure to attend the ESO Stroke Winter School in Bern: we suggest all readers apply for the next one as fast as they can!