American Journal of Cardiovascular Drugs

, Volume 4, Issue 2, pp 107–115

Adjunctive Use of Direct Thrombin Inhibitors in Patients Receiving Fibrinolytic Therapy for Acute Myocardial Infarction

  • John K. French
  • John J. Edmond
  • Wanzhen Gao
  • Harvey D. White
  • John W. Eikelboom
Review Article

Abstract

The direct thrombin inhibitors hirudin and bivalirudin inhibit both fluid-phase and clot-bound thrombin. These agents have been extensively studied in clinical trials in comparison with intravenous unfractionated heparin (UFH), as adjuncts to fibrinolytic therapy for ST-elevation myocardial infarction (STEMI) and in percutaneous coronary intervention (PCI), and they are currently undergoing further evaluation in patients with non-ST elevation acute coronary syndromes (NSTEACS).

In angiographic trials there were trends for patients treated with hirudin to be more likely to achieve Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 90 minutes than patients treated with UFH (65% versus 57% in TIMI-5; 41% versus 33% in Hirudin for the Improvement of Thrombolysis [HIT]-4; statistically nonsignificant differences in both trials). In Montréal Heart Institute trials and the multicenter Hirulog® and Early Reperfusion or Occlusion (HERO)-1 trial the use of bivalirudin was associated with an increased incidence of TIMI grade 3 flow (85% versus 31%, p = 0.006; and 48% versus 35%, p = 0.02, respectively). These studies used streptokinase as the fibrinolytic agent except in TIMI-5 where alteplase was used.

The initial clinical outcomes studies (Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes [GUSTO]-IIA and TIMI-9A) were discontinued early because of a high incidence of intracerebral bleeding (∼1.8%). Patients in these studies had either STEMI or NSTEACS, and thus not all were treated with fibrinolytic therapy. These studies were recommenced as GUSTO-IIB and TIMI-9B, using lower dosages of hirudin (0.1 mg/kg bolus + 0.1 mg/kg infusion for 96 hours). Neither TIMI-9B nor GUSTO-IIB showed an improvement in efficacy (death or reinfarction) or an increase in bleeding with hirudin. However, in the 1015 patients with STEMI treated with streptokinase in GUSTO-IIB, there was a 40% reduction in the combined incidence of death or myocardial infarction at 30 days (8.6% versus 14.4%, odds ratio [OR] 0.57, 95% confidence interval [CI] 0.38–0.87, p = 0.004).

In the HERO-2 trial, 17 073 patients receiving streptokinase for STEMI were randomized to receive either bivalirudin (0.25 mg/kg bolus and 0.5 mg/kg infusion for 12 hours followed by 0.25 mg/kg) or UFH (5000IU bolus and 800–1000 IU/h infusion titrated to an activated partial thromboplastin time [APTT] of 50–75 seconds) for a total of 48 hours. Thirty-day mortality was similar in both groups (10.8% with bivalirudin versus 10.9% with UFH, OR 0.99, 95% CI 0.90–1.09, p = 0.85). There was a 30% reduction in the incidence of reinfarction before 96 hours (1.6% with bivalirudin versus 2.3% with UFH, OR 0.70, 95% CI 0.56–0.87, p = 0.001). Patients treated with bivalirudin had significantly more moderate bleeding (1.4% versus 1.1% with UFH, OR 1.32, 95% CI 1.0–1.74, p = 0.05).

In a meta-analysis of patients with STEMI in the Direct Thrombin Inhibitor Trialists’ collaboration, direct thrombin inhibitors were found to reduce the rate of reinfarction at 30 days (3.9% versus 4.8% with UFH, OR 0.80, 95% CI 0.71–0.90, p < 0.001), but did not reduce mortality (9.1% versus 9.0%, OR 1.02, 95% CI 0.94–1.11, p = 0.68) or the combined incidence of death/reinfarction at 30 days (11.8% versus 12.4%, OR 0.95, 95% CI 0.88–1.02, p = 0.18). There was no increase in major bleeding or intracerebral bleeding with direct thrombin inhibitor therapy.

In conclusion, direct thrombin inhibitors reduce reinfarction, but not mortality, in patients with STEMI treated with fibrinolytic therapy. The major benefit of direct thrombin inhibitors appears to be in patients undergoing PCI, particularly after STEMI.

References

  1. 1.
    French JK, Williams BF, Hart HH, et al. Prospective evaluation of eligibility for thrombolytic therapy in acute myocardial infarction. BMJ 1996; 312: 1637–41PubMedCrossRefGoogle Scholar
  2. 2.
    Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation 1987; 76: 142–54PubMedCrossRefGoogle Scholar
  3. 3.
    TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase I findings. N Engl J Med 1985; 312: 932–6Google Scholar
  4. 4.
    Simes RJ, Topol EJ, Holmes Jr DR, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: importance of early and complete infarct artery reperfusion. Circulation 1995; 91: 1923–8PubMedCrossRefGoogle Scholar
  5. 5.
    White HD, Norris RM, Brown MA, et al. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987; 317: 850–5PubMedCrossRefGoogle Scholar
  6. 6.
    The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction [published erratum appears in N Engl J Med 1994; 330: 516]. N Engl J Med 1993; 329: 1615–22CrossRefGoogle Scholar
  7. 7.
    White HD, Cross DB, Elliott JM, et al. Long-term prognostic importance of patency of the infarct-related coronary artery after thrombolytic therapy for acute myocardial infarction. Circulation 1994; 89: 61–7PubMedCrossRefGoogle Scholar
  8. 8.
    White HD, French JK, Hamer AW, et al. Frequent reocclusion of patent infarctrelated arteries between 4 weeks and 1 year: effects of antiplatelet therapy. J Am Coll Cardiol 1995; 25: 218–23PubMedCrossRefGoogle Scholar
  9. 9.
    Ohman EM, Califf RM, Topol EJ, et al. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation 1990; 82: 781–91PubMedCrossRefGoogle Scholar
  10. 10.
    Eisenberg PR, Miletich JP. Induction of marked thrombin activity by pharmacologie concentrations of plasminogen activators in nonanticoagulated whole blood. Thromb Res 1989; 55: 635–43PubMedCrossRefGoogle Scholar
  11. 11.
    Lee CD, Mann KG. Activation/inactivation of human coagulation factor V by plasmin. Blood 1989; 73: 185–90PubMedGoogle Scholar
  12. 12.
    Eisenberg PR. Role of heparin in coronary thrombolysis. Chest 1992; 101 (4 Suppl.): 131S–9SPubMedGoogle Scholar
  13. 13.
    Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385–91PubMedCrossRefGoogle Scholar
  14. 14.
    Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci USA 1989; 86: 3619–23PubMedCrossRefGoogle Scholar
  15. 15.
    Hirsh J, Raschke R, Warkentin TE, et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1995; 108: 258S–75SPubMedCrossRefGoogle Scholar
  16. 16.
    Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330–5PubMedCrossRefGoogle Scholar
  17. 17.
    Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74: 1–23PubMedCrossRefGoogle Scholar
  18. 18.
    Toschi V, Lettino M, Gallo R, et al. Biochemistry and biology of hirudin. Coron Artery Dis 1996; 7: 420–8PubMedCrossRefGoogle Scholar
  19. 19.
    Zoldhelyi P, Webster MWI, Fuster V, et al. Recombinant hirudin in patients with chronic, stable coronary artery disease: safety, half-life and effect on coagulation parameters. Circulation 1993; 88: 2015–22PubMedCrossRefGoogle Scholar
  20. 20.
    Verstraete M. Modulating platelet function with direct thrombin inhibitors. Haemostasis 1996; 26: 70–7PubMedGoogle Scholar
  21. 21.
    Wallis RB. Hirudins: from leeches to man. Semin Thromb Hemost 1996; 22: 185–96PubMedCrossRefGoogle Scholar
  22. 22.
    Tripodi A, Chantarangkul V, Arbini AA, et al. Effects of hirudin on activated partial thromboplastin time determined with ten different reagents. Thromb Haemost 1993; 70: 286–8PubMedGoogle Scholar
  23. 23.
    Potzsch B, Madlener K, Seelig C, et al. Monitoring of R-hirudin anticoagulation during pulmonary bypass: assessment of whole blood ecarin clotting time. Thromb Haemost 1997; 77: 920–5PubMedGoogle Scholar
  24. 24.
    Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids. Semin Thromb Hemost 1996; 22: 197–202PubMedCrossRefGoogle Scholar
  25. 25.
    Maraganore JM, Bourdon P, Jablonski I, et al. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990; 29: 7095–101PubMedCrossRefGoogle Scholar
  26. 26.
    Bates SM, Weitz JI. Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin. Am J Cardiol 1998; 82: 12P–8PPubMedCrossRefGoogle Scholar
  27. 27.
    Witting JI, Bourdon P, Brezniak DV, et al. Thrombin-specific inhibition by and slow cleavage of hirulog-1. Biochem J 1992; 283: 737–43PubMedGoogle Scholar
  28. 28.
    Ren S, Fenton JWII, Maraganore JM, et al. Inhibition by hirulog-1 of generation of plasminogen activator inhibitor-1 from vascular smooth-muscle cells induced by thrombin. J Cardiovasc Pharmacol 1997; 29: 337–42PubMedCrossRefGoogle Scholar
  29. 29.
    Kranzhofer R, Maraganore J, Baciu R. Sytemic thrombin inhibition by hirulog does not alter medial smooth-muscle cell proliferation and inflammatory activation after vascular injury in the rabbit. Cardiovasc Drugs Ther 1999; 13: 429–34PubMedCrossRefGoogle Scholar
  30. 30.
    Burchenal JE, Marks DS, Mann JT, et al. Effects of direct thrombin inhibition with bivalirudin (hirulog) of restenosis after coronary angioplasty. Am J Cardiol 1998; 82: 511–5PubMedCrossRefGoogle Scholar
  31. 31.
    Fox I, Dawson A, Loynds P, et al. Anticoagulant activity of hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost 1993; 69: 157–63PubMedGoogle Scholar
  32. 32.
    Maraganore JM, Adelman BA. Hirulog: a direct thrombin inhibitor for management of acute coronary syndromes. Coron Artery Dis 1996; 7: 438–48PubMedCrossRefGoogle Scholar
  33. 33.
    Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol 2000; 12: 33F–6FPubMedGoogle Scholar
  34. 34.
    Robson R, White H, Aylward P, et al. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther 2002; 71: 433–9PubMedCrossRefGoogle Scholar
  35. 35.
    Weitz JI, Hirsch J. New anticoagulant drugs. Chest 2001; 119: 95S–107PubMedCrossRefGoogle Scholar
  36. 36.
    Fitzgerald D, Murphy N. Argatroban: a synthetic thrombin inhibitor of low relative molecular mass. Coron Artery Dis 1996; 7: 455–8PubMedCrossRefGoogle Scholar
  37. 37.
    McKeage K, Plosker GL. Argatroban. Drugs 2001; 61: 515–22PubMedCrossRefGoogle Scholar
  38. 38.
    Heit JA, Colwell CW, Francis CW. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose finding study. Arch Intern Med 2001; 161: 2215–21PubMedCrossRefGoogle Scholar
  39. 39.
    Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J Am Coll Cardiol 1994; 23: 993–1003PubMedCrossRefGoogle Scholar
  40. 40.
    Antman EM, for the TIMI 9B Investigators. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 1996; 94: 911–21PubMedCrossRefGoogle Scholar
  41. 41.
    The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIB Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335: 775–82CrossRefGoogle Scholar
  42. 42.
    Neuhaus KL, Molhoek GP, Zeymer U, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol 1999; 34: 966–73PubMedCrossRefGoogle Scholar
  43. 43.
    Lidón RM, Théroux P, Lespérance J, et al. A pilot, early angiographic patency study using a direct thrombin inhibitor as adjunctive therapy to streptokinase in acute myocardial infarction. Circulation 1994; 89: 1567–72PubMedCrossRefGoogle Scholar
  44. 44.
    Théroux P, Pérez-Villa F, Waters D, et al. Randomized double-blind comparison of two doses of hirulog with heparin as adjunctive therapy to streptokinase to promote early patency of the infarct-related artery in acute myocardial infarction. Circulation 1995; 91: 2132–9PubMedCrossRefGoogle Scholar
  45. 45.
    White HD, Aylward PE, Frey MJ, et al. Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96: 2155–61PubMedCrossRefGoogle Scholar
  46. 46.
    Schroder R, Zeymer U, Wegscheider K, et al. Comparison of the predictive value of ST segment elevation resolution at 90 and 180 min after start of streptokinase in acute myocardial infarction: a substudy of the Hirudin for Improvement of Thrombolysis (HIT)-4 study. Eur Heart J 1999; 20: 1563–71PubMedCrossRefGoogle Scholar
  47. 47.
    Andrews J, Straznicky IT, French JK, et al. ST-segment recovery adds to the assessment of TIMI 2 and 3 flow in predicting infarct wall motion after thrombolytic therapy. Circulation 2000; 101: 2138–43PubMedCrossRefGoogle Scholar
  48. 48.
    Antman EM, for the TIMI 9A Investigators. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial. Circulation 1994; 90: 1624–30PubMedCrossRefGoogle Scholar
  49. 49.
    The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90: 1631–7CrossRefGoogle Scholar
  50. 50.
    Granger CB, Van de Werf F, Armstrong PW, et al. Hirudin reduces death and myocardial (re)infarction at 6-months: follow-up results of the GUSTO IIb trial [abstract]. J Am Coll Cardiol 1998; 31 Suppl. A: 79ACrossRefGoogle Scholar
  51. 51.
    Metz BK, White HD, Granger CB, et al. Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb trial. J Am Coll Cardiol 1998; 31: 1493–8PubMedCrossRefGoogle Scholar
  52. 52.
    Simes RJ, Granger CB, Antman EM, et al. Impact of hirudin versus heparin on mortality and (re)infarction in patients with acute coronary syndromes: a prospective meta-analysis of the GUSTO-IIb and TIMI 9b trials [abstract]. Circulation 1996; 94 Suppl. I: I–430Google Scholar
  53. 53.
    Kong DF, Topol EJ, Bittl JA, et al. Clinical outcomes of bivalirudin for ischemic heart disease. Circulation 1999; 100: 2049–53PubMedCrossRefGoogle Scholar
  54. 54.
    Neuhaus KL, von Essen R, Tebbe U, et al. Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study: a study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK). Circulation 1994; 90: 1638–42PubMedCrossRefGoogle Scholar
  55. 55.
    The Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001; 358: 1855–63PubMedCrossRefGoogle Scholar
  56. 56.
    Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41,021 patients. Circulation 1995; 91: 1659–68PubMedCrossRefGoogle Scholar
  57. 57.
    The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001; 358: 605–13CrossRefGoogle Scholar
  58. 58.
    Mehta S, Eikelboom JW, Yusuf S. Risk of intracranial haemorrhage with bolus versus infusion thrombolytic therapy: a meta-analysis of over 100 000 patients. Lancet 2000; 356: 449–54PubMedCrossRefGoogle Scholar
  59. 59.
    Ferguson JJ. Meeting highlights: 47th Annual Scientific Sessions of the American College of Cardiology. Circulation 1998; 97: 2377–81PubMedCrossRefGoogle Scholar
  60. 60.
    The Direct Thrombin Inhibitor Trialists’ Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359: 294–302CrossRefGoogle Scholar
  61. 61.
    Granger CB, Pieper KS, Eikelboom J, et al. Effect of direct thrombin inhibitors on reducing death and myocardial infarction in acute coronary syndromes is greater in patients undergoing percutaneous coronary intervention [abstract]. Circulation 2002; 106 Suppl. II: II–494Google Scholar

Copyright information

© Adis Data Informotion BV 2004

Authors and Affiliations

  • John K. French
    • 1
    • 2
  • John J. Edmond
    • 1
  • Wanzhen Gao
    • 1
  • Harvey D. White
    • 1
  • John W. Eikelboom
    • 3
  1. 1.Cardiovascular Research UnitGreen Lane HospitalAucklandNew Zealand
  2. 2.Cardiology DepartmentLiverpool HospitalLiverpool, SydneyAustralia
  3. 3.Department of HaematologyRoyal Perth HospitalPerthAustralia

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