Advertisement

New Thrombolytic Agents

  • Uwe Zeymer
  • Karl-Ludwig Neuhaus
Chapter
Part of the Contemporary Cardiology book series (CONCARD)

Abstract

In over 90% of cases, a thrombotic occlusion of a coronary artery is the cause of an acute myocardial infarction (AMI) (1). Thrombolytic therapy has been shown to reduce short- and long-term mortality of AMI patients (2). As a result of several large placebo-controlled trials, thrombolysis has become a routine treatment in patients presenting within 6–12 h after symptom onset and with ST elevations or bundle branch block on electrocardiogram (ECG). The aim of the thrombolytic therapy is to achieve an early (within 30–90 min), complete (TIMI grade 3 flow), and sustained restoration of blood flow in the infarct-related artery. This “optimal reperfusion” is associated with a remarkably low in-hospital mortality of 3–4% (3, 4). The more rapid and complete the restoration of flow, the better the clinical outcome (Fig. 1). However, even with the most effective thrombolytic regimens available, rapid and complete perfusion can be achieved in only 50–60% of the patients (5, 6). Besides the initial failure of reperfusion, reocclusion after primarily successful thrombolysis (occuring in up to 15%) and bleeding complications (especially intracranial bleeding, observed in 0.5–1.0%) are the current problems of thrombolytic therapy. The ideal thrombolytic agent should be highly effective (high early and complete reperfusion rate), safe (low rate of hemorrhagic complications, e.g., intracranial bleeding), easy to administer (single-bolus application), and cheap. The most widely used agent worldwide, streptokinase, has limited efficacy with regard to early patency, has major side effects (including hypotension), and must be infused over at least 30 min (7). Recombinant tissue-type plasminogen activator (tPA; alteplase) achieves higher rates of early patency but necessitates a rather complicated dose regimen to achieve optimal efficacy (4, 8). Therefore the search for new thrombolytic regimens is still ongoing (9–11).

Keywords

Acute Myocardial Infarction Plasminogen Activator Acute Myocardial Infarction Patency Rate Thrombolytic Agent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    DeWood M, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303: 897–901.CrossRefPubMedGoogle Scholar
  2. 2.
    Fibrinolytic Therapy Trialists’ Collaborative Group. Indications for fibrinolytic therapy in suspected myocardial infarction. Lancet 1994: 343: 311–322.Google Scholar
  3. 3.
    Vogt A, von Essen R, Tebbe U, et al. Impact of early perfusion of the infarct-related artery on short-term mortality after thrombolysis for acute myocardial infarction: retrospective analysis of four German multicenter studies. J Am Coll Cardiol 1993; 21: 1391–1395.CrossRefPubMedGoogle Scholar
  4. 4.
    GUSTO-Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase or both on coronary-artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med 1991; 329: 1615–1622.Google Scholar
  5. 5.
    Vogt A, von Essen R, Tebbe U, et al. Frequency of achieving optimal reperfusion with thrombolysis in acute myocardial infarction (analysis of four German multicenter studies). Am J Cardiol 1994; 93: 1–4.CrossRefGoogle Scholar
  6. 6.
    Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993; 87: 1792–1805.Google Scholar
  7. 7.
    Neuhaus KL, Tebbe U, Sauer G, Kreuzer H, Köstering H. High dose intravenous streptokinase in acute myocardial infarction. Clin Cardiol 1983; 6: 426–434.CrossRefPubMedGoogle Scholar
  8. 8.
    Neuhaus KL, Feuerer W, Jeep-Tebbe S, et al. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1989; 14: 1566–1569.CrossRefPubMedGoogle Scholar
  9. 9.
    Zeymer U, Neuhaus KL. Development of new fibrinolytic agents. Herz 1995; 19: 314–325.Google Scholar
  10. 10.
    Bang N. Tissue-type plasminogen activator mutants. Theoretical and clinical considerations. Circulation 1989; 79: 1391–1392.CrossRefPubMedGoogle Scholar
  11. 11.
    Lijnen HR, Collen D. Strategies for the improvement of thrombolytic agents. Thromb Haemost 1991; 66: 88–110.PubMedGoogle Scholar
  12. 12.
    Holmes WE, Pennica D, Blaber M, et al. Cloning and expression of the gene for prourokinase in Escherichia coli. Bio/Technology 1985; 3: 923–929.CrossRefGoogle Scholar
  13. 13.
    Tebbe U, Günzler WA, Hopkins GR, et al. Thrombolytic therapy of acute myocardial infarction with saruplase, a single-chain urokinase-type plasminogen activator from recombinant bacteria. Fibrinolysis Proteolysis 1997; 11 (Suppl 2), 45–54.CrossRefGoogle Scholar
  14. 14.
    Pannell R, Gurewich V. Pro-urokinase-a study of ist stability in plasma and of a mechanism for ist selective fibrinolytic effect. Blood 1986; 6: 1215–1223.Google Scholar
  15. 15.
    Gurewich V, Pannell R, Louie S, et al. Effective and fibrinspecific clot lysis by a zymogen precursor form of urokinase (pro-urokinase). A study in vitro and in two animal species. J Clin Invest 1984; 73: 1731–1739.CrossRefPubMedGoogle Scholar
  16. 16.
    Koster RW, Cohen AF, Hopkins GR, et al. Pharmacokinetics and pharmacodynamics of saruplase, an unglycosylated single-chain urokinase-type plasminogen activator, in patients with acute myocardial infarction. Thromb Haemost 1994; 71: 740–744.Google Scholar
  17. 17.
    Van de Werf F, Vanhaeke J, de Geeest H, et al. Coronary thrombolysis with recombinant single-chain urokinase-type plasminogen activator in patients with acute myocardial infarction. Circulation 1986; 74: 1066–1070.CrossRefPubMedGoogle Scholar
  18. 18.
    Diefenbach C, Erbel R, Pop T, et al. Recombinant single-chain urokinase-type plasminogen activator during acute myocardial infarction. Am J Cardiol 1988; 61: 966–970.CrossRefPubMedGoogle Scholar
  19. 19.
    Tebbe U, Windeler J, Boesl I, et al, on behalf of the LIMITS Study Group. Thrombolysis with recombinant unglycosolated single-chain urokinase-type plasminogen activator (saruplase) in acute myocar-dial infarction: influence of heparin on early patency rate (LIMITS Study). J Am Coll Cardiol 1995; 26: 365–373.CrossRefPubMedGoogle Scholar
  20. 20.
    PRIMI Study Group. Randomised double-blind trial of recombinant pro-urokinase against streptokinase in acute myocardial infarction. Lancet 1989; I: 863–868.Google Scholar
  21. 21.
    Michels R, Hoffmann H, Windeler J, et al., on behalf of the SUTAMI Investigators. A double-blind multicentre comparison of the efficacy and safety of saruplase and urokinase in the treatment of acute myocardial infarction. Report of the SUTAMI study group. J Thromb Thrombolysis 1995; 2: 117–124.CrossRefPubMedGoogle Scholar
  22. 22.
    The Belgian Saruplase Alteplase Trial Group. Effects of alteplase and saruplase on haemostatic variables: a single-blind, randomised trial in patients with acute myocardial infarction. Coron Artery Dis 1991; 2: 349–355.Google Scholar
  23. 23.
    The SESAM Investigators. Early patency and reocclusion in acute myocardial infarction. A comparison between the thrombolytic agents saruplase and alteplase. Results of the SESAM trial. J Am Coll Cardiol 1994;24 (Suppl):A-345 (abstract).Google Scholar
  24. 24.
    Vermeer F, Bär F, Windeler J, Schenkel W. Saruplase, a new fibrin specific thrombolytic agent; final results of the PASS study in 1698 patients. Circulation 1993; 88: 292–297.Google Scholar
  25. 25.
    Tebbe U, Michels R, Adgey J, et al. Randomized, double-blind study comparing saruplase with streptokinase therapy in acute myocardial infarction: the COMPASS equivalence trial. J Am Coll Cardiol 1998; 31: 487–493.CrossRefPubMedGoogle Scholar
  26. 26.
    Kohnert U, Rudolph R, Verheijen JH, et al. Biochemical properties of the kringle 2 and protease domains are maintained in the refolded tPA deletion variant BM 06.022. Protein Eng 1992; 5: 93–100.CrossRefPubMedGoogle Scholar
  27. 27.
    Martin U, Sponer G, Strein K. Differential fibrinolytic properties of the recombinant plasminogen activator BM 06.022 in human plasma and clot systems in vitro. Blood Coagul Fibrinolysis 1993; 4: 235–242.CrossRefPubMedGoogle Scholar
  28. 28.
    Martin U, Köhler J, Sponer G, Strein K, Pharmocokinetics of the novel recombinant plasminogen activator BM 06.022 in rats, dogs, and non-human primates. Fibrinolysis 1992; 6: 39–43.Google Scholar
  29. 29.
    Martin U, Sponer G, Strein K. Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary thrombosis. J Am Coll Cardiol 1992; 19: 433–440.CrossRefPubMedGoogle Scholar
  30. 30.
    Martin U, von Möllendorf E, Akpan W, et al. Pharmacokinetic and hemostatic properties of the recombinant plasminogen activator BM 06.022 in healthy volunteers. Thromb Haemost 1991; 66: 569–574.PubMedGoogle Scholar
  31. 31.
    Neuhaus KL, von Essen R, Vogt A, et al. Dose finding with a novel recombinant plasminogen activator (BM 06.022) in patients with acute myocardial infarction: results of the German Recombinant Plasminogen Activator Study. J Am Coll Cardiol 1994; 24: 55–60.CrossRefPubMedGoogle Scholar
  32. 32.
    Tebbe U, von Essen R, Smolarz A, et al. Open, noncontrolled dose-finding study with a novel recombinant plasminogen activator (BM 06.022) given as a double bolus in patients with acute myocardial infarction. Am J Cardiol 1993; 72: 518–524.CrossRefPubMedGoogle Scholar
  33. 33.
    Smalling RW, Bode C, Kalbfleisch J, et al. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation 1995; 91: 2725–2732.CrossRefPubMedGoogle Scholar
  34. 34.
    Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996; 94: 891–898.CrossRefPubMedGoogle Scholar
  35. 35.
    INJECT Investigators. A randomised double-blind comparison of reteplase double bolus administration with streptokinase in patients with acute myocardial infarction (INJECT): a trial to investigate equivalence. Lancet 1995; 346: 329–336.CrossRefGoogle Scholar
  36. 36.
    The GUSTO III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337: 1118–1123.CrossRefGoogle Scholar
  37. 37.
    Larsen GR, Timony GA, Horgan PG, et al. Protein engineering of novel plasminogen-activators with increased thrombolytic potency in rabbits relative to activase. J Biol Chem 1991; 266: 8156–8161.PubMedGoogle Scholar
  38. 38.
    Hansen L, Blue Y, Barone E, Collen D, Larsen GR. Functional effects of asparagine-linked oligosaccharide on natural and variant tissue-type plasminogen activator. J Biol Chem 1988; 263: 15713–15719.PubMedGoogle Scholar
  39. 39.
    Phase I Study of Novel Plasminogen Activator, SUN9216 on the safety, pharmacological activity, and pharmacokinetics in healthy volunteers. Suntory Limited Protocol BA1101 Draft report.Google Scholar
  40. 40.
    Phase II. Safety and efficacy of SUN216 by i.v. bolus injection in patients with acute myocardial infarction: a multicenter study of clinical phase II. Suntory limited protocol BA2201 Draft report.Google Scholar
  41. 41.
    Yui Y, Saoki N, Iwade K, et al. A double-blind, dose-finding study for the i.v. bolus injection of SUN9216 (modified tissue plasminogen activator) in acute myocardial infarction. Clinical late phase II study. Jpn Pharmacol Ther 1997; 25: 245–271.Google Scholar
  42. 42.
    Yui Y, Kawai T, Hosada S, et al. Clinical efficacy of SUN9216 (modified tissue plasminogen activator) as compared to alteplase in patients with acute myocardial infarction. Jpn Pharmacol Ther 1997; 25: 269–302.Google Scholar
  43. 43.
    Den Heijer P for the InTIME-I Investigators. Intravenous nPA for treating infarcting myocardium early (InTIME). Presented at the 46th Annual Scientific Seession of the American College of Cardiology, March 18, 1997.Google Scholar
  44. 44.
    Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci USA 1994; 91: 3670–3674.CrossRefPubMedGoogle Scholar
  45. 45.
    Refino CJ, Paoni NF, Keyt BA, et al. A variant of tPA (T103N, KHRR 296-AAAA) that, by bolus, has increased potency and decreased systemic activation of plasminogen. Thromb Haemost 1993; 70: 313–319.PubMedGoogle Scholar
  46. 46.
    Benedict CR, Refino CJ, Keyt BA, et al. New variant of human plasminogen activator (tPA) with enhanced efficacy and lower incidence of bleeding compared with recombinant human TPA. Circulation 1995; 92: 3032–3040.CrossRefPubMedGoogle Scholar
  47. 47.
    Collen D, Stassen JM, Yasuda T, et al. Comparative thrombolytic properties of tissue-type plasminogen activator and of a plasminogen activator inhibitor-l-resistant glycosylation variant, in a combined arterial and venous thrombosis model in the dog. Thromb Haemost 1994; 72: 98–104.PubMedGoogle Scholar
  48. 48.
    Cannon CP, McCabe CH, Gibson M, et al for the TIMI 10A Investigators. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation 1997; 95: 351–356.CrossRefPubMedGoogle Scholar
  49. 49.
    Tanswell P, Tebbe U, Neuhaus KL, Glasle-Schwarz L, Wojcik J, Seifried E. Pharmacokinetics and fibrin specificity of alteplase during accelerated infusions in acute myocardial infarction. J Am Coll Cardiol 1992; 19: 1071–1075.CrossRefPubMedGoogle Scholar
  50. 49a.
    Cannon CP, McCabe CH, Gibson CM, et al. TNK-Tissue plasminogen activator compared with front-loaded plasminogen activator in acute myocardial infarction: primary results of the TIMI IOB trial. Circulation 1997; 96: I - 206.Google Scholar
  51. 50.
    Lack CH. Staphylokinase: an activator of plasma protease. Nature 1949; 161: 559–560.CrossRefGoogle Scholar
  52. 51.
    Collen D, Silence K, Demarsin E, De Mol M, Lijnen HR. Isolation and characterization of natural and recombinant staphylokinase. Fibrinolysis 1992; 6: 203–213.CrossRefGoogle Scholar
  53. 52.
    Schlott B, Hartmann M, Gührs KH, Birch-Hirschfeld E, Pohl HD, et al. High yield production and purification of recombinant staphylokinase for thrombolytic therapy. Biotechnology 1993; 12: 185–189.Google Scholar
  54. 53.
    Collen D, Lijnen HR. Staphylokinase, a fibrin-specific plasminogen activator with therapeutic potential? Blood 1994; 84: 680–686.PubMedGoogle Scholar
  55. 54.
    Declerck PJ, Vanderschueren S, Billiet J, Moreau H, Collen D. Prevalence and induction of circulating antibodies against recombinant staphylokinase. Thromb Haemost 1994; 71: 129–133.PubMedGoogle Scholar
  56. 55.
    Vanderschueren S, Stassen JM, Collen D. On the immunogenicity of recombinant staphylokinase in patients and animal models. Thromb Haemost 1994; 72: 297–301.PubMedGoogle Scholar
  57. 56.
    Collen D, Stockx L, Lacroix H, Suy R, Vanderschueren S. Recombinant staphylokinase variants with altered immunoreativity. IV: Identification of variants with reduced antibody induction but intact potency. Circulation 1997; 95: 463–472.CrossRefPubMedGoogle Scholar
  58. 57.
    Lijnen HR, de Cock F, Matsuo O, Collen D. Comparative fibrinolytic and fibrigenolytic properties of staphylokinase and streptokinase in plasma of different species in vitro. Fibrinolysis 1992; 6: 33–37.Google Scholar
  59. 58.
    Collen D, De Cock F, Vanlinthout I, Declerck PJ, Lijnen HR, Stassen JM. Comparative thrombolytic and immunogenic properties of staphylokinase and streptokinase. Fibrinolysis 1992; 6: 232–242.CrossRefGoogle Scholar
  60. 59.
    Collen D, Van de Werf F. Coronary thrombolysis with recombinant staphylokinase in patients with evolving myocardial infarction. Circulation 1993; 87: 1850–1853.CrossRefPubMedGoogle Scholar
  61. 60.
    Vanderschueren S, Barrios L, Kerdsinchai P, van den Heuvel P, Hermans L, Vrolix M, et al., for the STAR Trial Group. A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction. Circulation 1995; 92: 2044–2049.CrossRefPubMedGoogle Scholar
  62. 61.
    van de Werf F. TNK and Staphylokinase. Presented at the 10th Annual Symposium on Myocardial Reperfusion: Concepts and Controversies, Anaheim, CA, March 15, 1997.Google Scholar
  63. 62.
    Gulba DC, Praus M, Witt W. DSPA a: properties of the plasminogen activators of vampire bat Desmodus rotundus. Fibrinolysis 1995; 9 (Suppl 1): 91–96.Google Scholar
  64. 63.
    Collen D, Lu HR, Lijnen HR, Nelles L, Stassen JM. Thrombolytic and pharmacokinetic properties of chimeric tissue-type and urokinase-type plasminogen activators. Circulation 1991; 84: 1216–1224.CrossRefPubMedGoogle Scholar
  65. 64.
    Van de Werf F, Lijnen HR, Collen D. Coronary thrombolysis with K1K2Pu, a chimeric tisue-type and urokinase-type plasminogen activator: a feasibility study in six patients with acute myocardial infarction: Coron Artery Dis 1993; 10: 929–933.Google Scholar
  66. 65.
    Bode C, Matsueda GR, Hui KY, Haber E. Antibody directed urokinase: a specific fibrinolytic agent. Science 1985; 2229: 765–767.Google Scholar
  67. 66.
    Dewerchin M, Collen D. Enhancement of the thrombolytic potency of plasminogen activators by conjunction with clotspecific monoclonal antibodies. Bioconjugate Chem 1991; 2: 293–300.CrossRefGoogle Scholar
  68. 67.
    Bode C, Runge MS, Branscomb EE, Newell JB, Matsueda GR, Haber E. Antibody-directed fibrinolysis: an antibody specific for both, fibrin and tissue plasminogen activator. J Biol Chem 1989; 264: 944–948.PubMedGoogle Scholar
  69. 68.
    Bode C, Runge MS, Schönermark S, Eberle T, Newell JB, Kübler W, et al. Conjugation to antifibrin fab’ enhances fibrinolytic potency of single-chain urokinase plasminogen activator. Circulation 1990; 81: 1974 1980.Google Scholar
  70. 69.
    Schröder R, Wegscheider K, Schröder K, Dissmann R, Meyer-Sabellek W, for the INJECT Trial Group. Extent of early ST segment elevation resolution: a strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. J Am Coll Cardiol 1995; 26: 1657–1664.CrossRefPubMedGoogle Scholar
  71. 70.
    Zeymer U, Schröder R, Molhoek P, Tebbe U, Jessel A, Neuhaus KL, for the HIT-4 Investigators. 90-min patency and 180 min resolution of ST-segment elevation are equally effective predictors of 30-day mortality after AMI. Eur Heart J 1997;18 (abstract) Supp1:352.Google Scholar
  72. 71.
    Braunwald E, Cannon CP, McCabe CH. An approach to evaluating thrombolytic therapy in acute myocardial infarction. The “unsatisfactory outcome” endpoint. Circulation 1992; 86: 683–687.CrossRefPubMedGoogle Scholar
  73. 72.
    Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The early termination of clinical trials; causes, consequences, and control. Circulation 1994; 89: 2892–2907.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Uwe Zeymer
  • Karl-Ludwig Neuhaus

There are no affiliations available

Personalised recommendations