Argatroban and bivalirudin compared to unfractionated heparin in preventing thrombus formation on mechanical heart valves

Lars Maegdefessel; Torsten Linde; Thomas Michel; Kathrin Hamilton; Ulrich Steinseifer; Ivar Friedrich; Sebastian Schubert; Baerbel Hauroeder; Uwe Raaz; Michael Buerke; Karl Werdan; Axel Schlitt

doi:10.1160/TH08-09-0571

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 101(06): 1163-1169
DOI: 10.1160/TH08-09-0571

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Argatroban and bivalirudin compared to unfractionated heparin in preventing thrombus formation on mechanical heart valves

Results of an in-vitro study

Lars Maegdefessel

¹Department of Internal Medicine III at the Martin Luther-University Hospital Halle-Wittenberg, Germany

,

Torsten Linde

²Applied Medical Engineering at the Helmholtz Institute, RWTH Aachen University, Aachen, Germany

,

Thomas Michel

¹Department of Internal Medicine III at the Martin Luther-University Hospital Halle-Wittenberg, Germany

,

Kathrin Hamilton

²Applied Medical Engineering at the Helmholtz Institute, RWTH Aachen University, Aachen, Germany

,

Ulrich Steinseifer

²Applied Medical Engineering at the Helmholtz Institute, RWTH Aachen University, Aachen, Germany

,

Ivar Friedrich

³Department of Cardiovascular Surgery at the Martin Luther-University Hospital Halle-Wittenberg, Germany

,

Sebastian Schubert

¹Department of Internal Medicine III at the Martin Luther-University Hospital Halle-Wittenberg, Germany

,

Baerbel Hauroeder

⁴Central Institute of the German Federal Armed Forces, Koblenz, Germany

,

Uwe Raaz

¹Department of Internal Medicine III at the Martin Luther-University Hospital Halle-Wittenberg, Germany

,

Michael Buerke

¹Department of Internal Medicine III at the Martin Luther-University Hospital Halle-Wittenberg, Germany

,

Karl Werdan

¹Department of Internal Medicine III at the Martin Luther-University Hospital Halle-Wittenberg, Germany

,

Axel Schlitt

¹Department of Internal Medicine III at the Martin Luther-University Hospital Halle-Wittenberg, Germany

› Author Affiliations

Abstract

Summary

Prevention of valve thrombosis in patients after prosthetic mechanical heart valve replacement and heparin-induced thrombocytopenia (HIT) is still an open issue. The aim of the present in-vitro study was to investigate the efficacy of argatroban and bivalirudin in comparison to unfractionated heparin (UFH) in preventing thrombus formation on mechanical heart valves. Blood (230 ml) from healthy young male volunteers was anticoagulated either by UFH, argatroban bolus, argatroban bolus plus continuous infusion, bivalirudin bolus, or bivalirudin bolus plus continuous infusion. Valve prostheses were placed in a newly developed in-vitro thrombosis tester and exposed to the anticoagulated blood samples. To quantify the thrombi, electron microscopy was performed, and each valve was weighed before and after the experiment. Mean thrombus weight in group 1 (UFH) was 117 + 93 mg, in group 2 (argatroban bolus) 722 + 428 mg, in group 3 (bivalirudin bolus) 758 + 323 mg, in group 4 (argatroban bolus plus continuous infusion) 162 + 98 mg, and in group 5 (bivalirudin bolus plus continuous infusion) 166 + 141 mg (p-value <0.001). Electron microscopy showed increased rates of thrombus formation in groups 2 and 3. Argatroban and bivalirudin were as effective as UFH in preventing thrombus formation on valve prostheses in our in-vitro investigation when they were administered continuously. We hypothesise that continuous infusion of argatroban or bivalirudin are optimal treatment options for patients with HIT after mechanical heart valve replacement for adapting oral to parenteral anticoagulation or vice versa.

Keywords

Heart valve thrombosis - anticoagulation - argatroban - bivalirudin - unfractionated heparin

Full Text

References

References
1 Cannegieter SC, Torn M, Rosendaal FR. Oral anticoagulant treatment in patients with mechanical heart valves: how to reduce the risk of thromboembolic and bleeding complications. J Intern Med 1999; 245: 369-374.
2 Palareti G, Hirsh J, Legnani C. et al. Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study. Arch Intern Med 2000; 160: 470-478.
3 Bonow RO, Carabello B, Kanu C. et al. ACC/AHA guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease. Circulation 2006; 114: 84-231.
4 Vahanian A, Baumgartner H, Bax J. et al. Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology; ESC Committee for Practice Guidelines. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007; 28: 230-268.
5 Hirsh J. Heparin. N Engl J Med 1987; 324: 1565-1574.
6 Hull RD, Raskob GE, Mah AF. et al. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group. Arch Intern Med 2000; 160: 229-236.
7 Jang IK, Hursting MJ. When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation 2005; 111: 2671-2683.
8 Schlitt A, Maegdefessel L, Rupprecht HJ. et al. Comparison of fondaparinux, low molecular-weight heparin and unfractionated heparin in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Heart Valve Dis 2006; 15: 809-814.
9 Bellhouse BJ, Talbot C. The fluid mechanics of the aortic valve. J Fluid Mechanics 1969; 35: 721-735.
10 Reul H, Vahlbruch M, Effert S. et al. The Geometry of the Aortic Root in Health, at Valve Disease and after Valve Replacement. J of Biomechanics 1990; 23: 181-191.
11 Reul H, Talukter N. Heart valve mechanics. Quantitative Cardiovascular Studies (Edited by Hwang, N. H. C. et al.) University Park Press; Baltimore: 1979: 527-564.
12 Huang PY, Hellums JD. Aggregation and disaggregation kinetics of human blood platelets: Part II. Shear-induced platelet aggregation. Biophysical J 1993; 65: 344-353.
13 Felfernig M, Blaicher A, Kozek-Langenecker SA. et al. Effects of temperature of partial thomboplastin time in heparinised plasma in vitro. European J Anesthesiol 2001; 18: 467-470.
14 Schlitt A, Buerke M, Rupprecht HJ. et al. Effects of combined therapy of clopidogrel and aspirin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model. Thromb Res 2002; 107: 39-43.
15 Schlitt A, Buerke M, Rupprecht HJ. et al. Fondaparinux and enoxaparin in comparison to unfractionated heparin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model. Thromb Haemost 2003; 90: 245-251.
16 Lewis BE, Wallis DE, Kelton JG. et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163: 1849-1856.
17 Murray PT, Reddy BV, Ferrell J. et al. A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int 2004; 66: 2446-2453.
18 Lewis BE, Wallis DE, Walenga JM. et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103: 1838-1843.
19 Walenga JM, Ahmad S, Lewis BE. et al. Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb Res 2002; 105: 401-405.
20 Yeh RW, Jang IK. Argatroban: update. Am Heart J 2006; 151: 1131-1138.
21 Shammas NW. Bivalirudin: pharmacology and clinical applications. Cardiovasc Drug Rev 2005; 23: 345-360.
22 Kiser TH, Fish DN. Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 2006; 26: 452-460.
23 Koster A, Dyke CM, Lincoff AM. et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007; 83: 572-577.
24 Klein M, Tomer A, Weksler N. et al. Bivalirudin for anticoagulation in mechanical aortic valve replacement and heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis 2006; 17: 331-333.
25 White HD, Ohman EM, Stone GW. et al. Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol. 2008; 52: 807-814.
26 Cruz-Gonzalez I, Sanchez-Ledesma M, Jang IK. et al. Efficacy and safety of argatroban with or without glycoprotein IIb/IIIa inhibitor in patients with heparin induced thrombocytopenia undergoing percutaneous coronary intervention for acute coronary syndrome. J Thromb Thrombolysis. 2008; 25: 214-218.
27 Vanholder R, Camez A, Ringoir S. et al. Pharmacokinetics of recombinant hirudin in hemodialyzed endstage renal failure patients. Thromb Haemost 1997; 77: 650-655.
28 Maegdefessel L, Buerke M, Schlitt A. et al. Comparison of bivalirudin, enoxaparin, and unfractionated heparin in preventing cardiac catheter thrombosis, results of an in vitro study. Thromb Haemost 2008; 100: 693-698.
29 Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99: 830-839.
30 Warkentin TE, Greinacher A, Ofosu FA. et al. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost 2005; 94: 958-964.
31 Fenton 2nd JW, Ofosu FA, Hassouna HI. et al. Thrombin and antithrombotics. Semin Thromb Hemost 1998; 24: 87-91.
32 Mann KG, Brummel-Ziedins K, Butenas S. Models of blood coagulation. Blood Cells Mol Dis 2006; 36: 108-117.
33 Blat Y, Seiffert D. A renaissance for the contact system in blood coagulation?. Thromb Haemost 2008; 99: 457-460.