Bivalirudin, Blood Loss, and Graft Patency in Coronary Artery Bypass Surgery

A safe and effective alternative is needed for patients in whom unfractionated heparin (UFH) or protamine is contraindicated (e.g., those with heparin-induced thrombocytopenia or allergy to protamine). Furthermore, choice of anticoagulant may influence graft patency in coronary surgery and may therefore be important even when there is no contraindication to UFH. Direct thrombin inhibitors have several potential advantages over UFH, demonstrated in acute coronary syndromes. However, there are also potential difficulties with their use related to lack of reversal agents and paucity of clinical experience in monitoring their anticoagulant activity at the levels required for cardiac surgery with cardiopulmonary bypass (CPB).

In the first prospective randomized trial of an alternative to heparin in cardiac surgery, we compared bivalirudin (a short-acting direct thrombin inhibitor) with UFH in 100 patients undergoing off-pump coronary artery bypass (OPCAB) surgery. Blood loss for the 12 hours following study drug initiation in the bivalirudin group was not significantly greater than in the heparin group. Median graft flow was significantly higher in the bivalirudin group. We concluded that anticoagulation for OPCAB surgery with bivalirudin was feasible without a clinically important increase in perioperative blood loss. A larger study is needed to investigate the impact of improved graft patency on other clinical outcomes after cardiac surgery.

Off-pump - coronary artery bypass surgery - heparin - anticoagulants - blood loss - bivalirudin

REFERENCES

• 1 Merry A, Raudkivi P, Middleton N et al.. Bivalirudin versus heparin and protamine in off-pump coronary bypass surgery.  Ann Thorac Surg. 2004;  77 925-931
• 2 Gibbon J HJ. The development of the heart-lung apparatus.  Am J Surg. 1978;  135 608-619
• 3 Nunley R M, Lachiewicz P F. Mortality after total hip and knee arthroplasty in a medium-volume university practice.  J Arthroplasty. 2003;  18 278-285
• 4 Charlesworth D C, Likosky D S, Marrin C A et al.. Development and validation of a prediction model for strokes after coronary artery bypass grafting.  Ann Thorac Surg. 2003;  76 436-443
• 5 Engoren M C, Habib R H, Zacharias A et al.. Effect of blood transfusion on long-term survival after cardiac operation.  Ann Thorac Surg. 2002;  74 1180-1186
• 6 Spiess B D. Blood transfusion: the silent epidemic.  Ann Thorac Surg. 2001;  72 S1832-S1837
• 7 Spiess B D. Heparin: beyond an anticoagulant. In: Spiess BD The Relationship between Coagulation, Inflammation, and Endothelium. Baltimore, MD; Lippincott Williams & Wilkens 2000: 169-190
• 8 Bauer T L, Arepally G, Konkle B A et al.. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery.  Circulation. 1997;  95 1242-1246
• 9 Weitz J I, Crowther M. Direct thrombin inhibitors.  Thromb Res. 2002;  106 V275-V284
• 10 Spiess B D. Transfusion and outcome in heart surgery.  Ann Thorac Surg. 2002;  74 986-987
• 11 Williams R T, Damaraju L V, Mascelli M A et al.. Anti-platelet factor 4/heparin antibodies: an independent predictor of 30-day myocardial infarction after acute coronary ischemic syndromes.  Circulation. 2003;  107 2307-2312
• 12 Warkentin T E, Levine M N, Hirsh J et al.. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 1330-1335
• 13 Pouplard C, May M A, Iochmann S et al.. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin: clinical implications for heparin-induced thrombocytopenia.  Circulation. 1999;  99 2530-2536
• 14 Mattioli A V, Bonetti L, Sternieri S, Mattioli G. Heparin-induced thrombocytopenia in patients treated with unfractionated heparin: prevalence of thrombosis in a 1-year follow-up.  Ital Heart J. 2000;  1 39-42
• 15 Simoons M L. Investigators GI-A. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial.  Lancet. 2001;  357 1915-1924
• 16 Newman P M, Swanson R L, Chong B H. Heparin-induced thrombocytopenia: IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid.  Thromb Haemost. 1998;  80 292-297
• 17 Bates S M, Weitz J I. Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin.  Am J Cardiol. 1998;  82 12P-18P
• 18 Butterworth J, Lin Y A, Prielipp R C et al.. Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass.  Ann Thorac Surg. 2002;  74 1589-1595
• 19 Kimmel S E, Sekeres M, Berlin J A, Ellison N. Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass.  Anesth Analg. 2002;  94 1402-1408
• 20 Physician’s Desk Reference .Protamine. 2000
• 21 Frederiksen J W. Cardiopulmonary bypass in humans: bypassing unfractionated heparin.  Ann Thorac Surg. 2000;  70 1434-1443
• 22 Weitz J I. Low-molecular-weight heparins.  N Engl J Med. 1997;  337 688-698
• 23 Massonnet-Castel S, Pelissier E, Bara L et al.. Partial reversal of low molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation.  Haemostasis. 1986;  16 139-146
• 24 Newman P M, Chong B H. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation.  Blood. 2000;  96 182-187
• 25 Doherty D C, Ortel T L, de Bruijn N, Greenberg C S, Van Trigt III P. “Heparin-free” cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass.  Anesthesiology. 1990;  73 562-565
• 26 Illig K A, Ouriel K. Ancrod: understanding the agent.  Semin Vasc Surg. 1996;  9 303-314
• 27 Brieger D B, Mak K H, Kottke-Marchant K, Topol E J. Heparin-induced thrombocytopenia.  J Am Coll Cardiol. 1998;  31 1449-1459
• 28 Walls J T, Curtis J J, Silver D et al.. Heparin-induced thrombocytopenia in open heart surgical patients: sequelae of late recognition.  Ann Thorac Surg. 1992;  53 787-791
• 29 Laster J, Elfrink R, Silver D. Reexposure to heparin of patients with heparin-associated antibodies.  J Vasc Surg. 1989;  9 677-682
• 30 Koster A, Kukucka M, Bach F et al.. Anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II and renal impairment using heparin and the platelet glycoprotein IIb-IIIa antagonist tirofiban.  Anesthesiology. 2001;  94 245-251
• 31 Koster A, Meyer O, Fischer T et al.. One-year experience with the platelet glycoprotein IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II.  J Thorac Cardiovasc Surg. 2001;  122 1254-1255
• 32 Pötzsch B, Klovekorn W P, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia [letter].  N Engl J Med. 2000;  343 515
• 33 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia.  Circulation. 2003;  108 2062-2065
• 34 Nowak G, Bucha E. Prothrombin conversion intermediate effectively neutralizes toxic levels of hirudin.  Thromb Res. 1995;  80 317-325
• 35 Koster A, Kuppe H, Hetzer R et al.. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin.  Anesthesiology. 1998;  89 777-780
• 36 Fischer B E, Schlokat U, Himmelspach M, Dorner F. Binding of hirudin to meizothrombin.  Protein Eng. 1998;  11 715-721
• 37 Koster A, Chew D, Grundel M et al.. Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass.  Anesth Analg. 2003;  96 383-386
• 38 Hursting M J, Alford K L, Becker J C et al.. Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor.  Semin Thromb Hemost. 1997;  23 503-516
• 39 Lubenow N, Selleng S, Wollert H G et al.. Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative argatroban use.  Ann Thorac Surg. 2003;  75 577-579
• 40 Edwards J T, Hamby J K, Worrall N K. Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient.  Ann Thorac Surg. 2003;  75 1622-1624
• 41 Furukawa K, Ohteki H, Hirahara K, Narita Y, Koga S. The use of argatroban as an anticoagulant for cardiopulmonary bypass in cardiac operations.  J Thorac Cardiovasc Surg. 2001;  122 1255-1256
• 42 Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender.  Clin Pharmacol Therap. 2002;  71 433-439
• 43 Fox I, Dawson A, Loynds P et al.. Anticoagulant activity of hirulog, a direct thrombin inhibitor, in humans.  Thromb Haemost. 1993;  69 157-163
• 44 White H. Hirulog, Early Reperfusion or Occlusion-2 Trial I: thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial.  Lancet. 2001;  358 1855-1863
• 45 Fuchs J, Cannon C P. Hirulog in the treatment of unstable angina. Results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 trial.  Circulation. 1995;  92 727-733
• 46 Antman E M, McCabe C H, Braunwald E. Bivalirudin as a replacement for unfractionated heparin in unstable angina/non-ST-elevation myocardial infarction: observations from the TIMI 8 trial. The Thrombolysis in Myocardial Infarction.  Am Heart J. 2002;  143 229-234
• 47 Pötzsch B, Madlener K, Seelig C et al.. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass-assessment of the whole blood ecarin clotting time.  Thromb Haemost. 1997;  77 920-925
• 48 Despotis G J, Hogue C W, Saleem R et al.. The relationship between hirudin and activated clotting time: implications for patients with heparin-induced thrombocytopenia undergoing cardiac surgery.  Anesth Analg. 2001;  93 28-32
• 49 Pötzsch B, Hund S, Madlener K, Unkrig C, Müller-Berghaus G. Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay.  Thromb Res. 1997;  86 373-383
• 50 Koster A, Despotis G, Gruendel M et al.. The plasma supplemented modified activated clotting time for monitoring of heparinization during cardiopulmonary bypass: a pilot investigation.  Anesth Analg. 2002;  95 26-30
• 51 Koster A, Kuppe H, Crystal G J, Mertzlufft F. Cardiovascular surgery without cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II using anticoagulation with recombinant hirudin.  Anesth Analg. 2000;  90 292-298
• 52 Cho L, Kottke-Marchant K, Lincoff A M et al.. Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentrations.  Am J Cardiol. 2003;  91 1110-1113
• 53 Demir M, Iqbal O, Untch B et al.. Ecarin clotting time is sensitive to heparinoids: comparison of two different techniques.  Clin Appl Thromb Hemost. 2001;  7 38-43
• 54 Pivalizza E G. Monitoring of hirudin therapy with the Thrombelastograph.  J Clin Anesth. 2002;  14 456-458
• 55 Bittl J A, Strony J, Brinker J A et al.. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators.  N Engl J Med. 1995;  333 764-769
• 56 Topol E J, Bonan R, Jewitt D et al.. Use of a direct antithrombin, hirulog, in place of heparin during coronary angioplasty.  Circulation. 1993;  87 1622-1629
• 57 Mariani M A, Gu Y J, Boonstra P W et al.. Procoagulant activity after off-pump coronary operation: is the current anticoagulation adequate?.  Ann Thorac Surg. 1999;  67 1370-1375
• 58 The Direct Thrombin Inhibitor Trialists’ Collaborative Group . Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data.  Lancet. 2002;  359 294-302
• 59 Kong D F, Topol E J, Bittl J A et al.. Clinical outcomes of bivalirudin for ischemic heart disease.  Circulation. 1999;  100 2049-2053
• 60 Lincoff A M, Bittl J A, Harrington R A et al.. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial.  JAMA. 2003;  289 853-863
• 61 Puskas J D, Thourani V H, Marshall J J et al.. Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive off-pump coronary bypass patients.  Ann Thorac Surg. 2001;  71 1477-1484
• 62 Angelini G D, Taylor F C, Reeves B C, Ascione R. Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of two randomised controlled trials.  Lancet. 2002;  359 1194-1199
• 63 Zehr K J, Handa N, Bonilla L F, Abel M D, Holmes Jr D R. Pitfalls and results of immediate angiography after off-pump coronary artery bypass grafting.  Heart Surg Forum. 2000;  3 293-299
• 64 Kim K B, Lim C, Lee C et al.. Off-pump coronary artery bypass may decrease the patency of saphenous vein grafts.  Ann Thorac Surg. 2001;  72 S1033-S1037
• 65 Vasquez J C. Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery.  Ann Thorac Surg. 2002;  74 2177-2179
• 66 Spiess B D, DeAnda A, McCarthy A et al.. Off-pump CABG in a patient with HITT anticoagulated with bivalirudin: a case report.  Anesth Analg. 2002;  93 SCA70
• 67 Davis Z, Anderson R, Short D, Garber D, Valgiusti A. Favorable outcome with bivalirudin anticoagulation during cardiopulmonary bypass.  Ann Thorac Surg. 2003;  75 264-265