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Direct Thrombin Inhibitors in Acute Coronary Syndromes

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Book cover Antithrombotic Drug Therapy in Cardiovascular Disease

Part of the book series: Contemporary Cardiology ((CONCARD))

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Abstract

The acute coronary syndromes (ACS) represent a continuum of athereothrombotic diseases that result from near instantaneous platelet activation and the initiation of the coagulation cascade most often following plaque erosion/rupture. Due to the central role of thrombin in clot formation, many therapies have aimed at inhibiting the action of thrombin to slow or reverse the coagulation cascade and to minimize the morbidity of ACS. While unfractionated heparin has been the stalwart agent for the management of ACS, several unfavorable characteristics such as the inability to inhibit clot-bound thrombin and a vulnerability to circulating inhibitors have prompted the search for alternative agents. Direct thrombin inhibitors (DTIs) were developed in an effort to effectively block the prothrombotic effects of thrombin without the associated increase in hemorrhagic events seen with the use of heparin. Early trials evaluating the DTI hirudin for management of unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI) were largely disappointing. More recent data has demonstrated significantly lower bleeding rates with a similar effect on ischemic endpoints with the use of the DTI, bivalirudin, across the spectrum of ACS. As a result, the use of bivalirudin for most patients presenting with UA, NSTEMI, or STEMI is increasing. In this chapter, the data regarding the use of DTI in ACS will be presented and suggestions for their use in specific clinical scenarios will be given.

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References

  1. Weitz JI, Bates ER (2003) Direct thrombin inhibitors in cardiac disease. Cardiovasc Toxicol 3:13–25

    Article  PubMed  CAS  Google Scholar 

  2. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J (1990) Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 86:385–391

    Article  PubMed  CAS  Google Scholar 

  3. Hirsh J (1991) Heparin. N Engl J Med 324:1565–1574

    Article  PubMed  CAS  Google Scholar 

  4. Eitzman DT, Chi L, Saggin L, Schwartz RS, Lucchesi BR, Fay WP (1994) Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4. Circulation 89:1523–1529

    Article  PubMed  CAS  Google Scholar 

  5. Sobel M, Fish WR, Toma N et al (2001) Heparin modulates integrin function in human platelets. J Vasc Surg 33:587–594

    Article  PubMed  CAS  Google Scholar 

  6. Martel N, Lee J, Wells PS (2005) Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 106:2710–2715

    Article  PubMed  CAS  Google Scholar 

  7. Bijsterveld NR, Peters RJ, Murphy SA, Bernink PJ, Tijssen JG, Cohen M (2003) Recurrent cardiac ischemic events early after discontinuation of short-term heparin treatment in acute coronary syndromes: results from the Thrombolysis in Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) studies. J Am Coll Cardiol 42:2083–2089

    Article  PubMed  CAS  Google Scholar 

  8. Theroux P, Waters D, Lam J, Juneau M, McCans J (1992) Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 327:141–145

    Article  PubMed  CAS  Google Scholar 

  9. Marciniak E, Gockerman JP (1977) Heparin-induced decrease in circulating antithrombin-III. Lancet 2:581–584

    Article  PubMed  CAS  Google Scholar 

  10. Weitz JI (1997) Low-molecular-weight heparins. N Engl J Med 337:688–698

    Article  PubMed  CAS  Google Scholar 

  11. Bara L, Billaud E, Gramond G, Kher A, Samama M (1985) Comparative pharmacokinetics of a low molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 39:631–636

    Article  PubMed  CAS  Google Scholar 

  12. Young E, Wells P, Holloway S, Weitz J, Hirsh J (1994) Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 71:300–304

    PubMed  CAS  Google Scholar 

  13. Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE (1998) Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 114:489S–510S

    Article  PubMed  CAS  Google Scholar 

  14. Cosmi B, Fredenburgh JC, Rischke J, Hirsh J, Young E, Weitz JI (1997) Effect of nonspecific binding to plasma proteins on the antithrombin activities of unfractionated heparin, low-molecular-weight heparin, and dermatan sulfate. Circulation 95:118–124

    Article  PubMed  CAS  Google Scholar 

  15. Cohen M, Demers C, Gurfinkel EP et al (1997) A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 337:447–452

    Article  PubMed  CAS  Google Scholar 

  16. Antman EM, McCabe CH, Gurfinkel EP et al (1999) Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 100:1593–1601

    Article  PubMed  CAS  Google Scholar 

  17. Bozovich GE, Gurfinkel EP, Antman EM, McCabe CH, Mautner B (2000) Superiority of enoxaparin versus unfractionated heparin for unstable angina/non-Q-wave myocardial infarction regardless of activated partial thromboplastin time. Am Heart J 140:637–642

    Article  PubMed  CAS  Google Scholar 

  18. Cannon CP, Weintraub WS, Demopoulos LA et al (2001) Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 344:1879–1887

    Article  PubMed  CAS  Google Scholar 

  19. Ferguson JJ, Califf RM, Antman EM et al (2004) Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. Jama 292:45–54

    Article  PubMed  CAS  Google Scholar 

  20. Mahaffey KW, Cohen M, Garg J et al (2005) High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial. Jama 294:2594–2600

    Article  PubMed  CAS  Google Scholar 

  21. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators (2001) Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 358:605–613

    Article  Google Scholar 

  22. Wallentin L, Goldstein P, Armstrong PW et al (2003) Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 108:135–142

    Article  PubMed  CAS  Google Scholar 

  23. Antman EM, Morrow DA, McCabe CH et al (2006) Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 354:1477–1488

    Article  PubMed  CAS  Google Scholar 

  24. Tsuda Y, Szewczuk Z, Wang J, Yue SY, Purisima E, Konishi Y (1995) Interactions of hirudin-based inhibitor with thrombin: critical role of the IleH59 side chain of the inhibitor. Biochemistry 34:8708–8714

    Article  PubMed  CAS  Google Scholar 

  25. Eichler P, Friesen HJ, Lubenow N, Jaeger B, Greinacher A (2000) Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 96:2373–2378

    PubMed  CAS  Google Scholar 

  26. Huhle G, Hoffmann U, Song X, Wang LC, Heene DL, Harenberg J (1999) Immunologic response to recombinant hirudin in HIT type II patients during long-term treatment. Br J Haematol 106:195–201

    Article  PubMed  CAS  Google Scholar 

  27. Jang IK, Brown DF, Giugliano RP et al (1999) 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 33:1879–1885

    Article  PubMed  CAS  Google Scholar 

  28. Maraganore JM, Chao B, Joseph ML, Jablonski J, Ramachandran KL (1989) Anticoagulant activity of synthetic hirudin peptides. J Biol Chem 264:8692–8698

    PubMed  CAS  Google Scholar 

  29. Swan SK, Hursting MJ (2000) The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 20:318–329

    Article  PubMed  CAS  Google Scholar 

  30. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W (2002) Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 45:1757–1766

    Article  PubMed  CAS  Google Scholar 

  31. (1994) Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Circulation 90:1631–1637.

    Google Scholar 

  32. (1999) Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet 353:429–438

    Google Scholar 

  33. (1996) 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 335:775–782.

    Google Scholar 

  34. Direct Thrombin Inhibitor Trialists’ Collaborative Group (2002) Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 359:294–302

    Article  Google Scholar 

  35. Bittl JA, Strony J, Brinker JA et al (1995) Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 333:764–769

    Article  PubMed  CAS  Google Scholar 

  36. Lincoff AM, Bittl JA, Harrington RA et al (2003) 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 289:853–863

    Article  PubMed  CAS  Google Scholar 

  37. Stone GW, McLaurin BT, Cox DA et al (2006) Bivalirudin for patients with acute coronary syndromes. N Engl J Med 355:2203–2216

    Article  PubMed  CAS  Google Scholar 

  38. Lincoff AM, Steinhubl SR, Manoukian SV et al (2008) Influence oftiming of clopidogrel treatment on theefficacy and safety of bivalirudin in patients with non-st-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention: an analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Intv 1:639–648

    Google Scholar 

  39. Anderson JL, Adams CD, Antman EM et al (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 50:e1–e157

    Article  PubMed  Google Scholar 

  40. DeWood MA, Spores J, Notske R et al (1980) Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897–902

    Article  PubMed  CAS  Google Scholar 

  41. Antman EM (1994) Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation 90:1624–1630

    Article  PubMed  CAS  Google Scholar 

  42. Antman EM (1996) Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 94:911–921

    Article  PubMed  CAS  Google Scholar 

  43. White H (2001) Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 358:1855–1863

    Article  PubMed  CAS  Google Scholar 

  44. Stone GW, Witzenbichler B, Guagliumi G et al (2008) Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 358:2218–2230

    Article  PubMed  CAS  Google Scholar 

  45. Waksman R, Wolfram RM, Torguson RL et al (2006) Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes without ST-segment Elevation who Undergo Percutaneous Coronary Intervention. Results from SWITCH – a multicenter clinical trial. J Invasive Cardiol 18:370–375

    PubMed  Google Scholar 

  46. Gibson CM, Ten Y, Murphy SA et al (2007) Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (A REPLACE-2 analysis). Am J Cardiol 99:1687–1690

    Article  PubMed  Google Scholar 

  47. White HD, Chew DP, Hoekstra JW et al (2008) Safety and efficacy of switching from either unfractionated heparin or enoxaparin to bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 51:1734–1741

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

    Tyler L. Taigen MD & James E. Harvey MD

  2. Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    A. Michael Lincoff MD

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  1. Tyler L. Taigen MD
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  2. James E. Harvey MD
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  3. A. Michael Lincoff MD
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Correspondence to A. Michael Lincoff MD .

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Editors and Affiliations

  1. Western Reserve Heart Care, Corporate Dr. 1335, Hudson, 44236, U.S.A.

    Arman T. Askari

  2. Dept. Cardiovascular Medicine, Cleveland Clinic, Euclid Ave. 9500, Cleveland, 44195, U.S.A.

    A. Michael Lincoff

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Taigen, T.L., Harvey, J.E., Lincoff, A.M. (2010). Direct Thrombin Inhibitors in Acute Coronary Syndromes. In: Askari, A., Lincoff, A. (eds) Antithrombotic Drug Therapy in Cardiovascular Disease. Contemporary Cardiology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-235-3_9

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  • DOI: https://doi.org/10.1007/978-1-60327-235-3_9

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