The Thrombin Hypothesis in ACS: A Disappointing Disconnect between Bench Data and Bedside Clinical Trials

American Journal of Medicine

Volumn 123, Issue 2, 2010, Pages 103-110

  Cohen, Marc ^a  

^a BETH ISRAEL MEDICAL CENTER   (United States)

Author keywords

Acute coronary syndrome; Direct thrombin inhibitors; Factor Xa inhibitors

Indexed keywords

ARGATROBAN; BLOOD CLOTTING FACTOR 10A INHIBITOR; FONDAPARINUX; HEPARIN; HIRUDIN; HIRULOG; LOW MOLECULAR WEIGHT HEPARIN; OTAMIXABAN; THROMBIN; THROMBIN INHIBITOR; XIMELAGATRAN;

ACUTE CORONARY SYNDROME; ANTICOAGULANT THERAPY; CLINICAL TRIAL; DRUG EFFICACY; DRUG SAFETY; HEPARINIZATION; HUMAN; HYPOTHESIS; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ACUTE CORONARY SYNDROME; ANTICOAGULANTS; FACTOR XA; HEPARIN; HUMANS; PLATELET AGGREGATION INHIBITORS; PROTEASE INHIBITORS; THROMBIN; TREATMENT OUTCOME;

EID: 74549225152     PISSN: 00029343     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.amjmed.2009.09.001     Document Type: Review

References (54)

1. Oler A., Whooley M.A., Oler J., and Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 276 (1996) 811-815
2. Murphy S.A., Gibson C.M., Morrow D.A., et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 28 (2007) 2077-2086
3. Yusuf S., Mehta S.R., Chrolavicius S., et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 295 (2006) 1519-1530
4. Stone G.W., McLaurin B.T., Cox D.A., et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 355 (2006) 2203-2216
5. Stone G.W., Witzenbichler B., Guagliumi G., et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 358 (2008) 2218-2230
6. Kokolis S., Cavusoglu E., Clark L.T., and Marmur J.D. Anticoagulation strategies for patients undergoing percutaneous coronary intervention: unfractionated heparin, low-molecular-weight heparins, and direct thrombin inhibitors. Prog Cardiovasc Dis. 46 (2004) 506-523
7. Spencer F.A., Ball S.P., Zhang Q., et al. Enoxaparin, a low molecular weight heparin, inhibits platelet-dependent prothrombinase assembly and activity by factor-Xa neutralization. J Thromb Thrombolysis 9 (2000) 223-228
8. Weitz J.I., 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. 86 (1990) 385-391
9. Kumar R., Béguin S., and Hemker H.C. The influence of fibrinogen and fibrin on thrombin generation--evidence for feedback activation of the clotting system by clot bound thrombin. Thromb Haemost. 72 (1994) 713-721
10. Gurm H.S., and Bhatt D.L. Thrombin, an ideal target for pharmacological inhibition: a review of direct thrombin inhibitors. Am Heart J 149 1 Suppl (2005) S43-S53
11. Alexander J. Safety of the factor Xa inhibitor, Apixaban, in combination with antiplatelet therapy after acute coronary syndrome: results of the APPRAISE-1 dose guiding trial. Late-breaking abstract. European Society of Cardiology (ESC) Congress, 30 Aug 2008-03 Sep 2008, Munich, Germany.
12. Cohen M., Bhatt D.L., Alexander J.H., et al. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 115 (2007) 2642-2651
13. Weitz J.I., and Buller H.R. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation 105 (2002) 1004-1011
14. Weitz J.I., and Crowther M. Direct thrombin inhibitors. Thromb Res. 106 (2002) V275-V284
15. Frenkel E.P., Shen Y.M., and Haley B.B. The direct thrombin inhibitors: their role and use for rational anticoagulation. Hematol Oncol Clin North Am. 19 (2005) 119-145
16. Krupski W.C., Bass A., Kelly A.B., et al. Heparin-resistant thrombus formation by endovascular stents in baboons. Interruption by a synthetic antithrombin. Circulation 82 (1990) 570-577
17. Fuster V., Badimon L., Badimon J.J., et al. The porcine model for the understanding of thrombosis and atherogenesis. Mayo Clinic Proc. 66 (1991) 818-831
18. Meyer B.J., Badimon J.J., Chesebro J.H., et al. Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin. Circulation 97 (1998) 681-685
19. Wienen W., Stassen J.M., Priepke H., et al. Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost. 98 (2007) 333-338
20. Wienen W., Stassen J.M., Priepke H., et al. Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis. J Thromb Haemost. 5 (2007) 1237-1242
21. Berry C.N., Girardot C., Lecoffre C., and Lunven C. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost. 72 (1994) 381-386
22. Van Aken H., Bode C., Darius H., et al. Anticoagulation: the present and future. Clin Appl Thromb Hemost. 7 (2001) 195-204
23. Walenga J.M. An overview of the direct thrombin inhibitor argatroban. Pathophysiol Haemost Thromb. 32 Suppl 3 (2002) 9-14
24. Matsuo T., Koide M., and Kario K. Development of argatroban, a direct thrombin inhibitor, and its clinical application. Semin Thromb Hemost. 23 (1997) 517-522
25. Jang I.K., Brown D.F., Giugliano R.P., et al. 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 (1999) 1879-1885
26. Behar S., Hod H., and Kaplinsky E. Argatroban versus heparin as adjuvant therapy to thrombolysis for acute myocardial infarction: safety considerations-ARGAMI-2 Study. Circulation 98 Suppl 17 (1998) I453-I454
27. Andersen K., and Dellborg M. Heparin is more effective than inogatran, a low-molecular-weight thrombin inhibitor in suppressing ischemia and recurrent angina in unstable coronary disease. Thrombin Inhibition in Myocardial Ischemia (TRIM) Study Group. Am J Cardiol. 81 (1998) 939-944
28. Fung A.Y., Lorch G., Cambier P.A., et al. Efegatran sulfate as an adjunct to streptokinase versus heparin as an adjunct to tissue plasminogen activator in patients with acute myocardial infarction. ESCALAT Investigators. Am Heart J 138 (1999) 696-704
29. Wallentin L., Wilcox R.G., Weaver W.D., et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 362 (2003) 789-797
30. Petersen P., Grind M., and Adler J for the SPORTIF II Investigators. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study. J Am Coll Cardiol. 41 (2003) 1445-1451
31. 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 (1996) 775-782
32. Antman E.M. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 94 (1996) 911-921
33. 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 359 (2002) 294-302
34. Bates S.M., and Weitz J.I. Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin. Am J Cardiol. 82 (1998) 12P-18P
35. Robson R., White H., Aylward P., and Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, doses, and gender. Clin Pharmacol Ther. 71 (2002) 433-439
36. Bittl J.A., Strony J., Brinker J.A., et al. 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 (1995) 764-769
37. Lincoff A.M., Bittl J.A., Harrington R.A., 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 289 (2003) 853-863
38. Stone G.W., Ware J.H., Bertrand M.E., et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA 298 (2007) 2497-2506
39. White H., and 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 358 (2001) 1855-1863
40. Kastrati A., Neumann F.J., Mehilli J., et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med. 359 (2008) 688-696
41. Yusuf S., Mehta S.R., Chrolavicius S., et al., Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 354 (2006) 1464-1476
42. Rebello S.S., Bentley R.G., Morgan S.R., et al. Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis. Br J Pharmacol. 133 (2001) 1190-1198
43. Hinder M., Frick A., Jordaan P., et al. Direct and rapid inhibition of factor Xa by otamixaban: a pharmacokinetic and pharmacodynamic investigation in patients with coronary artery disease. Clin Pharmacol Ther. 80 (2006) 691-702
44. Study of otamixaban versus unfractionated heparin and eptifibatide in non-ST elevation acute coronary syndrome (SEPIA-ACS 1). ClinicalTrials.gov identifier: NCT00317395. Available at: www.clinicaltrials.gov.
45. Gibson C.M., Mega J.L., Hammett C.J., et al. Randomized comparison of rivaroxaban, an oral direct factor Xa inhibitor, with placebo in patients with acute coronary syndromes: the ATLAS ACS-TIMI 46 trial. Circulation 118 (2008) 2309-2317
46. Shimbo D., Osende J., Chen J., et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Thromb Haemost. 88 (2002) 733-738
47. Karnicki K., McBane II R.D., Miller R.S., et al. Inhibition and reversal of platelet-rich arterial thrombus in vivo: direct vs. indirect factor Xa inhibition. J Thromb Haemost. 2 (2004) 2162-2169
48. Cohen M., Demers C., Gurfinkel E.P., et al. 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 (1997) 447-452
49. Ferguson J.J., Califf R.M., Antman E.M., et al. 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 (2004) 45-54
50. White H.D., Kleiman N.S., Mahaffey K.W., et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am Heart J. 152 (2006) 1042-1050
51. Antman E.M., Morrow D.A., McCabe C.H., et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 354 (2006) 1477-1488
52. Cheng S., Morrow D.A., Sloan S., et al. Predictors of excessive anticoagulation with unfractionated heparin in STEMI. J Am Coll Cardiol. 51 Suppl 1 (2008) A204
53. Manoukian S.V., Feit F., Mehran R., et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol. 49 (2007) 1362-1368
54. Antman E.M., McCabe C.H., Gurfinkel E.P., et al. 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 (1999) 1593-1601