American Journal of Cardiovascular Drugs

, Volume 7, Issue 4, pp 249–257 | Cite as

Direct Antithrombins

Mechanisms, Trials, and Role in Contemporary Interventional Medicine
Review Article

Abstract

Direct thrombin inhibitors have several potential advantages over indirect thrombin inhibitors such as heparin. Bivalirudin, a bivalent direct thrombin inhibitor, is most commonly used in clinical practice and has a proven role in contemporary interventional medicine with elective percutaneous coronary intervention (PCI) as well as in patients with non-ST-elevation acute coronary syndrome (NSTEACS). Results from well-controlled clinical trials have shown that bivalirudin is associated with an approximate 50% reduction in major bleeding while having similar effects on incidence of death and myocardial infarction (MI) compared with herapin or enoxaparin and glycoprotein IIb/IIIa inhibitors. Bivalirudin has been successfully used in off- and on-pump cardiac surgery.

Argatroban is the most evaluated among the univalent direct thrombin inhibitors inhibiting only the catalytic site of thrombin. It has been associated with similar rates of major bleeding compared with heparin in patients with acute MI receiving either streptokinase or alteplase with no effects on clinical endpoints.

In a meta-analysis of 11 randomised trials where direct thrombin inhibitors (hirudin, bivalirudin, argatroban, efegatan or inogatran) were compared with unfractionated heparin in >35 000 patients with ST-elevation MI (STEMI) or NSTEACS there was no mortality difference between treatment groups but the incidence of MI at 30 days was significantly reduced in patients treated with direct thrombin inhibitors compared with heparin (4.7% vs 5.3%; p < 0.004).

The role of direct thrombin inhibitors in both primary angioplasty for STEMI and angioplasty after fibrinolytic therapy needs to be established. Overall, the efficacy and improved safety profile make bivalirudin an attractive first-line anticoagulant for elective PCI and in patients with NSTEACS undergoing an invasive strategy.

References

  1. 1.
    Bates SM, Weitz JI. Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin. Am J Cardiol 1998; 82: 12P–8P.PubMedCrossRefGoogle Scholar
  2. 2.
    Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001 Jan; 119 (1 Suppl.): 64S–94S.PubMedCrossRefGoogle Scholar
  3. 3.
    Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992; 326: 800–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci U S A 1989; 86: 3619–23.PubMedCrossRefGoogle Scholar
  5. 5.
    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: 385–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97: 544–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Hogg PJ, Jackson CM, Labanowski JK, et al. Binding of fibrin monomer and heparin to thrombin in a tenary complex alters the environment for the thrombin catalytic sites, reduces affinity for hirudin, and inhibits cleavage of fibrinogen. J Biol Chem 1996; 271: 26088–95.PubMedCrossRefGoogle Scholar
  8. 8.
    Tsuda Y, Szewczuk Z, Wang J, et al. Interactions of hirudin-based inhibitor with thrombin: critical role of the IleH59 side chain of the inhibitor. Biochemistry 1995; 34: 8708–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353: 1028–40.PubMedCrossRefGoogle Scholar
  10. 10.
    Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97: 251–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Robson R, White H, Aylward P, et al. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther 2002; 71: 433–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Cheneau E, Canos D, Kuchulakanti PK, et al. Value of monitoring activated clotting time when bivalirudin is used as the sole anticoagulation agent for percutaneous coronary intervention. Am J Cardiol 2004; 94: 789–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Bittl JA, Strony J, Brinker JA, et al., for the Hirulog Angioplasty Study Investigators. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995; 333: 764–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Bittl JA, Chaitman BR, Feit F, et al., on behalf of the Bivalirudin Angioplasty Study Investigators. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142: 952–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Lincoff AM, Bittl JA, Kleiman NS, et al. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial). Am J Cardiol 2004; 93: 1092–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289: 853–63.PubMedCrossRefGoogle Scholar
  17. 17.
    Lincoff AM, Kleiman NS, Kereiakes DJ, et al., for the REPLACE-2 Investigators. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004; 292: 696–703.PubMedCrossRefGoogle Scholar
  18. 18.
    Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Feit F, Voeltz M, Attubato M, et al. Predictors and impact hemorrhage on mortality following PCI (from the REPLACE-2 trial). Am J Cardiol. In press.Google Scholar
  20. 20.
    Ebrahimi R, Lincoff AM, Bittl JA, et al. Bivalirudin vs heparin in percutaneous coronary intervention: a pooled analysis. J Cardiovasc Pharmacol Ther 2005; 10: 209–16.PubMedCrossRefGoogle Scholar
  21. 21.
    Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 2004; 44: 1792–800.PubMedGoogle Scholar
  22. 22.
    Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203–16.PubMedCrossRefGoogle Scholar
  23. 23.
    Kirtane AJ, Piazza G, Murphy SA, et al. Correlates of bleeding events among moderate- to high-risk patients undergoing percutaneous coronary intervention and treated with eptifibatide: observations from the PROTECT-TIMI-30 trial. J Am Coll Cardiol 2006; 47: 2374–9.PubMedCrossRefGoogle Scholar
  24. 24.
    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: 1624–30.PubMedCrossRefGoogle Scholar
  25. 25.
    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: 1631–7.CrossRefGoogle Scholar
  26. 26.
    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: 1638–42.PubMedCrossRefGoogle Scholar
  27. 27.
    Cannon CP, McCabe CH, Henry TD, et al., for the TIMI 5 Investigators. 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: 993–1003.PubMedCrossRefGoogle Scholar
  28. 28.
    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: 911–21.PubMedCrossRefGoogle Scholar
  29. 29.
    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: the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIB investigators. N Engl J Med 1996; 335: 775–82.CrossRefGoogle Scholar
  30. 30.
    Neuhaus KL, Molhoek GP, Zeymer U, et al., for the HIT-4 Investigators. 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: 966–73.PubMedCrossRefGoogle Scholar
  31. 31.
    Zeymer U, Schroder R, Tebbe U, et al. Non-invasive detection of early infarct vessel patency by resolution of ST-segment elevation in patients with thrombolysis for acute myocardial infarction: results of the angiographic substudy of the Hirudin for Improvement of Thrombolysis (HIT)-4 trial. Eur Heart J 2001; 22: 769–75.PubMedCrossRefGoogle Scholar
  32. 32.
    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: 1855–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Jang I-K, Brown DFM, Giugliano RP, et al., for the MINT Investigators. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: Myocardial Infarction With Novastan and TPA (MINT) Study. J Am Coll Cardiol 1999; 33: 1879–85.PubMedCrossRefGoogle Scholar
  34. 34.
    Vermeer F, Vahanian A, Fels PW, et al., for the ARGAMI Study Group. Argatroban and alteplase in patients with acute myocardial infarction: the ARGAMI Study. J Thromb Thrombolysis 2000; 10: 233–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Kaplinsky E. Direct antithrombin-argatroban in acute myocardial infarction (ARGAMI-2) in late breaking clinical trials. J Am Coll Cardiol 1998; 32: 1–7.CrossRefGoogle Scholar
  36. 36.
    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: 294–302.CrossRefGoogle Scholar
  37. 37.
    Stella JF, Stella RE, Iaffaldano RA, et al. Anticoagulation with bivalirudin during percutaneous coronary intervention for ST-segment elevation myocardial infarction. J Invasive Cardiol 2004; 16: 451–4.PubMedGoogle Scholar
  38. 38.
    Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). Am Heart J 2002; 143: 847–53.PubMedCrossRefGoogle Scholar
  39. 39.
    Chew DP, Lincoff AM, Gurm H, et al. Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial). Am J Cardiol 2005; 95: 581–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Mahaffey KW, Lewis BE, Wildermann NM, et al. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol 2003; 15: 611–6.PubMedGoogle Scholar
  41. 41.
    Young G, Yonekawa KE, Nakagawa PA, et al. Differential effects of direct thrombin inhibitors and anti-thrombin-dependent anticoagulants on the dynamics of clot formation. Blood Coagul Fibrinolysis 2007; 18: 97–103.PubMedCrossRefGoogle Scholar
  42. 42.
    Nielsen VG, Steenwyk BL, Gurley WQ, et al. Argatroban, bivalirudin, and lepirudin do not decrease clot propagation and strength as effectively as heparin activated antithrombin in vitro. J Heart Lung Transplant 2006; 25: 653–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131: 515–6.CrossRefGoogle Scholar
  44. 44.
    Merry AF, Raudkivi PJ, Middleton NG, et al. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 2004; 77: 925–31.PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Dunedin School of Medicine, CardiologyOtago UniversityOtagoNew Zealand
  2. 2.Green Lane Cardiovascular ServiceAuckland City HospitalAucklandNew Zealand

Personalised recommendations