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• W2891737522 abstract "HomeStrokeVol. 49, No. 9Tenecteplase Knocking on the Door Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBTenecteplase Knocking on the DoorThe EXTEND-IA TNK Trial Michael D. Hill, MD, MSc, FRCPC and Patrik Michel, MD Michael D. HillMichael D. Hill Correspondence to Michael D. Hill, MD, MSc, Department of Clinical Neuroscience, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, HBA 2939, Health Science Centre, 3300 Hospital Dr NW, Calgary, AB T2N4N1, Canada. Email E-mail Address: [email protected] From the Departments of Clinical Neurosciences, Medicine, Radiology and Community Health Sciences, Hotchkiss Brain Institute, University of Calgary and Foothills Medical Center, Alberta, Canada (M.D.H.) Search for more papers by this author and Patrik MichelPatrik Michel Department of Neurology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland (P.M.). Search for more papers by this author Originally published17 Jul 2018https://doi.org/10.1161/STROKEAHA.118.022318Stroke. 2018;49:2276–2277If there is one lesson from multiple stroke trials from the past 10 years, it is the value of rapid recanalization of blocked arteries and reperfusing the brain. Doing so in appropriately selected patients has led to one of the most powerful effects ever reported in medicine. The Lazarus effect, where mute and hemiplegic patients doomed for a life of chronic dependency recover their speech and can walk within hours after acute treatment, is regularly observed.Although reperfusion with endovascular treatment (EVT) is highly effective, it does not apply to all patients with stroke principally because they do not have large, accessible vessel occlusions.1 Others may reach endovascular-capable centers only after prolonged transport during which they can receive medical therapy with intravenous thrombolysis. Many pragmatic reasons exist to support the search for highly active and better thrombolytic drugs.Tenecteplase, a tissue-type plasminogen activator modified by 3 amino acids from alteplase, has the potential to deliver this kind of performance. It has greater fibrin specificity resulting in no evidence of systemic fibrinogen depletion, resistance to plasminogen activator inhibitor resulting in an initial serum half-life of 20 minutes, and a mean terminal half-life of 100 minutes, such that it can be conveniently given as a bolus dose on a weight-adjusted basis. At a dose of 0.5 mg/kg, it has been a standard of care for treating acute ST-segment–elevation myocardial infarction for many years, being given even in the prehospital arena. Evidence for its potential in ischemic stroke treatment is starting to accrue from several acute stroke pilot studies.Haley et al2 conducted 2 sequential pilot studies comparing tenecteplase to alteplase. The first, a dose-escalation safety study, stopped after too many patients at the 0.5 mg/kg dose experienced symptomatic intracranial hemorrhage. The second adaptive-design dose-finding study (0.1, 0.25, 0.4 mg/kg) was stopped early because of slow enrollment.3 Interestingly, the study considered the 0.4 mg/kg dose to be inefficacious. Parsons et al4 (n=75) demonstrated that among patients with a penumbral pattern on computer tomographic perfusion imaging, tenecteplase (0.1 or 0.25 mg/kg) resulted in greater reperfusion in both arms, compared with alteplase. The ATTEST study (Alteplase Versus Tenecteplase for Thrombolysis After Ischemic Stroke; n=104) used 0.25 mg/kg tenecteplase and demonstrated clear safety but no efficacy advantage over alteplase.5 TEMPO-1 (Tenecteplase for Minor Stroke With Proven Occlusion; n=50) similarly showed safety in a dose-escalation study in minor ischemic strokes.6 An individual patient data meta-analysis of these trials confirmed that there was no difference between any dose of tenecteplase and alteplase for either efficacy or safety end points, but higher doses tended to increase the hemorrhage rates.7 Finally, the NORTEST study (Norwegian Tenecteplase Stroke Trial; n=1100) also showed near identical efficacy and safety of tenecteplase at 0.4 mg/kg compared with standard alteplase dose, but among milder strokes and without advanced imaging.8In this context, EXTEND-IA TNK (Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase) combines the momentum of recent success with endovascular thrombectomy with the evolving literature examining tenecteplase treatment of ischemic stroke.9,10 The study enrolled 202 patients with stroke to be treated within 4.5 hours of symptom onset and having an internal carotid, middle cerebral, or basilar artery occlusion and evidence of a penumbral pattern on computed tomographic perfusion imaging. After ≈80 patients were enrolled, the computed tomographic perfusion requirement was removed. The primary outcome was first angiographic imaging showing reperfusion of 50% of the affected territory or absence of a target thrombus for EVT. Surprisingly, it was achieved in 22% of the tenecteplase 0.25 mg/kg patients compared with 10% of the alteplase patients, making EVT redundant in these patients. Clinical outcomes at 90 days were numerically better in the tenecteplase group.Is this the proof that tenecteplase is a better thrombolytic treatment than alteplase? The answer is not yet. First, the alteplase (control) group in this study contained more women, more atrial fibrillation, longer times from onset-to-thrombolysis, and greater use of general anesthesia, all of which may cumulatively change the prognosis. Second, such positive results were not present in previous comparative studies by other groups on a clinical level. And third, the question of the most effective tenecteplase dose remains: would 0.4 mg/kg not be better than 0.25 mg/kg, at least for large vessel occlusions? Or should the dose be adapted to a thrombus-size approach where the physician choses higher thrombolytic doses in the presence of higher thrombus burden, and vice versa? Could such imaging-informed precision medicine also be modified to reduce hemorrhage risk by including leukoaraiosis, chronic strokes, and the extent of early established infarct into the dose calculation?Before implementing such novel trial designs and treatments, several basic stroke studies with tenecteplase need to be completed. The EXTEND-IA TNK group is repeating their trial to compare tenecteplase doses of 0.25 and 0.4 mg/kg. This reminds us of the ENCHANTED trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study) that showed no difference between alteplase doses of 0.6 versus 0.9 mg/kg for long-term outcome despite less hemorrhages in the lower dose group.11 Four other phase III trials using tenecteplase are now ongoing, all using the 0.25 mg/kg tenecteplase dosing. The TASTE study (Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation) is a global trial following on from Parsons’ pilot trial. It compares tenecteplase with standard dose alteplase and plans for a maximum sample size of 1024 subjects. ATTEST-2 in the UK is similarly examining tenecteplase and alteplase, aiming for 1870 subjects. The TEMPO-2 study is recruiting patients with minor stroke and a proven occlusion: the comparison between tenecteplase and antiplatelets will be performed within 12 hours in 1274 subjects. Finally, the TWIST study (Tenecteplase in Wake-Up Ischemic Stroke Trial) from Norway is proposing a trial of tenecteplase versus best standard treatment in patients with stroke on awakening. Basic computed tomographic imaging will be used for selecting the 500 planned patients.Given the success of EVT for large vessel occlusion, the need for pretreatment by intravenous thrombolysis has been questioned. Ongoing clinical trials assessing the withholding of intravenous alteplase (MRCLEAN NO-IV [Multicenter Randomized CLinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands No IV Alteplase], SWIFT DIRECT [Solitair Wieth the Intention for Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire Stent-Retriever Thrombectomy in Acute Anterior Circulation Stroke]) will test this question. In our view, there are multiple compelling reasons to offer intravenous thrombolysis and work on its improvement, as attempted by the EXTEND-IA TNK group. First, the hub-and-spoke system for stroke care cannot and will not disappear. Medical treatment can be given in an equipped and trained primary hospital before transfer for EVT at a tertiary hospital. Second, we see from the current study most overtly, that medical treatment may work well in 1 of 5 patients but not well enough to obviate the need EVT. Patients who reperfuse earlier medically will, on average, fare better. Third, the current rate of excellent reperfusion with EVT is ≈80%. This means that EVT cannot be counted on in a significant proportion (a fifth) of patients. Reasons can be technical or simply because of the nature of the underlying thrombus or stroke mechanism. Fourth, concurrent use of thrombolysis with EVT is associated with a lower rate of infarcts-in-a-new-territory because of fragmented pieces of thrombus.12 Finally, there is no obvious safety benefit for withholding intravenous thrombolysis given that rates of symptomatic intracranial hemorrhage are similar with or without preceding thrombolysis.Intravenous thrombolysis is here to stay, but it can be improved. Although the standard comparator (ie, 0.9 mg/kg of alteplase) remains effective, more incisive intravenous treatments will be proven. Important progress has recently been obtained with antiplatelets, anticoagulation, and thrombectomy devices. Tenecteplase is a good candidate for better thrombolytic treatment. The landmark EXTEND-IA TNK trial increases our confidence that it is an excellent first-line stroke treatment. Its good safety profile and practical advantages with bolus dosing loom large when time and transportation are so critical to stroke outcomes.We look forward to and encourage the stroke community to participate in active and future stroke trials with tenecteplase.DisclosuresDr Hill received grant from Boehringer-Ingelheim to the University of Calgary for the TEMPO-2 trial (related to the topic area). Dr Hill received grants from Stryker and from Medtronic to the University of Calgary and Stock ownership in Calgary Scientific Inc (unrelated). Dr Michel has received within the last 2 years through his institution speaker fees and honoraria from scientific advisory boards from Boehringer-Ingelheim (related to the topic area). All this support is goes to his institution and is used for stroke education and research.FootnotesCorrespondence to Michael D. Hill, MD, MSc, Department of Clinical Neuroscience, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, HBA 2939, Health Science Centre, 3300 Hospital Dr NW, Calgary, AB T2N4N1, Canada. Email michael.[email protected]caReferences1. Vanacker P, Lambrou D, Eskandari A, Mosimann PJ, Maghraoui A, Michel P. Eligibility and predictors for acute revascularization procedures in a stroke center.Stroke. 2016; 47:1844–1849.LinkGoogle Scholar2. Haley EC, Lyden PD, Johnston KC, Hemmen TM, Investigators TNKiS. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke.Stroke. 2005; 36:607–612.LinkGoogle Scholar3. Haley EC, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, et al. Phase iib/iii trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.Stroke. 2010; 41:707–711.LinkGoogle Scholar4. Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke.N Engl J Med. 2012; 366:1099–1107. doi: 10.1056/NEJMoa1109842.CrossrefMedlineGoogle Scholar5. Huang X, Cheripelli BK, Lloyd SM, Kalladka D, Moreton FC, Siddiqui A, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study.Lancet Neurol. 2015; 14:368–376.CrossrefMedlineGoogle Scholar6. Coutts SB, Dubuc V, Mandzia J, Kenney C, Demchuk AM, Smith EE, et al. Tenecteplase-tissue-type plasminogen activator evaluation for minor ischemic stroke with proven occlusion.Stroke. 2015; 46:769–774.LinkGoogle Scholar7. Huang X, MacIsaac R, Thompson JL, Levin B, Buchsbaum R, Haley EC, et al. Tenecteplase versus alteplase in stroke thrombolysis: an individual patient data meta-analysis of randomized controlled trials.Int J Stroke. 2016; 11:534–543.CrossrefMedlineGoogle Scholar8. Logallo N, Novotny V, Assmus J, Kvistad CE, Alteheld L, Ronning OM, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (nor-test): a phase 3, randomised, open-label, blinded endpoint trial.Lancet Neurol. 2017; 16:781–788.CrossrefMedlineGoogle Scholar9. Campbell BC, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Yan B, et al. Tenecteplase versus alteplase before endovascular thrombectomy (extend-ia tnk): a multicenter, randomized, controlled study.Int J Stroke. 2018; 13:328–334.CrossrefMedlineGoogle Scholar10. Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke.N Engl J Med. 2018; 378:1573–1582.CrossrefMedlineGoogle Scholar11. Anderson CS, Robinson T, Lindley RI, Arima H, Lavados PM, Lee TH, et al; ENCHANTED Investigators and Coordinators. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke.N Engl J Med. 2016; 374:2313–2323. doi: 10.1056/NEJMoa1515510CrossrefMedlineGoogle Scholar12. Ganesh A, Al-Ajlan FS, Sabiq F, Assis Z, Rempel JL, Butcher K, et al; ESCAPE Trial Investigators. Infarct in a new territory after treatment administration in the ESCAPE randomized controlled trial (endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT to recanalization times).Stroke. 2016; 47:2993–2998. doi: 10.1161/STROKEAHA.116.014852LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Nikitin D, Choi S, Mican J, Toul M, Ryu W, Damborsky J, Mikulik R and Kim D (2021) Development and Testing of Thrombolytics in Stroke, Journal of Stroke, 10.5853/jos.2020.03349, 23:1, (12-36), Online publication date: 31-Jan-2021. Chalos V, LeCouffe N, Uyttenboogaart M, Lingsma H, Mulder M, Venema E, Treurniet K, Eshghi O, van der Worp H, van der Lugt A, Roos Y, Majoie C, Dippel D, Roozenbeek B, Coutinho J, van Oostenbrugge R, van Zwam W, Boiten J, Vos J, Jansen I, Goldhoorn R, Schonewille W, Wermer M, van Walderveen M, Staals J, Hofmeijer J, Martens J, Lycklama à Nijeholt G, Emmer B, de Bruijn S, van Dijk L, Lo R, van Dijk E, Boogaarts H, de Kort P, Peluso J, van den Berg J, van Hasselt B, Aerden L, Dallinga R, Schreuder T, Heijboer R, Keizer K, Yo L, den Hertog H, Sturm E, Sprengers M, Jenniskens S, van den Berg R, Yoo A, Beenen L, Roosendaal S, van der Kallen B, van den Wijngaard I, van Es A, Bot J, van Doormaal P, Flach H, el Ghannouti N, Sterrenberg M, Puppels C, Pellikaan W, Sprengers R, Elfrink M, de Meris J, Vermeulen T, Geerlings A, van Vemde G, Simons T, van Rijswijk C, Messchendorp G, Bongenaar H, Bodde K, Kleijn S, Lodico J, Droste H, Wollaert M, Jeurrissen D, Bos E, Drabbe Y, Zweedijk B, Khalilzada M, Compagne K, Geuskens R, van Straaten T, Ergezen S, Harmsma R, de Jong A, Hinsenveld W, Berkhemer O, Boers A, Groot P, Mens M, van Kranendonk K, Kappelhof M, Tolhuijsen M and Alves H (2019) Endovascular Treatment With or Without Prior Intravenous Alteplase for Acute Ischemic Stroke, Journal of the American Heart Association, 8:11, Online publication date: 4-Jun-2019. September 2018Vol 49, Issue 9 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.118.022318PMID: 30018162 Manuscript receivedJune 22, 2018Manuscript acceptedJune 29, 2018Originally publishedJuly 17, 2018Manuscript revisedJune 22, 2018 Keywordstenecteplasestrokeendovascular treatmentreperfusiontissue-type plasminogen activatorPDF download Advertisement" @default.
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