Antifibrinolytic use in adult cardiac surgery

Current Opinion in Hematology

Volumn 14, Issue 5, 2007, Pages 455-467

  Umscheid, Craig A ^a,b,c   Kohl, Benjamin A ^b   Williams, Kendal ^a,b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c MSCE   (United States)

Author keywords

Antifibrinolytic agents; Aprotinin; Cardiopulmonary bypass; Hemorrhage; Meta analysis

Indexed keywords

AMINOCAPROIC ACID; APROTININ; CLOPIDOGREL; PLACEBO; TRANEXAMIC ACID;

ANTICOAGULANT THERAPY; BLEEDING; BLOOD TRANSFUSION; CLINICAL TRIAL; COGNITIVE DEFECT; COMBINATION CHEMOTHERAPY; DISEASE SEVERITY; DRUG COST; DRUG EFFECT; DRUG HYPERSENSITIVITY; DRUG SAFETY; DRUG USE; EVIDENCE BASED PRACTICE; HEART INFARCTION; HEART SURGERY; HUMAN; KIDNEY DYSFUNCTION; KIDNEY FAILURE; LOW DRUG DOSE; PRIORITY JOURNAL; REOPERATION; REVIEW; STROKE; THROMBOSIS;

ADULT; ANTIFIBRINOLYTIC AGENTS; CARDIAC SURGICAL PROCEDURES; CARDIOPULMONARY BYPASS; HEMORRHAGE; HUMANS; KIDNEY FAILURE; STROKE;

EID: 34648812809     PISSN: 10656251     EISSN: 15317048     Source Type: Journal    
DOI: 10.1097/MOH.0b013e328270b89e     Document Type: Review

References (56)

1. Brister SJ, Ofosu FA, Buchanan MR. Thrombin generation during cardiac surgery: is heparin the ideal anticoagulant? Thromb Haemost 1993; 70:259-262.
2. Knudsen L, Hasenkam JM, Kure HH, et al. Monitoring thrombin generation with prothrombin fragment 1.2 assay during cardiopulmonary bypass surgery. Thromb Res 1996; 84:45-54.
3. Koster A, Sanger S, Knorig FJ, et al. Autologous plasma and platelet sequestration at the beginning of cardiopulmonary bypass: a pilot investigation in five patients undergoing extended vascular surgery in deep hypothermia. Asaio J 2002; 48:106-109.
4. Chen RH, Frazier OH, Cooley DA. Antifibrinolytic therapy in cardiac surgery. Tex Heart Inst J 1995; 22:211-215.
5. Despotis GJ, Avidan MS, Hogue CW Jr. Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72:S1821-S1831.
6. Landis RC, Asimakopoulos G, Poullis M, et al. The antithrombotic and antiinflammatory mechanisms of action of aprotinin. Ann Thorac Surg 2001; 72:2169-2175.
7. Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg 2001; 71:745-754.
8. Prentice CR. Basis of antifibrinolytic therapy. J Clin Pathol Suppl (R Coll Pathol) 1980; 14:35-40.
9. Fergusson D, Glass KC, Hutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clin Trials 2005; 2:218-229.
10. Alderman EL, Levy JH, Rich JB, et al. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998; 116:716-730.
11. Kuitunen A, Hiippala S, Vahtera E, et al. The effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic response after cardiac surgery. Acta Anaesthesiol Scand 2005; 49:1272-1279.
12. Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007; 297:471-479. This observational study compares mortality associated with aprotinin to TXA, ACA, and placebo, and suggests that aprotinin is associated with increased mortality at 5 years of follow-up.
13. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354:353-365. This observational study compares the efficacy and safety of aprotinin to TXA, ACA, and placebo in adult cardiac surgery, and suggests that aprotinin is associated with increased renal, cardiovascular, and neurologic events. This study led to an FDA advisory and an update of aprotinin's package insert.
14. ••] that aprotinin is associated with increased renal dysfunction.
15. Beattie WS, Karkouti K. Con: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006; 103:1360-1364.
16. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17:1-12.
17. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ 2004; 328:1490.
18. Wei M, Jian K, Guo Z, et al. Effects of half-dose aprotinin in off-pump coronary artery bypass grafting. World J Surg 2006; 30:1108-1114. This low-quality RCT of half-dose aprotinin in off-pump coronary artery bypass surgery failed to demonstrate an association between aprotinin and reduced rate of transfusion. The study may have been limited by its small sample size.
19. Poston RS, White C, Gu J, et al. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. Ann Thorac Surg 2006; 81:104-110. This high-quality RCT examines the efficacy and safety of aprotinin as compared with placebo in 60 off-pump CAGB surgery patients, and demonstrates a potential association between aprotinin and decreased transfusion rates in off-pump cardiac surgery, albeit statistically insignificant. The study is limited by its small sample size.
20. Cicekcioglu F, Cagli K, Emir M, et al. Effects of minimal dose aprotinin on blood loss and fibrinolytic system-complement activation in coronary artery bypass grafting surgery. J Card Surg 2006; 21:336-341. This high-quality RCT of low-dose aprotinin in coronary artery bypass surgery failed to demonstrate an association between aprotinin and reduced rate of transfusion. The study may have been limited by its small sample size.
21. Vanek T, Jares M, Fajt R, et al. Fibrinolytic inhibitors in off-pump coronary surgery: a prospective, randomized, double-blind TAP study (tranexamic acid, aprotinin, placebo). Eur J Cardiothorac Surg 2005; 28:563-568.
22. van der Linden J, Lindvall G, Sartipy U. Aprotinin decreases postoperative bleeding and number of transfusions in patients on clopidogrel undergoing coronary artery bypass graft surgery: a double-blind, placebo-controlled, randomized clinical trial. Circulation 2005; 112:I276-I280.
23. Diprose P, Herbertson MJ, O'Shaughnessy D, et al. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005; 94:271-278.
24. Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004; 128:442-448.
25. Taggart DP, Djapardy V, Naik M, Davies A. A randomized trial of aprotinin (Trasylol) on blood loss, blood product requirement, and myocardial injury in total arterial grafting. J Thorac Cardiovasc Surg 2003; 126:1087-1094.
26. Englberger L, Markart P, Eckstein FS, et al. Aprotinin reduces blood loss in off-pump coronary artery bypass (OPCAB) surgery. Eur J Cardiothorac Surg 2002; 22:545-551.
27. Alvarez JM, Jackson LR, Chatwin C, Smolich JJ. Low-dose postoperative aprotinin reduces mediastinal drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: a prospective, randomized, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 2001; 122:457-463.
28. Casati V, Guzzon D, Oppizzi M, et al. Tranexamic acid compared with high-dose aprotinin in primary elective heart operations: effects on perioperative bleeding and allogeneic transfusions. J Thorac Cardiovasc Surg 2000; 120:520-527.
29. Casati V, Guzzon D, Oppizzi M, et al. Hemostatic effects of aprotinin, tranexamic acid and epsilon-aminocaproic acid in primary cardiac surgery. Ann Thorac Surg 1999; 68:2252-2256.
30. Henry DA, Moxey AJ, Carless PA, et al. Antifibrinolytic use for minimising perioperative allogeneic blood transfusion (Cochrane Review). Cochrane Database Syst Rev 1999; 4:CD001886.
31. Santos AT, Kalil RA, Bauemann C, et al. A randomized, double-blind, and placebo-controlled study with tranexamic acid of bleeding and fibrinolytic activity after primary coronary artery bypass grafting. Braz J Med Biol Res 2006; 39:63-69.
32. Casati V, Della Valle P, Benussi S, et al. Effects of tranexamic acid on postoperative bleeding and related hematochemical variables in coronary surgery: comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 2004; 128:83-91.
33. Andreasen JJ, Nielsen C. Prophylactic tranexamic acid in elective, primary coronary artery bypass surgery using cardiopulmonary bypass. Eur J Cardiothorac Surg 2004; 26:311-317.
34. Zabeeda D, Medalion B, Sverdlov M, et al. Tranexamic acid reduces bleeding and the need for blood transfusion in primary myocardial revascularization. Ann Thorac Surg 2002; 74:733-738.
35. Casati V, Sandrelli L, Speziali G, et al. Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: a prospective, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 2002; 123:1084-1091.
36. Casati V, Gerli C, Franco A, et al. Tranexamic acid in off-pump coronary surgery: a preliminary, randomized, double-blind, placebo-controlled study. Ann Thorac Surg 2001; 72:470-475.
37. Armellin G, Casella S, Guzzinati S, et al. Tranexamic acid in aortic valve replacement. J Cardiothorac Vasc Anesth 2001; 15:331-335.
38. Kikura M, Levy JH, Tanaka KA, Ramsay JG. A double-blind, placebo-controlled trial of epsilon-aminocaproic acid for reducing blood loss in coronary artery bypass grafting surgery. J Am Coll Surg 2006; 202:216-222. This high-quality RCT of ACA compared with placebo in 100 CAGB surgery patients suggests no significant association between ACA and the number of patients transfused. The study is limited by its small sample size.
39. Brown JR, Birkmeyer NJ, O'Connor GT. Aprotinin in cardiac surgery. N Engl J Med 2006; 354:1953-1957. This letter to the editor updates a previously published meta-analysis of RCTs examining the association between aprotinin and renal outcomes. It suggests that aprotinin is associated with renal dysfunction, but not renal failure. Major strengths of this letter include the large sample size and the randomized source of the data.
40. Harmon DC, Ghori KG, Eustace NP, et al. Aprotinin decreases the incidence of cognitive deficit following CABG and cardiopulmonary bypass: a pilot randomized controlled study. Can J Anaesth 2004; 51:1002-1009.
41. Hayashida N, Isomura T, Sato T, et al. Effects of minimal-dose aprotinin on coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997; 114:261-269.
42. Lass M, Welz A, Kochs M, et al. Aprotinin in elective primary bypass surgery. Graft patency and clinical efficacy. Eur J Cardiothorac Surg 1995; 9:206-210.
43. Lemmer JH Jr, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994; 107:543-551.
44. Laub GW, Riebman JB, Chen C, et al. The impact of aprotinin on coronary artery bypass graft patency. Chest 1994; 106:1370-1375.
45. Wei M, Kuukasjarv P, Laurikka J, et al. Cardioprotective effect of pump prime aprotinin in coronary artery bypass grafting. Cardiovasc Drugs Ther 2002; 16:37-42.
46. Ranaboldo CJ, Thompson JF, Davies JN, et al. Prospective randomized placebo-controlled trial of aprotinin for elective aortic reconstruction. Br J Surg 1997; 84:1110-1113.
47. Beierlein W, Scheule AM, Dietrich W, Ziemer G. Forty years of clinical aprotinin use: a review of 124 hypersensitivity reactions. Ann Thorac Surg 2005; 79:741-748.
48. Augoustides JG, Kilbaugh T, Harris H, et al. Fatal thrombosis after mitral valve replacement for endocarditis: aprotinin and disseminated intravascular coagulation. Anesthesiology 2006; 104:213. This case report documents a fatal thrombosis associated with the use of aprotinin after mitral valve replacement for endocarditis.
49. Augoustides JG, Lin J, Gambone AJ, Cheung AT. Fatal thrombosis in an adult after thoracoabdominal aneurysm repair with aprotinin and deep hypothermic circulatory arrest. Anesthesiology 2005; 103:215-216.
50. Fanashawe MP, Shore-Lesserson L, Reich DL. Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology 2001; 95:1525-1527.
51. Bennett-Guerrero E, Sorohan JG, Gurevich ML, et al. Cost-benefit and efficacy of aprotinin compared with epsilon-aminocaproic acid in patients having repeated cardiac operations: a randomized, blinded clinical trial. Anesthesiology 1997; 87:1373-1380.
52. Harmon DE. Cost/benefit analysis of pharmacologic hemostasis. Ann Thorac Surg 1996; 61:S21-S25.
53. Ray MJ, Brown KF, Burrows CA, O'Brien MF. Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass. Ann Thorac Surg 1999; 68:940-945.
54. Harris G. F.D.A. says Bayer failed to reveal drug risk study. New York Times 2006; 30 September:A1.
55. The BART study. Blood conservation using antifibrinolytics: a randomized trial in a cardiac surgery population - the BART study. Current Controlled Trials 2007. http://controlled-trials.com/ISRCTN15166455/bart [accessed 5 April 2007].
56. Smeeth L, Haines A, Ebrahim S. Numbers needed to treat derived from meta-analyses - sometimes informative, usually misleading. BMJ 1999; 318:1548-1551.