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01-08-2008 | Leading Article

Novel Thrombolytic Drugs

Will They Make a Difference in the Treatment of Ischaemic Stroke?

Authors: Dr Atte Meretoja, Turgut Tatlisumak

Published in: CNS Drugs | Issue 8/2008

Abstract

Treatment of acute ischaemic stroke aims to recanalize the occluded artery, salvage the at-risk brain tissue and thus minimize neurological sequelae. Efforts a decade ago have led to the only currently approved medical treatment for acute ischaemic stroke, i.e. intravenous alteplase given within 3 hours of stroke onset. Recanalization occurs in only one-half of the patients receiving alteplase, and only approximately 5% of all ischaemic stroke patients in industrialized countries receive this treatment. Studies are currently being carried out to determine whether intravenous alteplase would be safe and effective for up to 4.5 hours after ischaemic stroke onset, and whether it should be followed by an intra-arterial approach.

Two novel thrombolytic drugs being studied for acute ischaemic stroke are desmoteplase and tenecteplase. Although the first trials were promising, the most recent evidence suggests that desmoteplase is not superior to placebo, even in carefully selected patients, in the 3- to 9-hour time window after stroke onset. Tenecteplase has only been studied for acute ischaemic stroke in a single noncontrolled, dose-finding trial in the 3-hour time window after stroke onset, which suggested a similar efficacy to that demonstrated in the historical data from the alteplase trials. A trial to compare the safety and efficacy of tenecteplase versus alteplase is ongoing.

Safer and more effective thrombolytic drugs for the treatment of ischaemic stroke are thus being sought. Such agents will be welcome, but they are not here yet. While waiting we are likely to see the emergence of additive therapies, including ultrasound insonation, neuroprotective/regenerative agents and invasive intra-arterial techniques. Novel thrombolytic drugs, or other novel therapies, possess great potential to make a difference in the future, but the most urgent priority now is in the organization of stroke treatment in such a way that more patients receive the currently available optimal treatments.

The use of trade names is for product identification purposes only and does not imply endorsement.

Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006 May 27; 367(9524): 1747–57PubMedCrossRef

Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics: 2007 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007 Feb 6; 115(5): e69–171PubMedCrossRef

Tiainen M, Poutiainen E, Kovala T, et al. Cognitive and neurophysiological outcome of cardiac arrest survivors treated with therapeutic hypothermia. Stroke 2007 Aug; 38(8): 2303–8PubMedCrossRef

Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav 2007 May; 87(1): 179–97PubMedCrossRef

Saver JL. Time is brain: quantified. Stroke 2006 Jan; 37(1): 263–6PubMedCrossRef

Wardlaw JM, Zoppo G, Yamaguchi T, et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003; (3): CD000213

Saver JL. Number needed to treat estimates incorporating effects over the entire range of clinical outcomes: novel derivation method and application to thrombolytic therapy for acute stroke. Arch Neurol 2004 Jul; 61(7): 1066–70PubMedCrossRef

Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004 Mar 6; 363(9411): 768–74PubMedCrossRef

Stroke trials registry: ECASS III [online]. Available from URL: http://strokecenter.org/trials/ [Accessed 2007 Jul 28]

10.

Van De Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999 Aug 28; 354(9180): 716–22CrossRef

11.

Clark WM, Albers GW, Madden KP, et al. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thromblytic Therapy in Acute Ischemic Stroke Study Investigators. Stroke 2000 Apr; 31(4): 811–6

12.

Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999 Dec 1; 282(21): 2019–26

13.

Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004 Nov 18; 351(21): 2170–8PubMedCrossRef

14.

Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006 May; 37(5): 1227–31PubMedCrossRef

15.

Hacke W, Albers G, Al-Rawi Y, 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 Jan; 36(1): 66–73PubMedCrossRef

16.

Hacke W. Desmoteplase in Acute Ischemic Stroke-2 (DIAS-2) trial [oral presentation]. XVI European Stroke Conference; 2007 May 29–Jun 1; Glasgow

17.

Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995 Oct 4; 274(13): 1017–25PubMedCrossRef

18.

Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998 Oct 17; 352(9136): 1245–51

19.

Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 1999 Dec; 30(12): 2598–605PubMedCrossRef

20.

Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke study. Stroke 2004 Apr; 35 (4): 904-11

21.

The Interventional Management of Stroke (IMS) II study. Stroke 2007 Jul; 38 (7): 2127-35

22.

Stroke trials registry: IMS -III [online]. Available from URL: http://strokecenter.org/trials/ [Accessed 2007 Jul 28]

23.

Ogawa A, Mori E, Minematsu K, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan. Stroke 2007 Oct; 38(10): 2633–9PubMedCrossRef

24.

Stroke trials registry: MR RESCUE [online]. Available from URL: http://strokecenter.org/trials/ [Accessed 2007 Nov 28]

25.

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 Dec 14; 333 (24): 1581-7

26.

del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators: Prolyse in Acute Cerebral Thromboembolism. Stroke 1998 Jan; 29(1): 4–11

27.

Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999 Dec 1; 282(21): 2003–11

28.

Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007 Jan 27; 369(9558): 275–82PubMedCrossRef

29.

ClinicalTrials.gov. Study of tenecteplase (TNK) in acute ischemic stroke (TNK-S2B). Identifier NCT00252239 [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00252239 [Accessed 2007 Jul 28]

30.

Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. Stroke 1994 Nov; 25(11): 2220–6PubMedCrossRef

31.

Rankin J. Cerebral vascular accidents in patients over the age of 60: II. Prognosis. Scott Med J 1957 May; 2(5): 200–15

32.

van Swieten JC, Koudstall PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1998 May; 19(5): 604–7CrossRef

33.

Saver JL. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke 2007 Aug; 38(8): 2279–83PubMedCrossRef

34.

Schumacher HC, Bateman BT, Boden-Albala B, et al. Use of thrombolysis in acute ischemic stroke: analysis of the Nationwide Inpatient Sample 1999 to 2004. Ann Emerg Med 2007 Aug; 50(2): 99–107PubMedCrossRef

35.

Lindsberg PJ, Happola O, Kallela M, et al. Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment. Neurology 2006 Jul 25; 67(2): 334–6PubMedCrossRef

36.

Boode B, Weizen V, Franke C, et al. Estimating the number of stroke patients eligible for thrombolytic treatment if delay could be avoided. Cerebrovasc Dis 2007; 23(4): 294–8PubMedCrossRef

37.

Kaste M. Evidence, education and practice. Cerebrovasc Dis 2006; 22(5–6): 342–9PubMedCrossRef

38.

Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007 Mar; 38(3): 967–73PubMedCrossRef

39.

Christou I, Alexandrov AV, Burgin WS, et al. Timing of recanalization after tissue plasminogen activator therapy determined by transcranial doppler correlates with clinical recovery from ischemic stroke. Stroke 2000 Aug; 31(8): 1812–6PubMedCrossRef

40.

Sugg RM, Noser EA, Shaltoni HM, et al. Intra-arterial reteplase compared to urokinase for thrombolytic recanalization in acute ischemic stroke. AJNR Am J Neuroradiol 2006 Apr; 27(4): 769–73PubMed

41.

Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics 2007 Jul; 4(3): 420–7PubMedCrossRef

42.

Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005 Jul; 36(7): 1432–8PubMedCrossRef

43.

Smith WS. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke: results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol 2006 Jun–Jul; 27(6): 1177–82PubMed

44.

Molina CA, Saver JL. Extending reperfusion therapy for acute ischemic stroke: emerging pharmacological, mechanical, and imaging strategies. Stroke 2005 Oct; 36(10): 2311–20PubMedCrossRef

45.

Nikas D, Reimers B, Elisabetta M, et al. Percutaneous interventions in patients with acute ischemic stroke related to obstructive atherosclerotic disease or dissection of the extracranial carotid artery. J Endovasc Ther 2007 Jun; 14(3): 279–88PubMedCrossRef

46.

Meretoja A, Tatlisumak T. Thrombolytic therapy in acute ischemic stroke: basic concepts. Curr Vasc Pharmacol 2006 Jan; 4(1): 31–44PubMedCrossRef

47.

Hawkey C. Plasminogen activator in saliva of the vampire bat Desmodus rotundus. Nature 1966 Jul 23; 211(5047): 434–5PubMedCrossRef

48.

Gardell SJ, Duong LT, Diehl RE, et al. Isolation, characterization, and cDNA cloning of a vampire bat salivary plasminogen activator. J Biol Chem 1989 Oct 25; 264(30): 17947–52PubMed

49.

Kratzschmar J, Haendler B, Langer G, et al. The plasminogen activator family from the salivary gland of the vampire bat Desmodus rotundus: cloning and expression. Gene 1991 Sep 15; 105(2): 229–37PubMedCrossRef

50.

Bringmann P, Gruber D, Liese A, et al. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J Biol Chem 1995 Oct 27; 270(43): 25596–603PubMedCrossRef

51.

Ny T, Elgh F, Lund B. The structure of the human tissue-type plasminogen activator gene: correlation of intron and exon structures to functional and structural domains. Proc Natl Acad Sci U S A 1984 Sep; 81(17): 5355–9PubMedCrossRef

52.

Renatus M, Stubbs MT, Huber R, et al. Catalytic domain structure of vampire bat plasminogen activator: a molecular paradigm for proteolysis without activation cleavage. Biochemistry 1997 Nov 4; 36(44): 13483–93PubMedCrossRef

53.

Reddrop C, Moldrich RX, Beart PM, et al. Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury. Stroke 2005 Jun; 36(6): 1241–6PubMedCrossRef

54.

Lopez-Atalaya JP, Roussel BD, Ali C, et al. Recombinant Desmodus rotundus salivary plasminogen activator crosses the blood-brain barrier through a low-density lipoprotein receptor-related protein-dependent mechanism without exerting neurotoxic effects. Stroke 2007 Mar; 38(3): 1036–43PubMedCrossRef

55.

Liberatore GT, Samson A, Bladin C, et al. Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke 2003 Feb; 34(2): 537–43PubMedCrossRef

56.

Muschick P, Zeggert D, Donner P, et al. Thrombolytic properties of Desmodus (Vampire Bat) salivary plasminogen activator DSPAα1, alteplase and streptokinase following intravenous bolus injection in a rabbit model of carotid artery thrombosis. Fibrinolysis 1993; 7(4): 284–90

57.

Hare TR, Gardell SJ. Vampire bat salivary plasminogen activator promotes robust lysis of plasma clots in a plasma milieu without causing fluid phase plasminogen activation. Thromb Haemost 1992 Aug 3; 68(2): 165–9PubMed

58.

Witt W, Baldus B, Bringmann P, et al. Thrombolytic properties of Desmodus rotundus (vampire bat) salivary plasminogen activator in experimental pulmonary embolism in rats. Blood 1992 Mar 1; 79(5): 1213–7PubMed

59.

Meden P, Tatlisumak T, Takano K, et al. Thrombolysis with recombinant Desmodus saliva plasminogen activator (rD-SPAμ1) in a rat embolie stroke model [abstract]. Cerebrovasc Dis 1996; 6(3): 190CrossRef

60.

Witt W, Maass B, Baldus B, et al. Coronary thrombolysis with Desmodus salivary plasminogen activator in dogs: fast and persistent recanalization by intravenous bolus administration. Circulation 1994 Jul; 90(1): 421–6PubMedCrossRef

61.

Tanswell P, Tebbe U, Neuhaus KL, et al. Pharmacokinetics and fibrin specificity of alteplase during accelerated infusions in acute myocardial infarction. J Am Coll Cardiol 1992 Apr; 19(5): 1071–5PubMedCrossRef

62.

Bell WR. Present-day thrombolytic therapy: therapeutic agents: pharmacokinetics and pharmacodynamics. Rev Cardiovasc Med 2002; 3Suppl. 2: S34–44PubMed

63.

Modi NB, Fox NL, Clow FW, et al. Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction. J Clin Pharmacol 2000 May; 40(5): 508–15PubMedCrossRef

64.

Mahoney FI, Barthel D. Functional evaluation: the Barthel Index. Md State Med J 1965 Feb; 14: 56–61

65.

Haley Jr EC, Lyden PD, Johnston KC, et al. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke 2005 Mar; 36(3): 607–12PubMedCrossRef

66.

Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci U S A 1994 Apr 26; 91(9): 3670–4PubMedCrossRef

67.

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

68.

Van de Werf F, Barron HV, Armstrong PW, et al. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-PA. Eur Heart J 2001 Dec; 22(24): 2253–61PubMedCrossRef

69.

Thomas GR, Thibodeaux H, Errett CJ, et al. A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolie stroke and peripheral bleeding. Stroke 1994 Oct; 25(10): 2072–8PubMedCrossRef

70.

Chapman DF, Lyden P, Lapchak PA, et al. Comparison of TNK with wild-type tissue plasminogen activator in a rabbit embolie stroke model. Stroke 2001 Mar; 32(3): 748–52PubMedCrossRef

71.

Lapchak PA, Araujo DM, Zivin JA. Comparison of tenecteplase with alteplase on clinical rating scores following small clot embolie strokes in rabbits. Exp Neurol 2004 Jan; 185(1): 154–9PubMedCrossRef

72.

Khatri P, Broderick JP, Pancioli AM. Risk of thrombolysis-associated intracerebral hemorrhage: the need to compare apples with apples [letter]. Stroke 2005 Jun; 36(6): 1109–10PubMedCrossRef

73.

Stroke trials registry: TNKilas trial [online]. Available from URL: http://strokecenter.org/trials/ [Accessed 2007 Jul 28]

Title: Novel Thrombolytic Drugs
Will They Make a Difference in the Treatment of Ischaemic Stroke?
Authors: Dr Atte Meretoja
Turgut Tatlisumak
Publication date: 01-08-2008
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 8/2008
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.2165/00023210-200822080-00001

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Novel Thrombolytic Drugs

Will They Make a Difference in the Treatment of Ischaemic Stroke?

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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