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Argatroban during percutaneous transluminal coronary angioplasty: Results of a dose-verification study

  • Clinical Investigation and Epidemiology
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Abstract

Background. Thrombin is a key enzyme in thrombogenesis. In animals, specific antithrombotic therapy at the time of coronary angioplasty reduced the incidence of subacute occlusion and inhibited the restenosis response. Argatroban is a highly selective synthetic thrombin antagonist that binds in a competitive manner. This is a report of a dose-verification study, assessing the safety and feasibility of intravenous Argatroban administration in patients undergoing percutaneous transluminal coronary angioplasty. Methods. Before angioplasty an intravenous bolus of 30 μg/kg argatroban was administered, followed by a continuous infusion of 3.5 μg/kg/min for 72 hours. Bolus injection was repeated, and the infusion rate was increased in order to achieve an activated coagulation time (ACT) of over 300 seconds. Following interim analysis, the bolus and initial infusion rate for the subsequent treatment groups was determined. Study endpoints were the occurrence of adverse events, coagulation tests, and qualitative angiogram reading. Patients were monitored by continuous 12-lead electrocardiographic recording over 24 hours, and underwent control angiography 18–24 hours following angioplasty. Results. Four treatment groups, comprised of 2, 8, 9, and 11 patients, respectively, were studied. The first two patients were excluded from analysis, since the initial dose was ineffective to attain an ACT-authorizing coronary angioplasty. The group with the highest dosage received a 250 μg/kg intravenous bolus of argatroban, followed by a 4 hour infusion of 15 μg/kg/min. At 4 hours the infusion rate was lowered to 3.8 μg/kg/min and was continued for 68 hours without adjustment for catheter removal. The adverse event profile included myocardial infarction, aortocoronary bypass graft, bailout procedures, and repeat coronary angioplasty. Thrombin-time (TT), activated partial thromboplastin time (APTT), and prothrombin time (PT) were significantly related to argatroban plasma concentration, as demonstrated by regression analyses (R-square 0.64, 0.71, and 0.84, respectively). Prothrombin fragments 1 and 2 and thrombin-antithrombin III complex did not fit into a mathematical model, but showed slightly increased levels after reduction or cessation of the infusion rate. Conclusions. This dose-verification study, including 30 patients at four dose levels, indicated that argatroban infusion in coronary angioplasty patients can be administered safely, and results in an adequate and predictable level of anticoagulation.

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References

  1. Ip JH, Fuster V, Israel D, Badimon L, Badimon J, Chesebro JH. The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty. J Am Coll Cardiol 1991;17:77B-88B.

    Google Scholar 

  2. Mann KG, Tracy PB, Nesheim ME. Assembly and function of prothrombinase complex on synthetic and natural membranes. Oates JA, Harviger J, Ross R, (eds). In: Interaction of Platelets with the Vessel Wall. Bethesda, MD: American Physiological Society, 1985;47–57.

    Google Scholar 

  3. Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L, Fuster V. Effects of thrombin inhibition on the development of acute platelet thrombus deposition during angioplasty in pigs: Heparin versus recombinant hirudin, a specific thrombin inhibitor. Circulation 1989;79:657–665.

    Google Scholar 

  4. Heras M, Chesebro JH, Webster MWI, et al. Hirudin, heparin and placebo during deep arterial injury in the pig. The in vivo role of thrombins in platelet-mediated thrombosis. Circulation 1990;82:1476–1484.

    Google Scholar 

  5. Fitzgerald DJ, Fitzgerald GA. Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator. Proc Natl Acad Sci USA 1989;86:7585–7589.

    Google Scholar 

  6. Callas DD, Hoppensteadt D, Fareed J. Comparative studies on the anticoagulant and protease generation inhibitory actions of newly developed site-directed thrombin inhibitory drugs. Efegatran, argatroban, hirulog, and hirudin. Semin Thromb Hemost 1995;21:177–183.

    Google Scholar 

  7. Cheseboro JH, Badimon L, Fuster V. Importance of antithrombin therapy during coronary angioplasty. J Am Coll Cardiol 1991;17:96B-100B.

    Google Scholar 

  8. Badimon L, Badimon J, Lassila R, Heras M, Chesebro JH, Fuster V. Thrombin inhibition by hirudin decreases platelet thrombus growth on areas of severe vessel wall injury. J Am Coll Cardiol 1989;13:145A.

    Google Scholar 

  9. Umemura K, Kawai H, Ishihara H, Nakashima M. Inhibitory effect of clopidogrel, vapiprost and argatroban on the middle cerebral artery thrombosis in the rat. Jpn J Pharmacol 1995;67:253–825.

    Google Scholar 

  10. Suzuki S, Sakamoto S, Adachi K, et al. Effect of argatroban on thrombus formation during acute coronary occlusion after balloon angioplasty. Thromb Res 1995;77:369–373.

    Google Scholar 

  11. Valji J, Arun K, Bookstein JJ. Use of a direct thrombin inhibitor (argatroban) during pulse-spray thrombolysis in experimental thrombosis. J Vasc Interv Radial 1995;6:91–95.

    Google Scholar 

  12. Berry CN, Girard D, Lochot S, Lecoffre C. Antithrombotic actions of argatroban in rat models of venous, ‘mixed’ and arterial thrombosis, and its effects on the tail transection bleeding time. Br J Pharmacol 1994;113:1209–1214.

    Google Scholar 

  13. Nishiyama H, Umemura K, Saniabadi AR, Takiguchi Y, Uematsu T, Nakashima M. Enhancement of thrombolytic efficacy of tissue-type plasminogen activator by adjuvants in the guinea pig thrombosis model. Eur J Pharmacol 1994;264:191–198.

    Google Scholar 

  14. Sasaki Y, Morii S, Yamashita T, Yamamoto J. Antithrombotic effect of argatroban on the pial vessels of the rat: A study with He-Ne laser-induced thrombus formation. Haemostasis 1993;23:104–111.

    Google Scholar 

  15. Yamashita T, Yamamoto J, Sasaki Y, Matsuoka A. The antithrombotic effect of low molecular weight synthetic thrombin inhibitors, argatoban and PPACK, on He-Ne laser-induced thrombosis in rat mesenteric microvessels. Thromb Res 1993;69:93–100.

    Google Scholar 

  16. Jackson CV, Wilson HC, Growe VG, Shuman RT. Reversible tripeptide thrombin inhibitors as adjunctive agents to coronary thrombolysis: A comparison with heparin in a canine model of coronary artery thrombosis. J Cardiovasc Pharmacol 1993;21:587–594.

    Google Scholar 

  17. Tomoda H. Experimental evaluation of coronary thrombodynamics and effects of pharmacological interventions in acute coronary syndromes Jpn Circ J 1992;56:1184–1190.

    Google Scholar 

  18. Matsuo T, Kario K, Kodama K, Okamoto S. Clinical application of the synthetic thrombin inhibitor, argatroban (MD-805). Semin Thromb Hemost 1992;18:155–160.

    Google Scholar 

  19. Schneider J. Heparin and the thrombin inhibitor argatroban enhance flbrinolysis by infused or bolus-injected saruplase (r-scu-PA) in rabbit femoral artery thrombosis. Thromb Res 1991;64:677–689.

    Google Scholar 

  20. Jang IK, Gold HK, Ziskind AA, Leinbach RC, Fallon JT, Collen D. Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition. Circulation 1990;81:219–225.

    Google Scholar 

  21. Matsuo T, Yamada T, Yamanashi T, Ryo R. Anticoagulant therapy with MD 805 of a hemodialysis patient with heparin-induced thrombocytopenia. Thromb Res 1990;58:663–666.

    Google Scholar 

  22. Matsuo T, Yamada T, Yamanashi T, Komada K. Choice of anticoagulant in congenital antithrombin III-deficient patient with chronic renal failure undergoing regular haemodialysis. Clin Lab Haemat 1989;11:213–219.

    Google Scholar 

  23. Clarke RJ, Mayo G, Fitzgerald GA, Fitzgerald DJ. Combined administation of aspirin and a specific thrombin inhibitor in man. Circulation 1991;83:1510–1518.

    Google Scholar 

  24. Gold HK, Torres FW, Garabedian HD, 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 Card 1993;21:1039–1047.

    Google Scholar 

  25. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331:489–495.

    Google Scholar 

  26. Serruys PW, Foley DP, de Feyter PJ, eds. Quantitative Coronary Angiography in Clinical Practice. Dordrecht: Kluwer Academic Publishers, 1994.

    Google Scholar 

  27. Blackburn H, Keys A, Simonson E, Rautaharju P, Punsar S. The electrocardiograms in population studies: A classification system. Circulation 1960;21:1160–1175.

    Google Scholar 

  28. Hull R, Hirsch J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982;307:1676–1681.

    Google Scholar 

  29. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial: Phase I findings. N Engl J Med 1985;213:932–936.

    Google Scholar 

  30. Chesebro JH, Badimon L, Fuster V. Importance of antithrombin therapy during coronary angioplasty. J Am Coll Cardiol 1991;17:96B-100B.

    Google Scholar 

  31. Wilentz JR, Sanborn TA, Haudenschild CC, Valeri CR, Ryan TJ, Faxon DP. Platelet accumulation in experimental angioplasty: Time course and relation to vascular injury. Circulation 1987;75:636–642.

    Google Scholar 

  32. Groves H, Kinlough-Rathbone RL, Mustard JF. Development of nonthrombogenicity of injured rabbit aortas despite inhibition of platelet adherence. Arteriosclerosis 1986;6:189–195.

    Google Scholar 

  33. Steele PM, Chesebro JH, Stanson AW, et al. Balloon angioplasty: Natural history of the pathophysiological response to injury in a pig model. Circ Res 1985;57:105–112.

    Google Scholar 

  34. Avendano A, Ferguson JJ. Comparison of Hemochron and HemoTec activated coagulation time target values during percutaneous transluminal coronary angioplasty J Am Coll Cardiol 1994;23:907–910.

    Google Scholar 

  35. Huisveld IA, van den Burg PJM, Meijer P, et al. Catheter unsuitable for the study of turn-over products of coagulation, fibrinolysis and platelet activation. Fibrinolysis 1992;6:78–80.

    Google Scholar 

  36. van Genderen PJJ, Gomes M, Stibbe J. The reliability of Hickman catheter blood for the assessment of activation markers of coagulation and fibrinolysis in patients with hematological malignancies. Thrombo Res 1994;73:247–254.

    Google Scholar 

  37. Zoldhelyi P, Bichler J, Owen GO, et al. Persistent thrombin generation in humans during specific thrombin inhibition with hirudin. Circulation 1994;90:2671–2678.

    Google Scholar 

  38. Bos AA van den, Deckers JW, Heyndrickx GR, et al. Safety and efficacy of recombinant hirudin (CGP 39 393) versus heparin in patients with stable angina undergoing coronary angioplasty. Circulation 1993;88:2058–2066.

    Google Scholar 

  39. Willerson JT, Casscells W. Thrombin inhibitors in unstable angina: Rebound or continuation of angina after argatroban withdrawal? J Am Coll Cardiol 1993;21:1048–1051.

    Google Scholar 

  40. Braunwald E. Unstable angina pectoris. A classification. Circulation 1989;89:410.

    Google Scholar 

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Authors and Affiliations

  1. Thoraxcenter, Rotterdam, the Netherlands

    Jean-Paul R. Herrman

  2. Ziekenhuis De Weezenlanden, Zwolle, the Netherlands

    Harry Suryapranata

  3. Academisch Ziekenhuis, Groningen, the Netherlands

    Peter den Heijer

  4. Synthélabo Recherche, Bagneux Cédex, France

    Laurence Gabriël & Patrick W. Serruys MD, PhD, FESC, FACC (Professor of Interventional Cardiology)

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  1. Jean-Paul R. Herrman
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  2. Harry Suryapranata
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  3. Peter den Heijer
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  4. Laurence Gabriël
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  5. Michael J. B. Kutryk
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  6. Patrick W. Serruys MD, PhD, FESC, FACC
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Herrman, JP.R., Suryapranata, H., den Heijer, P. et al. Argatroban during percutaneous transluminal coronary angioplasty: Results of a dose-verification study. J Thromb Thrombol 3, 367–375 (1996). https://doi.org/10.1007/BF00133080

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  • DOI: https://doi.org/10.1007/BF00133080

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