This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zoldhelyi, P. Articles by Chesebro, J. H. Search for Related Content PubMed PubMed Citation Articles by Zoldhelyi, P. Articles by Chesebro, J. H.

Circulation, Vol 88, 2015-2022, Copyright © 1993 by American Heart Association

ARTICLES

Recombinant hirudin in patients with chronic, stable coronary artery disease. Safety, half-life, and effect on coagulation parameters

P Zoldhelyi, MW Webster, V Fuster, DE Grill, D Gaspar, SJ Edwards, CF Cabot and JH Chesebro
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn.

BACKGROUND. Because the specific antithrombin hirudin prevents platelet- rich arterial thrombus and accelerates thrombolysis in a variety of animal models, it has promise as antithrombotic therapy. We therefore studied the half-life, effect on anticoagulant parameters, and safety of hirudin in patients with coronary artery disease. METHODS AND RESULTS. Thirty-eight men and 1 woman (age [mean +/- SD], 60.4 +/- 6.9 years) with angiographic coronary disease were allocated in a single- blind ascending dosage study to a 6-hour i.v. infusion of recombinant hirudin (CGP 39,393) or matching placebo. The median terminal half-life for hirudin, measured by ELISA, was 2.7, 2.3, 2.9, 3.1, and 2.0 hours for the 0.02, 0.05, 0.1, 0.2, and 0.3 mg.kg-1 x h-1 groups, respectively. Activated partial thromboplastin times (aPTT) at 3, 4, and 6 hours were averaged into a plateau value. The aPTT plateau-to- baseline ratios were 1.5 +/- 0.1, 2.0 +/- 0.1, 2.3 +/- 0.1, 2.7 +/- 0.1, and 2.9 +/- 0.1, respectively, with hirudin infused at 0.02, 0.05, 0.1, 0.2, and 0.3 mg.kg-1 x h-1. From 62% to 77% of the aPTT plateau value was seen within 30 minutes of starting the infusions and was directly related to dose. The aPTT-to-baseline ratios correlated well with plasma hirudin levels (r = .88), whereas poor correlation and sensitivity were observed between plasma hirudin levels and activated coagulation time (ACT)-to-baseline ratios (r = .44). Plasma levels of hirudin and ACT in seconds correlated overall well (r = .80), but considerable overlap occurred between baseline ACT and ACT at plasma hirudin concentrations < 1000 ng/mL. Prothrombin times were significantly prolonged only at a dosage of > or = 0.05 mg.kg-1 x h-1 and were 11.8 +/- 0.5 (INR = 1.0), 12.3 +/- 0.7 (INR = 1.1), 13.3 +/- 1.2 (INR = 1.4), 14.2 +/- 0.4 (INR = 1.7), and 15.8 +/- 0.9 (INR = 2.3) seconds for each respective hirudin dosage. Thrombin times were beyond range (> 600 seconds) at 6 hours in all except 2 patients who received the lowest dosage. All parameters returned to baseline between 8 and 18 hours after the infusion. Bleeding times were not significantly prolonged. No side effects occurred. No antibodies to hirudin were detected 2 weeks after the infusion. CONCLUSIONS. Recombinant hirudin has a terminal half-life of 2 to 3 hours. The aPTT correlates well with plasma levels of hirudin and allows close titration over a wide range of anticoagulation, while ACT and prothrombin time are relatively insensitive for monitoring hirudin administration. At anticoagulant levels effective in experimental thrombosis, a 6-hour infusion of hirudin is well tolerated and safe in a predominantly male group of patients with stable coronary atherosclerosis.

This article has been cited by other articles:

				J. L Stephens, J. M Koerber, J. C Mattson, and M. A Smythe Effect of Lepirudin on the International Normalized Ratio Ann. Pharmacother., January 1, 2005; 39(1): 28 - 31. [Abstract] [Full Text] [PDF]

				M. Tobu, O. Iqbal, D. Hoppensteadt, B. Neville, H. L. Messmore, and J. Fareed Anti-Xa and Anti-IIa Drugs Alter International Normalized Ratio Measurements: Potential Problems in the Monitoring of Oral Anticoagulants Clinical and Applied Thrombosis/Hemostasis, October 1, 2004; 10(4): 301 - 309. [Abstract] [PDF]

				P. Eichler, N. Lubenow, U. Strobel, and A. Greinacher Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin Blood, January 15, 2004; 103(2): 613 - 616. [Abstract] [Full Text] [PDF]

				A. Greinacher, P. Eichler, D. Albrecht, U. Strobel, B. Potzsch, and B. I. Eriksson Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance Blood, April 1, 2003; 101(7): 2617 - 2619. [Abstract] [Full Text] [PDF]

				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]

				C. N. Berry, G. Lassalle, C. Lunven, J.-M. Altenburger, F. Guilbert, A. Lale, J.-P. Herault, C. Lecoffre, C. Pfersdorff, J.-M. Herbert, et al. SSR182289A, a Novel, Orally Active Thrombin Inhibitor: In Vitro Profile and ex Vivo Anticoagulant Activity J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1189 - 1198. [Abstract] [Full Text] [PDF]

				M. Demir, O. Iqbal, B. Untch, D. A. Hoppensteadt, B. S. Gaikwad, and J. Fareed Ecarin Clotting Time is Sensitive to Heparinoids: Comparison of Two Different Techniques Clinical and Applied Thrombosis/Hemostasis, January 1, 2001; 7(1): 38 - 43. [Abstract] [PDF]

				P. Eichler, H.-J. Friesen, N. Lubenow, B. Jaeger, and A. Greinacher Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance Blood, October 1, 2000; 96(7): 2373 - 2378. [Abstract] [Full Text] [PDF]

				M.D Flather, J.I Weitz, S Yusuf, J Pogue, B Sussex, J Campeau, J Gill, R Schuld, C.D Joyner, A.L Morris, et al. Reactivation of coagulation after stopping infusions of recombinant hirudin and unfractionated heparin in unstable angina and myocardial infarction without ST elevation: results of a randomized trial Eur. Heart J., September 1, 2000; 21(17): 1473 - 1481. [Abstract] [PDF]

				J. Oldgren, R. Linder, L. Grip, A. Siegbahn, and L. Wallentin Activated partial thromboplastin time and clinical outcome after thrombin inhibition in unstable coronary artery disease Eur. Heart J., November 2, 1999; 20(22): 1657 - 1666. [Abstract] [PDF]

				J. I. Weitz, E. Young, M. Johnston, A. R. Stafford, J. C. Fredenburgh, and J. Hirsh Vasoflux, a New Anticoagulant With a Novel Mechanism of Action Circulation, February 9, 1999; 99(5): 682 - 689. [Abstract] [Full Text] [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]

				P. K. Shah New Antithrombotic Drugs for Coronary Artery Disease Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 1996; 1(2): 165 - 176. [PDF]

				A. Bernabei, A. K. Rao, S. Niewiarowski, R. W. Colman, L. Sun, and L. H. Edmunds Jr. Recombinant desulfatohirudin as a substitute for heparin during cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., August 1, 1994; 108(2): 381 - 381. [Full Text]