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Therapeutic Potential of Tenecteplase in the Management of Acute Ischemic Stroke

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Abstract

Given that alteplase has been the only approved thrombolytic agent for acute ischemic stroke for almost two decades, there has been intense interest in more potent and safer agents over the last few years. Tenecteplase is a bioengineered mutation of alteplase with advantageous pharmacodynamics and pharmacokinetics. The superiority of tenecteplase over alteplase has been proven by in vitro and animal studies, and it was approved for use in myocardial infarction more than a decade ago. In patients with acute ischemic stroke, tenecteplase has shown promise in randomized phase II trials and the drug is currently being tested in four phase III clinical trials that will start delivering definite results in the near future: NOR-TEST (NCT01949948), TASTE (ACTRN12613000243718), TEMPO-2 (NCT02398656), and TALISMAN (NCT02180204).

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References

  1. Bluhmki E, Chamorro A, Davalos A, Machnig T, Sauce C, Wahlgren N, et al. Stroke treatment with alteplase given 3.0–4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8(12):1095–102.

    Article  CAS  PubMed  Google Scholar 

  2. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581–7.

    Article  Google Scholar 

  3. Hennerici MG, Kay R, Bogousslavsky J, Lenzi GL, Verstraete M, Orgogozo JM, et al. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial. Lancet. 2006;368(9550):1871–8.

    Article  CAS  PubMed  Google Scholar 

  4. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66–73.

    Article  CAS  PubMed  Google Scholar 

  5. Albers GW, von Kummer R, Truelsen T, Jensen JK, Ravn GM, Gronning BA, et al. Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Neurol. 2015;14(6):575–84.

    Article  CAS  PubMed  Google Scholar 

  6. Tanswell P, Modi N, Combs D, Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet. 2002;41(15):1229–45.

    Article  CAS  PubMed  Google Scholar 

  7. Haley EC Jr, 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(4):707–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 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(12):1099–107.

    Article  CAS  PubMed  Google Scholar 

  9. 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(4):368–76.

    Article  CAS  PubMed  Google Scholar 

  10. Huang X, Fulton R, Parsons M, Levi C, Campbell B, Bladin C, Haley E, Thompson JLP, Levin B, Buchsbaum R, Muir KW, Tenecteplase versus Alteplase in acute ischaemic stroke thrombolysis: a meta-analysis of individual patient data from randomised studies. Abstract - oral presentation. 1st ESO conference, Glasgow, April 17-19, 2015

  11. Logallo N, Kvistad CE, Nacu A, Naess H, Waje-Andreassen U, Asmuss J, et al. The Norwegian Tenecteplase Stroke Trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke. BMC Neurol. 2014;14:106.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Parsons M. Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation (TASTE) trial. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363714. Accessed 27 May 2015.

  13. Davydov L, Cheng JW. Tenecteplase: a review. Clin Ther. 2001;23(7):982–97 (discussion 981).

  14. Smalling RW. Molecular biology of plasminogen activators: what are the clinical implications of drug design? Am J Cardiol. 1996;78(12A):2–7.

    Article  CAS  PubMed  Google Scholar 

  15. Keyt BA, Paoni NF, Refino CJ, Berleau L, Nguyen H, Chow A, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci. 1994;91(9):3670–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Refino CJ, Paoni NF, Keyt BA, Pater CS, Badillo JM, Wurm FM, et al. A variant of t-PA (T103N, KHRR 296-299 AAAA) that, by bolus, has increased potency and decreased systemic activation of plasminogen. Thromb Haemost. 1993;70(2):313–9.

    CAS  PubMed  Google Scholar 

  17. Collen D, Stassen JM, Yasuda T, Refino C, Paoni N, Keyt B, et al. Comparative thrombolytic properties of tissue-type plasminogen activator and of a plasminogen activator inhibitor-1-resistant glycosylation variant, in a combined arterial and venous thrombosis model in the dog. Thromb Haemost. 1994;72(1):98–104.

    CAS  PubMed  Google Scholar 

  18. Thomas GR, Thibodeaux H, Errett CJ, Badillo JM, Keyt BA, Refino CJ, et al. A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding. Stroke. 1994;25(10):2072–8 (discussion 2078–9).

  19. Cannon CP, McCabe CH, Gibson CM, Ghali M, Sequeira RF, McKendall GR, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation. 1997;95(2):351–6.

    Article  CAS  PubMed  Google Scholar 

  20. Cannon CP, Gibson CM, McCabe CH, Adgey AA, Schweiger MJ, Sequeira RF, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation. 1998;98(25):2805–14.

  21. Van de Werf F, Cannon CP, Luyten A, Houbracken K, McCabe CH, Berioli S, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J. 1999;137(5):786–91.

    Article  PubMed  Google Scholar 

  22. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, Van De Werf F, Adgey J, Ardissino D, Armstrong PW, Aylward P, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354(9180):716–22.

  23. Haley EC Jr, Lyden PD, Johnston KC, Hemmen TM, Investigators TNKiS. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 2005;36(3):607–12.

    Article  CAS  PubMed  Google Scholar 

  24. Molina CA, Ribo M, Rubiera M, Santamarina E, Delgado-Mederos R, Maisterra O, et al. TNK induces faster MCA recanalization and leads to better short- and long-term clinical outcome than native tPA. The TNK-TPA Reperfusion Stroke Study [abstract]. Stroke. 2008;39(2):563.

    Google Scholar 

  25. Parsons MW, Miteff F, Bateman GA, Spratt N, Loiselle A, Attia J, et al. Acute ischemic stroke Imaging-guided tenecteplase treatment in an extended time window. Neurology. 2009;72(10):915–21.

    Article  CAS  PubMed  Google Scholar 

  26. 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(3):769–74.

    Article  CAS  PubMed  Google Scholar 

  27. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20.

    Article  PubMed  Google Scholar 

  28. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30.

    Article  CAS  PubMed  Google Scholar 

  29. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18.

    Article  CAS  PubMed  Google Scholar 

  30. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285–95.

    Article  CAS  PubMed  Google Scholar 

  31. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296–306.

    Article  CAS  PubMed  Google Scholar 

  32. Logallo N, Kvistad CE, Naess H, Waje-Andreassen U, Thomassen L. Mild stroke: safety and outcome in patients receiving thrombolysis. Acta Neurol Scand Suppl. 2014;198:37–40.

    Article  PubMed  Google Scholar 

  33. Laurencin C, Philippeau F, Blanc-Lasserre K, Vallet AE, Cakmak S, Mechtouff L, et al. Thrombolysis for acute minor stroke: outcome and barriers to management. Results from the RESUVAL Stroke Network. Cerebrovasc Dis. 2015;40(1–2):3–9.

    Article  PubMed  Google Scholar 

  34. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768–74.

    Article  PubMed  Google Scholar 

  35. Mikulik R, Kadlecova P, Czlonkowska A, Kobayashi A, Brozman M, Svigelj V, et al. Factors influencing in-hospital delay in treatment with intravenous thrombolysis. Stroke. 2012;43(6):1578–83.

    Article  PubMed  Google Scholar 

  36. Weber JE, Ebinger M, Rozanski M, Waldschmidt C, Wendt M, Winter B, et al. Prehospital thrombolysis in acute stroke: results of the PHANTOM-S pilot study. Neurology. 2013;80(2):163–8.

    Article  CAS  PubMed  Google Scholar 

  37. Tsikouris JP, Tsikouris AP. A review of available fibrin-specific thrombolytic agents used in acute myocardial infarction. Pharmacotherapy. 2001;21(2):207–17.

    Article  CAS  PubMed  Google Scholar 

  38. Modi NB, Fox NL, Clow FW, Tanswell P, Cannon CP, Van de Werf F, et al. Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction. J Clin Pharmacol. 2000;40(5):508–15.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Nicola Logallo, Christopher E. Kvistad & Lars Thomassen

  2. Center for Neurovascular Diseases, Haukeland University Hospital, Bergen, Norway

    Nicola Logallo, Christopher E. Kvistad & Lars Thomassen

Authors
  1. Nicola Logallo
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  2. Christopher E. Kvistad
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  3. Lars Thomassen
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Correspondence to Nicola Logallo.

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Authors did not received any funding for the preparation of this manuscript.

Conflicts of Interest

NL is the principal investigator of the NOR-TEST study. CEK is a member of the NOR-TEST executive working group. LT is the study chair of the NOR-TEST study. NOR-TEST is an investigator-driven academic trial with no connections to pharmaceutical companies. NOR-TEST is supported by a 3-year grant from the Norwegian Research Council (Project No. 229006).

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Logallo, N., Kvistad, C.E. & Thomassen, L. Therapeutic Potential of Tenecteplase in the Management of Acute Ischemic Stroke. CNS Drugs 29, 811–818 (2015). https://doi.org/10.1007/s40263-015-0280-9

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  • DOI: https://doi.org/10.1007/s40263-015-0280-9

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