Clinical trials of recombinant hirudin in acute coronary syndromes

Coronary Artery Disease

Volumn 7, Issue 6, 1996, Pages 429-437

  Challapalli, Ram ^a   Lefkovits, Jeffrey ^a   Topol, Eric J ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

Author keywords

anticoagulation; antithrombins; myocardial infarction; unstable angina

Indexed keywords

ANTITHROMBIN; LEPIRUDIN;

ANTICOAGULATION; BLOOD CLOT LYSIS; CLINICAL TRIAL; DRUG EFFICACY; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HUMAN; PHASE 2 CLINICAL TRIAL; PHASE 3 CLINICAL TRIAL; PRIORITY JOURNAL; Q WAVE; RECOMBINANT DNA TECHNOLOGY; REVIEW; ST SEGMENT ELEVATION; THROMBOCYTE ACTIVATION; UNSTABLE ANGINA PECTORIS;

EID: 0029782577     PISSN: 09546928     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019501-199606000-00005     Document Type: Review

References (49)

1. Dewood MA, Spores J, Notske R: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980, 303:897-902. A convincing study which demonstrated the presence of a thrombus in acute myocardial infarction.
2. Davies M, Thomas A: Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death and crescendo angina. Br Heart J 1985, 53:63-75.
3. Chesebro J, Fuster V: Thrombosis in unstable angina. N Engl J Med 1992, 327:192-194.
4. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction; ISIS-2. Lancet 1988, ii:349-360. This landmark trial established the effectiveness of the combination of streptokinase and aspirin in the treatment of acute myocardial infarction in over 17 000 patients.
5. Gruppo Italiano per lo Studio della Streptochinase nell' Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986, i:397-402. This landmark study was the first trial that established the effectiveness of thrombolytic therapy in acute myocardial infarction.
6. The GUSTO Investigators: An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993, 329:673-682. This huge international trial involving over 41 000 patients established the combination of accelerated t-PA, intravenous heparin and aspirin to be the best current thrombolytic strategy.
7. Williams DO, Topol EJ, Califf RM, Roberts R, Mancini GBJ, Joelson JM, et al.: Intravenous recombinant tissue-type plasminogen activator in patients with unstable angina pectoris. Circulation 1990, 82:376-383.
8. The TIMI IIIb Investigators: Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-q-wave myocardial infarction: results of the TIMI IIIB Trial. Circulation 1994, 89:1545-1556. The limitations of current antithrombotic therapy in unstable angina and non-Q-wave infarction are demonstrated in the control arm of this trial.
9. Scheiber TL, Rizik D, White C, Sharma GVR, Cowley M, Macina G, et al.: Randomized trial of thrombolysis versus heparin in unstable angina. Circulation 1992, 86:1407-1414.
10. Nicklas J, Topol EJ, Kander N, O'Neill WW, Walton JA, Ellis SG, et al.: Randomized, double-blind, placbo-controlled trial of tissue plasminogen activator in unstable angina. J Am Coll Cardiol 1989, 13:434-441.
11. Freeman MR, Langer A, Wilson RF, Morgan CD, Armstrong PW: Thrombolysis in unstable: randomized double-blind trial of t-PA and angina placebo. Circulation 1992, 86:150-157.
12. Bar FW, Verheugt FW, Col J, Materne P, Monassier JP, Geslin PG, et al.: Thrombolysis in paients with unstable angina improves the angiographic but not the clinical outcome. Circulation 1992, 86:131-177.
13. The RISC Group: Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990, 336:827-830. This trial established the effectiveness of aspirin compared with placebo and intermittent intravenous heparin injections in the treatment of unstable angina and non-Q-wave infarction.
14. Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, et al.: Aspirin, heparin or both to treat acute unstable angina. N Engl J Med 1988, 319:1105-1111. This trial demonstrated the superiority of continuous intravenous heparin compared with aspirin and placebo in terms of limiting important clinical events in patients presenting in the acute phase of unstable angina.
15. Hirsh J: Heparin. N Engl J Med 1991, 324:1565-1574.
16. Markwardt F, Nowak G, Sturzebecher J, Griessbach U, Walsmann P, Vogel G: Pharmacokinetics and anticoagulant effect of hirudin in man. Thromb Haemost 1984, 52:160-163.
17. Talbot M: Biology of recombinant hirudin (CGP 39393): a new prospect in the treatment of thrombosis. Semin Thromb Hemost 1989, 15:293-301.
18. The GUSTO Angiographic Investigators: The comparative effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med 1993, 329:1615-1622. A substudy of the GUSTO I trial that confirmed the prognostic importance of establishing early coronary artery patency when treating acute myocardial infarction.
19. Lincoff AM, Topol EJ: Illusion of reperfusion; does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993, 87:1792-1805. An excellent review that highlights the limitations of current thrombolytic strategies.
20. Hsia J, Hamilton WP, Kleinman N, Roberts R, Chaitman BR, Ross AM: A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1990, 323:1433-1437.
21. de Bono DP, Simoons JL, Tijssen J, Arnold AER, Betriu A, Burgersdijk C, et al.: Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomized double blind European Cooperative Study Group trial. Br Heart J 1992, 67:122-128.
22. Bleich SD, Nichols TC, Schumacher RR, Cooke DH, Tate DA, Teichman SL: Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990, 66:1412-1417.
23. Topol EJ, George BS, Kereiakes DJ, Stump DC, Candela RJ, Abbottsmith CW, et al.: A randomized controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction. Circulation 1989, 79:281-286.
24. Theroux P, Waters D, Lam J, Juneu M, McCans J: Reactivation of unstable angina after discontinuation of heparin. N Engl J Med 1992, 327:141-145. Aspirin therapy was found to reduce the incidence of recurrent ischemic events after cessation of intravenous heparin in patients with unstable angina.
25. Fenton JW II: Thrombin interactions with hirudin. Semin Thromb Hemost 1989, 15:265-268.
26. Loscalzo J, Melnick B, Handin RI: The interaction of platelet factor 4 and glycosoaminoglycans. Arch Biochem Biophys 1985, 240:446-455.
27. Topol EJ, Fuster V, Harrington RA, Califf RM, Kleinman NS, Kereiakes DJ, et al.: Recombinant hirudin for unstable angina pectoris: a multicenter, randomized angiographic trial. Circulation 1994, 89:1557-1566. A hirudin pilot trial which demonstrated an advantage for the use of intravenous hirudin in patients with unstable angina compared with intravenous heparin in terms of several angiographically measured endpoints.
28. Hogg PJ, Jackson CM: Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci USA 1989, 86:3619-3623.
29. Weitz JI, Huboda M, Massel D, Maraganore J, Hirsh J: Clot-bound thrombin is protected from inhibition by heparin-antithrombin but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990, 86:385-391.
30. Markwardt F: Development of hirudin as an antithrombotic agent. Semin Thromb Hemost 1989, 15:269-282.
31. Kelly AB, Marzec UM, Krupski W, Bass A, Cadroy Y, Hanson SR, et al.: Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 1991, 77:1006-1012.
32. Heras M, Chesebro JH, Webster MWI, Mruk JJ, Grill DE, Penny WJ, et al.: Hirudin, heparin and placebo during deep arterial injury in the pig. The in vivo role of thrombin in platelet-mediated thrombosis. Circulation 1990, 82:1476-1484.
33. Verstraete M, Nurmohamed M, Kienast J, Siebeck M, Silling-Engelhardt G, Buller H, et al.: Biologic effects of recombinant hirudin (CGP 39 393) in human volunteers. J Am Coll Cardiol 1993, 22:1080-1088.
34. Zoldhelyi P, Webster MWI, Fuster V, Grill DE, Gaspar D, Edwards SJ, et al.: Recombinant hirudin in patients with chronic stable coronary disease: safety, half life and effect on coagulation parameters. Circulation 1993, 88 (part 1):2015-2022.
35. Neuhaus KL, Niederer W, Wagner J, Maurer W, von Essen R, Tebbe U, et al.: HIT (Hirudin for the Improvement of Thrombolysis): Results of a dose escalation study [abstract]. Circulation 1993, 88 (No.4, part 2):I292.
36. Cannon CP, McCabe CH, Henry TD, Schweiger MJ, Gibson RS, Mueller HS, 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, 23:993-1003. This pilot trial compared four doses of hirudin with standard heparin as adjunctive therapy to t-PA in the treatment of acute myocardial infarction. Hirudin-treated patients had better angiographic results and fewer adverse clinical events.
37. Lee LV, for the TIMI 6 Investigators: Initial experience with hirudin and streptokinase in acute myocardial infarction: results of the TIMI 6 trial. Am J Cardiol 1994, 75:7-13.
38. 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, 90:1631-1637. This phase III trial of hirudin in acute coronary syndromes was temporarily halted after enrollment of 2564 patients because of an unexpected excess of bleeding. Surprisingly, the use of streptokinase with either agent resulted in an especially high rate of bleeding.
39. Antman EM, for the TIMI 9A Investigators: Hirudin in acute myocardial infarction: safety report form the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation 1994, 90:1624-1630. This phase III trial of hirudin involved only patients with acute myocardial infarction. After enrollment of 757 patients the trial was temporarily halted because of an unexpected excess of bleeding with both study drugs.
40. Neuhaus KL, van Essen R, Tebbe U, Jessel A, Heinrichs H, Maurer W, et al.: Safety observations from the pilot phase of the randomized r-hirudin for improvement of thrombolysis (HIT-III) study. Circulation 1994, 90:1638-1642. This phase III trial of hirudin in acute myocardial infarction was also halted prematurely because of an excess of bleeding.
41. Serruys PW, Herrman JPR, Simon R, Rutsch W, Bode C, Laarman GJ, et al.: A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995, 333:757-763. The use of hirudin was evaluated in 1154 patients with unstable angina undergoing angioplasty. Hirudin therapy was found to result in a reduction in acute ischemic events; however, this benefit did not persist during a 7-month follow-up period.
42. Granger CB, Califf RM, Hirsh J, Woodlief LH, Topol EJ, for the GUSTO Investigators: APTTs after thrombolysis and standard intravenous heparin are often low and correlate with body weight, age, and sex: experience from the GUSTO trial [abstract]. Circulation 1992, 86:I1027.
43. Hsia J, Kleinman N, Aguirre F, Chairman BR, Roberts R, Ross AM: Heparin-prolongation of partial thromboplastin time after thrombolysis: relation to coronary patency. J Am Coll Cardiol 1992, 20:31-35.
44. Mellott MJ, Holahan MA, Lynch JJ, Hasuk GP, Dunwiddie CT: Acceleration of recombinant tissue-type plasminogen activator-induced reperfusion and prevention of reocclusion by recombinant antistasin, a selective Factor Xa inhibitor, in a canine model of femoral arterial thrombosis. Circ Res 1992, 70:1152-1160.
45. Sitko GR, Ramjit DR, Stabilito II, Lehman D, Lynch JJ, Vlasuk GP: Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective Factor Xa inhibitor, tick anticoagulant peptide. Circulation 1992, 85:805-815.
46. Nicolini FA, Lee P, Rios G, Kotke-Marchant K, Topol EJ: Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis. Circulation 1994.
47. Gold HK, Torres FW, Garabedian HD, Werner W, Jang IK, Khan A, et al.: Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol 1993, 21:1039-1047.
48. Garabedian HD, Gold HK, Hagstrom JN, Collen D, Bovill EG: Accelerated thrombin generation accompanying specific thrombin inhibition in unstable angina pectoris patients [abstract]. Circulation 1993, 88 (No 4, part 2):I264.
49. Zoldhelyi P, Bichler J, Whyte G, Owen WG, Grill DE, Fuster V, et al.: Persistent thrombin generation in humans during specific thrombin inhibition with hirudin. Circulation 1994, 90:2671-2678. This study illustrates an important potential limitation of antithrombin therapy with hirudin.