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

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.

OBJECTIVES. The purpose of this study was to assess the value of recombinant desulfatohirudin (hirudin) as adjunctive therapy to thrombolysis in acute myocardial infarction. BACKGROUND. Failure to achieve initial reperfusion and reocclusion of the infarct-related artery remain major limitations of thrombolytic therapy despite aggressive regimens of heparin and aspirin. Hirudin, a direct thrombin inhibitor, has been shown in experimental models to enhance thrombolysis and reduce reocclusion. METHODS. The Thrombolysis in Myocardial Infarction (TIMI) 5 trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin, given with front-loaded tissue-type plasminogen activator and aspirin to 246 patients with acute myocardial infarction. Patients received either intravenous heparin or hirudin at one of four ascending doses for 5 days. Patients underwent coronary angiography at 90 min and at 18 to 36 h, unless rescue angioplasty was performed. RESULTS. The primary end point, TIMI grade 3 flow in the infarct-related artery at 90 min and 18 to 36 h without death or reinfarction before the 18- to 36-h catheterization was achieved in 97 (61.8%) of 157 evaluable hirudin-treated patients compared with 39 (49.4%) of 79 evaluable heparin-treated patients (p = 0.07). All four doses of hirudin led to similar findings in the angiographic and clinical end points. At 90 min, TIMI grade 3 flow was present in 105 (64.8%) of 162 hirudin-treated patients compared with 48 (57.1%) of 84 heparin-treated patients (p = NS). Infarct-related artery patency (TIMI grade 2 or 3 flow) was similar in the two groups (82.1% and 78.6%, respectively). At 18 to 36 h, 129 (97.8%) of 132 hirudin-treated patients had a patent infarct-related artery compared with 58 (89.2%) of 65 heparin-treated patients (p = 0.01). Reocclusion by 18 to 36 h occurred in 2 (1.6%) of 123 hirudin-treated patients versus 4 (6.7%) of 60 heparin-treated patients (p = 0.07). Death or reinfarction occurred during the hospital period in 11 (6.8%) of 162 hirudin-treated patients compared with 14 (16.7%) of 84 heparin-treated patients (p = 0.02). Major spontaneous hemorrhage occurred in 1.2% of hirudin-treated patients versus 4.7% of heparin-treated patients (p = 0.09), and major hemorrhage at an instrumented site occurred in 16.3% and 18.6%, respectively (p = NS). CONCLUSIONS. Hirudin is a promising agent compared with heparin as adjunctive therapy with thrombolysis for acute myocardial infarction, and its evaluation in larger trials is warranted.

This article has been cited by other articles:

				J. Eikelboom, H. White, and S. Yusuf The evolving role of direct thrombin inhibitors in acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 70S - 78S. [Abstract] [Full Text] [PDF]

				The Task Force on the Management of Acute Myocardi, F. Van de Werf, D. Ardissino, A. Betriu, D. V. Cokkinos, E. Falk, K. A.A. Fox, D. Julian, M. Lengyel, F.-J. Neumann, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation Eur. Heart J., January 1, 2003; 24(1): 28 - 66. [Full Text] [PDF]

				J. Lopez-Sendon Coronary reperfusion in the clinical setting: antithrombotic support to thrombolysis in the coronary care unit Eur. Heart J. Suppl., June 1, 2001; 3(suppl_C): C55 - C61. [Abstract] [PDF]

				G. N. Levine, M. N. Ali, and A. I. Schafer Antithrombotic Therapy in Patients With Acute Coronary Syndromes Arch Intern Med, April 9, 2001; 161(7): 937 - 948. [Abstract] [Full Text] [PDF]

				G. I. Barbash, Y. Birnbaum, K. Bogaerts, M. Hudson, E. Lesaffre, Y. Fu, S. Goodman, K. Houbracken, K. Munsters, C. B. Granger, et al. Treatment of Reinfarction After Thrombolytic Therapy for Acute Myocardial Infarction : An Analysis of Outcome and Treatment Choices in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and Assessment of the Safety of a New Thrombolytic (ASSENT 2) Studies Circulation, February 20, 2001; 103(7): 954 - 960. [Abstract] [Full Text] [PDF]

				E.M Antman, C.M Gibson, J.A de Lemos, R.P Giugliano, C.H McCabe, P Coussement, I Menown, C.A Nienaber, T.C Rehders, M.J Frey, et al. Combination reperfusion therapy with abciximab and reduced dose reteplase: results from TIMI 14 Eur. Heart J., December 1, 2000; 21(23): 1944 - 1953. [Abstract] [PDF]

				E. M. Antman, R. P. Giugliano, C. M. Gibson, C. H. McCabe, P. Coussement, N. S. Kleiman, A. Vahanian, A. A. J. Adgey, I. Menown, H.-J. Rupprecht, et al. Abciximab Facilitates the Rate and Extent of Thrombolysis : Results of the Thrombolysis In Myocardial Infarction (TIMI) 14 Trial Circulation, June 1, 1999; 99(21): 2720 - 2732. [Abstract] [Full Text] [PDF]

				G. Frostfeldt, G. Ahlberg, G. Gustafsson, G. Helmius, B. Lindahl, A. Nygren, A. Siegbahn, E. Swahn, P. Venge, and L. Wallentin Low molecular weight heparin (dalteparin) as adjuvant treatment to thrombolysis in acute myocardial infarction--a pilot study: Biochemical Markers in Acute Coronary Syndromes (BIOMACS II) J. Am. Coll. Cardiol., March 1, 1999; 33(3): 627 - 633. [Abstract] [Full Text] [PDF]

				S. M. Bates and J. I. Weitz Prevention of activation of blood coagulation during acute coronary ischemic syndromes: beyond aspirin and heparin Cardiovasc Res, February 1, 1999; 41(2): 418 - 432. [Abstract] [Full Text] [PDF]

				C. P. Cannon, C. M. Gibson, C. H. McCabe, A. A. J. Adgey, M. J. Schweiger, R. F. Sequeira, G. Grollier, R. P. Giugliano, M. Frey, H. S. Mueller, et al. TNK–Tissue Plasminogen Activator Compared With Front-Loaded Alteplase in Acute Myocardial Infarction : Results of the TIMI 10B Trial Circulation, December 22, 1998; 98(25): 2805 - 2814. [Abstract] [Full Text] [PDF]

				J. I. Weitz, B. Leslie, and M. Hudoba 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, February 17, 1998; 97(6): 544 - 552. [Abstract] [Full Text] [PDF]

				O. Gurevitz, A. Goldfarb, H. Hod, M. Feldman, B. Shenkman, D. Varon, M. Eldar, and A. Inbal Recombinant von Willebrand Factor Fragment AR545C Inhibits Platelet Aggregation and Enhances Thrombolysis With rtPA in a Rabbit Thrombosis Model Arterioscler. Thromb. Vasc. Biol., February 1, 1998; 18(2): 200 - 207. [Abstract] [Full Text] [PDF]

				A H Gershlick and R S More Recent advances: Treatment of myocardial infarction BMJ, January 24, 1998; 316(7127): 280 - 284. [Full Text]

				G. Franco Gensini, A. Colella, and M. Comeglio State-of-the-Art Review: Antiplatelet Agents and Thrombin Inhibitors: Combined Modality Therapy Clinical and Applied Thrombosis/Hemostasis, April 1, 1997; 3(2): 82 - 85. [PDF]

				E. M. Ohman, N. S. Kleiman, G. Gacioch, S. J. Worley, F. I. Navetta, J. D. Talley, H. V. Anderson, S. G. Ellis, M. D. Cohen, D. Spriggs, et al. Combined Accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein IIb/IIIa Integrin Receptor Blockade With Integrilin in Acute Myocardial Infarction: Results of a Randomized, Placebo-Controlled, Dose-Ranging Trial Circulation, February 18, 1997; 95(4): 846 - 854. [Abstract] [Full Text]

				C. P. Cannon, C. H. McCabe, C. M. Gibson, M. Ghali, R. F. Sequeira, G. R. McKendall, J. Breed, N. B. Modi, N. L. Fox, R. P. Tracy, et al. TNK-Tissue Plasminogen Activator in Acute Myocardial Infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A Dose-Ranging Trial Circulation, January 21, 1997; 95(2): 351 - 356. [Abstract] [Full Text]

				R. P. Schwarz JR, J.-C. P. Becker, R. L. Brooks, M. J. Hursting, J. L. Joffrion, G. D. Knappenberger, T. P. Kogan, P. W. Kogan, and A. A. McKinney State-of-the-Art Review: The Preclinical and Clinical Pharmacology of Novastan (Argatroban): A Small-Molecule, Direct Thrombin Inhibitor Clinical and Applied Thrombosis/Hemostasis, January 1, 1997; 3(1): 1 - 15. [Abstract] [PDF]

				A. K. Rao, L. Sun, J. H. Chesebro, V. Fuster, R. A. Harrington, D. Schwartz, P. Gallo, D. Matos, and E. J. Topol Distinct Effects of Recombinant Desulfatohirudin (Revasc) and Heparin on Plasma Levels of Fibrinopeptide A and Prothrombin Fragment F1.2 in Unstable Angina: A Multicenter Trial Circulation, November 15, 1996; 94(10): 2389 - 2395. [Abstract] [Full Text]

				C. V. Jackson, J. Satterwhite, and E. Roberts Preclinical and Clinical Pharmacology of Efegatran (LY294468) : A Novel Antithrombin for the Treatment of Acute Coronary Syndromes Clinical and Applied Thrombosis/Hemostasis, October 1, 1996; 2(4): 258 - 267. [Abstract] [PDF]

				C. R. McKenzie, D. R. Abendschein, and P. R. Eisenberg Sustained Inhibition of Whole-Blood Clot Procoagulant Activity by Inhibition of Thrombus-Associated Factor Xa Arterioscler. Thromb. Vasc. Biol., October 1, 1996; 16(10): 1285 - 1291. [Abstract] [Full Text]

				The Global Use of Strategies to Open Occluded Coro A Comparison of Recombinant Hirudin with Heparin for the Treatment of Acute Coronary Syndromes N. Engl. J. Med., September 12, 1996; 335(11): 775 - 782. [Abstract] [Full Text] [PDF]

				J. Loscalzo Thrombin Inhibitors in Fibrinolysis: A Hobson's Choice of Alternatives Circulation, September 1, 1996; 94(5): 863 - 865. [Full Text]

				E. M. Antman Hirudin in Acute Myocardial Infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B Trial Circulation, September 1, 1996; 94(5): 911 - 921. [Abstract] [Full Text]

				M. Ragni, P. Cirillo, I. Pascucci, A. Scognamiglio, D. D'Andrea, N. Eramo, M. D. Ezekowitz, A. B. Pawashe, M. Chiariello, and P. Golino Monoclonal Antibody Against Tissue Factor Shortens Tissue Plasminogen Activator Lysis Time and Prevents Reocclusion in a Rabbit Model of Carotid Artery Thrombosis Circulation, May 15, 1996; 93(10): 1913 - 1918. [Abstract] [Full Text]

				J. A. Bittl, J. Strony, J. A. Brinker, W. H. Ahmed, C. R. Meckel, B. R. Chaitman, J. Maraganore, E. Deutsch, B. Adelman, and 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., September 21, 1995; 333(12): 764 - 769. [Abstract] [Full Text] [PDF]

				J. Fuchs and C. P. Cannon Hirulog in the Treatment of Unstable Angina : Results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 Trial Circulation, August 15, 1995; 92(4): 727 - 733. [Abstract] [Full Text]

				D. R. Abendschein, Y. Y. Meng, S. Torr-Brown, and B. E. Sobel Maintenance of Coronary Patency After Fibrinolysis With Tissue Factor Pathway Inhibitor Circulation, August 15, 1995; 92(4): 944 - 949. [Abstract] [Full Text]

				N. A. Prager, D. R. Abendschein, C. R. McKenzie, and P. R. Eisenberg Role of Thrombin Compared With Factor Xa in the Procoagulant Activity of Whole Blood Clots Circulation, August 15, 1995; 92(4): 962 - 967. [Abstract] [Full Text]

				S.-K. Yao, S. Akhtar, T. Scott-Burden, J. C. Ober, P. Golino, L. M. Buja, W. Casscells, and J. T. Willerson Endogenous and Exogenous Nitric Oxide Protect Against Intracoronary Thrombosis and Reocclusion After Thrombolysis Circulation, August 15, 1995; 92(4): 1005 - 1010. [Abstract] [Full Text]

				R. W. Smalling, C. Bode, J. Kalbfleisch, S. Sen, P. Limbourg, F. Forycki, G. Habib, R. Feldman, S. Hohnloser, and A. Seals More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction Circulation, June 1, 1995; 91(11): 2725 - 2732. [Abstract] [Full Text]

				P. Theroux, F. Perez-Villa, D. Waters, J. Lesperance, F. Shabani, and R. Bonan 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, April 15, 1995; 91(8): 2132 - 2139. [Abstract] [Full Text]

				J. P. Carteaux, A. Gast, T. B. Tschopp, and S. Roux Activated Clotting Time as an Appropriate Test to Compare Heparin and Direct Thrombin Inhibitors Such as Hirudin or Ro 46-6240 in Experimental Arterial Thrombosis Circulation, March 1, 1995; 91(5): 1568 - 1574. [Abstract] [Full Text]

				J. S. Mruk, P. Zoldhelyi, M. W.I. Webster, M. Heras, D. E. Grill, D. R. Holmes Jr, V. Fuster, and J. H. Chesebro Does Antithrombotic Therapy Influence Residual Thrombus After Thrombolysis of Platelet-Rich Thrombus? : Effects of Recombinant Hirudin, Heparin, or Aspirin Circulation, February 15, 1995; 93(4): 792 - 799. [Abstract] [Full Text]

				HIRUDIN SHOWS PROMISE AS A POST-THROMBOLYTIC THERAPY Journal Watch (General), April 22, 1994; 1994(422): 5 - 5. [Full Text]

				E. M. Antman, H. W. Louwerenburg, H. F. Baars, J. C.L. Wesdorp, B. Hamer, J.-P. Bassand, F. Bigonzi, G. Pisapia, C. M. Gibson, H. Heidbuchel, et al. Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction: Results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial Circulation, April 9, 2002; 105(14): 1642 - 1649. [Abstract] [Full Text] [PDF]