Top

Drug Safety

Published in:

01-03-2008 | Review Article

A Benefit-Risk Review of Systemic Haemostatic Agents

Part 1: In Major Surgery

Authors: Dr Ian S. Fraser, Robert J. Porte, Peter A. Kouides, Andrea S. Lukes

Published in: Drug Safety | Issue 3/2008

Abstract

Systemic haemostatic agents play an important role in the management of blood loss during major surgery where significant blood loss is likely and their use has increased in recent times as a consequence of demand for blood products outstripping supply and the risks associated with transfusions. Their main application is as prophylaxis to reduce bleeding in major surgery, including cardiac and orthopaedic surgery and orthotopic liver transplantation. Aprotinin has been the predominant agent used in this setting; of the other antifibrinolytic agents that have been studied, tranexamic acid is the most effective and e-aminocaproic acid may also have a role. Eptacog alfa (recombinant factor VIIa) has also shown promise. Tranexamic acid, e-aminocaproic acid and eptacog alfa are generally well tolerated; however, when considering the methods to reduce or prevent blood loss intra- and postoperatively, the benefits of these agents need to be weighed against the risk of adverse events. Recently, concerns have been raised about the safety of aprotinin after an association between increased renal dysfunction and mortality was shown in retrospective observational studies and an increase in allcause mortality with aprotinin relative to tranexamic acid or e-aminocaproic acid was seen after a pre-planned periodic analysis of the large BART (Blood conservation using Antifibrinolytics in a Randomized Trial) study. The latter finding resulted in the trial being halted, and aprotinin has subsequently been withdrawn from the market pending detailed analysis of efficacy and safety results from the study. Part 1 of this benefit-risk review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in surgery, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting.

Levi MM, Vink R, de Jonge E. Management of bleeding disorders by prohemostatic therapy. Int J Hematol 2002 Aug; 76 Suppl. 2: 139–44PubMedCrossRef

Levy JH. Hemostatic agents. Transfusion (Paris) 2004; 44 (12 Suppl.): 58–62SCrossRef

Fraser IS, Porte RJ, Kouides PA, et al. A benefit-risk review of systemic haemostatic agents. Part 2: in excessive or heavy menstrual bleeding. Drug Saf. In press

Karski JM, Balatbat JT. Blood conservation strategies in cardiac surgery. Semin Cardiothorac Vasc Anesth 2003; 7(2): 175–88CrossRef

Beguin C, Closon M-C, Vanderkerckhove P, et al. Concentration of transfusion resources on a few pathologies and a few patients: analysis of a comprehensive in-hospital patient database. Transfusion (Paris) 2007; 47(2): 217–27CrossRef

Tobias JD. Strategies for minimizing blood loss in orthopedic surgery. Semin Hematol 2004 Jan; 41 (1 Suppl. 1): 145–56PubMedCrossRef

Norfolk DR, Seghatchian J. Pharmacological therapies to minimise platelet transfusion. Transfus Sci 2000 Jun; 22(3): 149–53PubMedCrossRef

Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007 May 31; 356(22): 2301–11PubMedCrossRef

Barrons RW, Jahr JS. A Review of post-cardiopulmonary bypass bleeding, aminocaproic acid, tranexamic acid, and aprotinin. Am J Ther 1996 Dec; 3(12): 821–38PubMedCrossRef

10.

Levy JH. Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation. Am J Health Syst Pharm 2005; 62 Suppl. 4: S15–9PubMedCrossRef

11.

Levy JH. Novel concepts in treatment and prevention of bleeding. Anesth Analg 2005; 100 (3. Suppl.): 43–7

12.

Erstad BL. What is the evidence for using hemostatic agents in surgery? Eur Spine J 2004; 13 Suppl. 1: S28–33PubMedCrossRef

13.

Porte RJ, Leebeek FWG. Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002; 62(15): 2193–211PubMedCrossRef

14.

Roy SN, Bhattacharya S. Benefits and risks of pharmacological agents used for the treatment of menorrhagia. Drug Saf 2004; 27(2): 75–90PubMedCrossRef

15.

Marietta M, Facchini L, Pedrazzi P, et al. Pathophysiology of bleeding in surgery. Transplant Proc 2006 Apr; 38(3): 812–4PubMedCrossRef

16.

Xia VW, Steadman RH. Antifibrinolytics in orthotopic liver transplantation: current status and controversies. Liver Transpl 2005 Jan; 11(1): 10–8PubMedCrossRef

17.

Bayer HealthCare. Trasylol (aprotinin injection). US prescribing information. West Haven (CT): Bayer Pharmaceuticals Corporation, 2006 Dec

18.

Horrow JC, Van Riper DF, Strong MD, et al. Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery. Circulation 1991; 84(5): 2063–70PubMedCrossRef

19.

Karkouti K, Beattie WS, Wijeysundera DN, et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion (Paris) 2005 Jan; 45(1): 26–34CrossRef

20.

Diprose P, Herbertson MJ, O’Shaughnessy D, et al. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth 2005 Nov; 95(5): 596–602PubMedCrossRef

21.

Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999; 57(6): 1005–32PubMedCrossRef

22.

Slaughter TF, Greenberg CS. Antifibrinolytic drugs and perioperative hemostasis. Am J Hematol 1997 Sep; 56(1): 32–6PubMedCrossRef

23.

US FDA. FDA requests marketing suspension of Trasylol [online]. Available from URL: http://www.fda.gov [Accessed 2007 Nov 6]

24.

Bayer Healthcare Pharmaceuticals. Important Trasylol safety information [online]. Available from URL: http://www.trasylol.com/Trasylol_11_05_07_DHCP.pdf [Accessed 2007 Nov 6]

25.

Electronic Medicines Compendium. Trasylol SPC from the eMC [online]. Available from URL: http://emc.medicines.org.uk [Accessed 2007 Apr 24]

26.

Menichetti A, Tritapepe L, Ruvolo G, et al. Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. J Cardiovasc Surg (Torino) 1996; 37(4): 401–7

27.

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 Mar; 94(3): 271–8PubMedCrossRef

28.

Cosgrove III DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992 Dec; 54(6): 1031–6; discussion 1036–8PubMedCrossRef

29.

Lemmer Jr JH, 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 Feb; 107(2): 543–51, discussion 551–3PubMed

30.

Bidstrup BP, Royston D, Sapsford RN, et al. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989 Mar; 97(3): 364–72PubMed

31.

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 Oct; 28(4): 563–8PubMedCrossRef

32.

Bailey CR, Wielogorski AK. Randomised placebo controlled double blind study of two low dose aprotinin regimens in cardiac surgery. Br Heart J 1994 Apr; 71(4): 349–53PubMedCrossRef

33.

Ray MJ, O’Brien MF. Comparison of epsilon aminocaproic acid and low-dose aprotinin in cardiopulmonary bypass: efficiency, safety and cost. Ann Thorac Surg 2001 Mar; 71(3): 838–43PubMedCrossRef

34.

Pugh SC, Wielogorski AK. A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1995 Jun; 9(3): 240–4PubMedCrossRef

35.

Landymore RW, Murphy JT, Lummis H, et al. The use of low-dose aprotinin, epsilon-aminocaproic acid or tranexamic acid for prevention of mediastinal bleeding in patients receiving aspirin before coronary artery bypass operations [letter]. Eur J Cardiothorac Surg 1997 Apr; 11(4): 798–800PubMedCrossRef

36.

Nuttall GA, Oliver WC, Ereth MH, et al. Comparison of blood-conservation strategies in cardiac surgery patients at high risk for bleeding. Anesthesiology 2000 Mar; 92(3): 674–82PubMedCrossRef

37.

Corbeau JJ, Monrigal JP, Jacob JP, et al. Comparison of effects of aprotinin and tranexamic acid on blood loss in heart surgery [in French]. Ann Fr Anesth Reanim 1995; 14(2): 154–61PubMedCrossRef

38.

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 Dec; 87(6): 1373–80PubMedCrossRef

39.

Hekmat K, Zimmermann T, Kampe S, et al. Impact of tranexamic acid vs. aprotinin on blood loss and transfusion requirements after cardiopulmonary bypass: a prospective, randomised, double-blind trial. Curr Med Res Opin 2004; 20(1): 121–6PubMedCrossRef

40.

Lentschener C, Cottin P, Bouaziz H, et al. Reduction of blood loss and transfusion requirement by aprotinin in posterior lumbar spine fusion. Anesth Analg 1999 Sep; 89(3): 590–7PubMed

41.

Murkin JM, Haig GM, Beer KJ, et al. Aprotinin decreases exposure to allogeneic blood during primary unilateral total hip replacement. J Bone Joint Surg Am 2000 May; 82(5): 675–84PubMed

42.

Lentschener C, Benhamou D, Mercier FJ, et al. Aprotinin reduces blood loss in patients undergoing elective liver resection. Anesth Analg 1997 Apr; 84(4): 875–81PubMed

43.

Garcia-Huete L, Domenech P, Sabate A, et al. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 1997 Nov; 26(5): 1143–8PubMedCrossRef

44.

Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group. Lancet 2000 Apr 15; 355(9212): 1303–9PubMedCrossRef

45.

Ickx BE, van der Linden PJ, Melot C, et al. Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation. Transfusion (Paris) 2006 Apr; 46(4): 595–605CrossRef

46.

Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relationship of tranexamic acid. Anesthesiology 1995; 82(2): 383–92PubMedCrossRef

47.

Nakashima A, Matsuzaki K, Fukumura F, et al. Tranexamic acid reduces blood loss after cardiopulmonary bypass. ASAIO J 1993; 39(3): M185–9PubMedCrossRef

48.

Karski J, Djaiani G, Carroll J, et al. Tranexamic acid and early saphenous vein graft patency in conventional coronary artery bypass graft surgery: a prospective randomized controlled clinical trial. J Thorac Cardiovasc Surg 2005 Aug; 130(2): 309–14PubMedCrossRef

49.

Katsaros D, Petricevic M, Snow NJ, et al. Tranexamic acid reduces postbypass blood use: a double-blinded, prospective, randomized study of 210 patients. Ann Thorac Surg 1996 Apr; 61(4): 1131–5PubMedCrossRef

50.

Wei M, Jian K, Guo Z, et al. Tranexamic acid reduces postoperative bleeding in off-pump coronary artery bypass grafting. Scand Cardiovasc J 2006 Apr; 40(2): 105–9PubMedCrossRef

51.

Benon G, Fredin H. Fibrinolytic inhibition with tranexamic acid reduces blood loss and blood transfusion after knee arthroplasty. J Bone Joint Surg [Br] 1996; 78-B: 434–40

52.

Zohar E, Ellis M, Ifrach N, et al. The postoperative blood-sparing efficacy of oral versus intravenous tranexamic acid after total knee replacement. Anesth Analg 2004 Dec; 99(6): 1679–83PubMedCrossRef

53.

Hiippala ST, Strid LJ, Wennerstrand MI, et al. Tranexamic acid radically decreases blood loss and transfusions associated with total knee arthroplasty. Anesth Analg 1997 Apr; 84(4): 839–44PubMed

54.

Camarasa MA, Olle G, Serra-Prat M, et al. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. Br J Anaesth 2006 May; 96(5): 576–82PubMedCrossRef

55.

Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, double-blind study in 100 patients. Acta Orthopaedica 2005; 76(3): 314–9PubMed

56.

Wu CC, Ho WM, Cheng SB, et al. Perioperative parenteral tranexamic acid in liver tumor resection: a prospective randomized trial toward a “blood transfusion”-free hepatectomy. Ann Surg 2006 Feb; 243(2): 173–80PubMedCrossRef

57.

Dalmau A, Sabate A, Acosta F, et al. Tranexamic acid reduces red cell transfusion better than epsilon-aminocaproic acid or placebo in liver transplantation. Anesth Analg 2000; 91(1): 29–34PubMed

58.

DelRossi AJ, Cernaianu AC, Botros S, et al. Prophylactic treatment of postperfusion bleeding using EACA. Chest 1989 Jul; 96(1): 27–30PubMedCrossRef

59.

Arom KV, Emery RW. Decreased postoperative drainage with addition of epsilon-aminocaproic acid before cardiopulmonary bypass. Ann Thorac Surg 1994 May; 57(5): 1108–12; discussion 1112–3PubMedCrossRef

60.

Salzman EW, Weinstein MJ, Weintraub RM, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial. N Engl J Med 1986 May 29; 314(22): 1402–6PubMedCrossRef

61.

Kobrinsky NL, Letts RM, Patel LR, et al. l-Desamino-8-D-arginine vasopressin (desmopressin) decreases operative blood loss in patients having Harrington rod spinal fusion surgery: a randomized, double-blinded, controlled trial. Ann Intern Med 1987 Oct; 107(4): 446–50PubMed

62.

Karnezis TA, Stulberg SD, Wixson RL, et al. The hemostatic effects of desmopressin on patients who had total joint arthroplasty. A double-blind randomized trial. J Bone Joint Surg Am 1994 Oct; 76(10): 1545–50PubMed

63.

Schott U, Sollen C, Axelsson K, et al. Desmopressin acetate does not reduce blood loss during total hip replacement in patients receiving dextran. Acta Anaesthesiol Scand 1995 Jul; 39(5): 592–8PubMedCrossRef

64.

Dobkowski WB, Murkin JM. A risk-benefit assessment of aprotinin in cardiac surgical procedures. Drug Saf 1998 Jan; 18(1): 21–41PubMedCrossRef

65.

Royston D, Chhatwani A. Safety aspects of aprotinin therapy in cardiac surgery patients. Expert Opin Drug Saf 2006 Jul; 5(4): 539–52PubMedCrossRef

66.

Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth Analg 1997; 85(6): 1258–67PubMed

67.

Levy JH. Efficacy and safety of aprotinin in cardiac surgery. Orthopedics 2004 Jun; 27 (6 Suppl.): S659–62PubMed

68.

Samama CM. A direct antifibrinolytic agent in major orthopedic surgery. Orthopedics 2004 Jun; 27 (6 Suppl.): S675–80PubMed

69.

Bitan FD. Aprotinin in spine surgery: review of the literature. Orthopedics 2004 Jun; 27 (6 Suppl.): S681–3PubMed

70.

Amar D, Grant FM, Zhang H, et al. Antifibrinolytic therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery. Anesthesiology 2003 Feb; 98(2): 337–42 228PubMedCrossRef

71.

Shiga T, Wajima Z, Inoue T, et al. Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials. Anesth Analg 2005 Dec; 101(6): 1602–7PubMedCrossRef

72.

Sodha NR, Boodhwani M, Bianchi C, et al. Aprotinin in cardiac surgery. Expert Rev Cardiovasc Ther 2006 Mar; 4(2): 151–60PubMedCrossRef

73.

Molenaar IQ, Warnaar N, Groen H, et al. Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2007 Jan; 7(1): 185–94PubMedCrossRef

74.

Levi M, Cromheecke ME, De Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354(9194): 1940–7PubMedCrossRef

75.

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 Sep; 128(3): 442–8PubMedCrossRef

76.

Henry DA, Moxey AJ, Carless PA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001; (1): CD001886

77.

Nuttall GA, Brost BC, Connis RT, et al. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on perioperative blood transfusion and adjuvant therapies. Anesthesiology 2006; 105(1): 198–208CrossRef

78.

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 Dec; 103(6): 1360–4PubMedCrossRef

79.

Ceriana P, Maurelli M, Locatelli A, et al. Anaphylactic reaction to aprotinin [letter]. J Cardiothorac Vasc Anesth 1995 Aug; 9(4): 477–8PubMedCrossRef

80.

Wuthrich B, Schmid P, Schmid ER, et al. IgE-mediated anaphylactic reaction to aprotinin during anaesthesia [letter]. Lancet 1992 Jul 18; 340(8812): 173–4PubMedCrossRef

81.

Bohrer H, Bach A, Fleischer F, et al. Adverse haemodynamic effects of high-dose aprotinin in a paediatric cardiac surgical patient. Anaesthesia 1990 Oct; 45(10): 853–4PubMedCrossRef

82.

Chiu J, Ketchum LH, Reid TJ. Transfusion-sparing hemostatic agents. Curr Opin Hematol 2002 Nov; 9(6): 544–50PubMedCrossRef

83.

Levy JH, Sypniewski E. Aprotinin: a pharmacologic overview. Orthopedics 2004 Jun; 27 (6 Suppl): S653–8PubMed

84.

Vucicevic Z, Suskovic T. Acute respiratory distress syndrome after aprotinin infusion. Ann Pharmacother 1997 Apr; 31(4): 429–32PubMed

85.

Augoustides JG, Lin J, Gambone AJ, et al. Fatal thrombosis in an adult after thoracoabdominal aneurysm repair with aprotinin and deep hypothermie circulatory arrest [letter]. Anesthesiology 2005 Jul; 103(1): 215–6PubMedCrossRef

86.

Augoustides JG, Kilbaugh T, Harris H, et al. Fatal thrombosis after mitral valve replacement for endocarditis: aprotinin and disseminated intravascular coagulation [letter]. Anesthesiology 2006 Jan; 104(1): 213PubMedCrossRef

87.

Ramsay MA, Randall HB, Burton EC. Intravascular thrombosis and thromboembolism during liver transplantation: antifibrinolytic therapy implicated? Liver Transpl 2004 Feb; 10(2): 310–4PubMedCrossRef

88.

Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993 Apr; 55(4): 1033–41PubMedCrossRef

89.

Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion (Paris) 2006; 46(3): 327–38CrossRef

90.

Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007 Feb 7; 297(5): 471–9PubMedCrossRef

91.

Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006 Jan 26; 354(4): 353–65PubMedCrossRef

92.

Warnaar N, Mallett SV, de Boer MT, et al. The impact of aprotinin on renal function after liver transplantation: an analysis of 1,043 patients. Am J Transplant 2007 Oct; 7(10): 2378–87PubMedCrossRef

93.

US Food and Drug Administration. FDA statement regarding new Trasylol data [online]. Available from URL: http://www.fda.gov [Accessed 2006 Oct 5]

94.

Royston D, van Haaften N, De Vooght P. Aprotinin: friend or foe? A review of recent medical literature. Eur J Anaesthesiol 2007 Jan; 24(1): 6–14PubMed

95.

Body SC, Mazer CD. Pro: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006 Dec; 103(6): 1354–9PubMedCrossRef

96.

Current Controlled Trials Ltd. Blood conservation using antifib-rinolytics: a randomized trial in a cardiac surgery population. The BART study [online]. Available from URL: http://control-led-trials.com [Accessed 2007 Apr 27]

97.

Ottawa Health Research Institute. Information about the Blood conservation using Antifibrinolytics in a Randomized Trial (BART) study [online]. Available from URL: http://www.ohri.ca [Accessed 2007 Nov 7]

98.

Wellington K, Wagstaff AJ. Tranexamic acid: a review of its use in the management of menorrhagia. Drugs 2003; 63(13): 1417–33PubMedCrossRef

99.

Murphy GJ, Mango E, Lucchetti V, et al. A randomized trial of tranexamic acid in combination with cell salvage plus a meta-analysis of randomized trials evaluating tranexamic acid in off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg 2006 Sep; 132(3): 475–80PubMedCrossRef

100.

Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006; 105(5): 1034–46PubMedCrossRef

101.

Carless PA, Moxey AJ, Stokes BJ, et al. Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials. BMC Cardiovascular Disorders 2005; 5: 19PubMedCrossRef

102.

Erstad BL. Systemic hemostatic medications for reducing surgical blood loss. Ann Pharmacother 2001 Jul-2001 31; 35(7–8): 925–34PubMedCrossRef

103.

Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients undergoing total knee arthroplasty: results of a meta-analysis of randomized controlled trials. Transfusion (Paris) 2005 Aug; 45(8): 1302–7CrossRef

104.

Gill JB, Rosenstein A. The use of antifibrinolytic agents in total hip arthroplasty: a meta-analysis. J Arthroplasty 2006 Sep; 21(6): 869–73PubMedCrossRef

105.

Gai MY, Wu LF, Su QF, et al. Clinical observation of blood loss reduced by tranexamic acid during and after Caesarian section: a multi-center, randomized trial. Eur J Obstet Gynecol Reprod Biol 2004; 112(2): 154–7PubMedCrossRef

106.

Federici AB, Sacco R, Stabile F, et al. Optimising local therapy during oral surgery in patients with von Willebrand disease: effective results from a retrospective analysis of 63 cases. Haemophilia 2000 Mar; 6(2): 71–7PubMedCrossRef

107.

Nitu-Whalley IC, Griffioen A, Harrington C, et al. Retrospective review of the management of elective surgery with 229 desmopressin and clotting factor concentrates in patients with von Willebrand disease. Am J Hematol 2001 Apr; 66(4): 280–4PubMedCrossRef

108.

Pharmacia and Upjohn Company. Cyclokapron® (tranexamic acid tablets and tranexamic acid injection) [prescribing information]. Kalamazoo (MI): Pharmacia and Upjohn Company, 2005 Nov

109.

Carrion-Carrion C, Del Pozo-Losada J, Gutierrez-Ramos R, et al. Bullous eruption induced by tranexamic acid [letter]. Ann Pharmacother 1994; 28(11): 1305–6PubMed

110.

Kavanagh GM, Sansom JE, Harrison P, et al. Tranexamic acid (Cyklokapron)-induced fixed-drug eruption [letter]. Br J Dermatol 1993; 128(2): 229–30PubMedCrossRef

111.

Lucas-Polomeni MM, Delavai Y, Menestret P, et al. A Case of anaphylactic shock with tranexamique acid (Exacyl) [in French]. Ann Fr Anesth Reanim 2004; 23(6): 607–9PubMedCrossRef

112.

Cravens GT, Brown MJ, Brown DR, et al. Antifibrinolytic therapy use to mitigate blood loss during staged complex major spine surgery: Postoperative visual color changes after tranexamic acid administration. Anesthesiology 2006; 105(6): 1274–6PubMedCrossRef

113.

Snir M, Axer-Siegel R, Buckman G, et al. Central venous stasis retinopathy following the use of tranexamic acid. Retina 1990; 10(3): 181–4PubMed

114.

Thiagarajamurthy S, Levine A, Dunning J. Does prophylactic tranexamic acid safely reduce bleeding without increasing thrombotic complications in patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2004; 3(3): 489–94PubMedCrossRef

115.

Rydin E, Lundberg PO. Tranexamic acid and intracranial throm-bosis [letter]. Lancet 1976 Jul 3; 2(7975): 49PubMedCrossRef

116.

Woo KS, Tse LK, Woo JL, et al. Massive pulmonary thromboembolism after tranexamic acid antifibrinolytic therapy. Br J Clin Pract 1989 Dec; 43(12): 465–6PubMed

117.

Mandai AKJ, Missouris CG. Tranexamic acid and acute myocardial infarction. Br J Cardiol 2005; 12(4): 306–7

118.

Taparia M, Cordingley FT, Leahy MF. Pulmonary embolism associated with tranexamic acid in severe acquired haemophilia. Eur J Haematol 2002 May; 68(5): 307–9PubMedCrossRef

119.

Koo JR, Lee YK, Kim YS, et al. Acute renal cortical necrosis caused by an antifibrinolytic drug (tranexamic acid). Nephrol Dial Transplant 1999; 14(3): 750–2PubMedCrossRef

120.

Lindoff C, Rybo G, Astedt B. Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications. Thromb Haemost 1993; 70(2): 238–40PubMed

121.

Sundstrom A, Seaman H, Alfredsson L. tranexamic acid, menorrhagia, and venous thromboembolism: a case control study using the GRPD [abstract no. 214]. Pharmacoepidemiol Drug Saf 2005; 14 Suppl.: S108

122.

Bekassy Z, Astedt B. Treatment with the fibrinolytic inhibitor tranexamic acid: risk for thrombosis? Acta Obstet Gynecol Scand 1990; 69(4): 353–4PubMedCrossRef

123.

Tanaka K, Kondo C, Takagi K, et al. Effects of nafamostat mesilate on platelets and coagulofibrinolysis during cardiopulmonary bypass surgery. ASAIO J 1993 Jul-1993 30; 39(3): M545–9PubMedCrossRef

124.

Sato T, Tanaka K, Kondo C, et al. Nafamostat mesilate administration during cardiopulmonary bypass decreases postoperative bleeding after cardiac surgery. ASAIO Trans 1991 Jul-1991 30; 37(3): M194–5PubMed

125.

Murase M, Usui A, Tomita Y, et al. Nafamostat mesilate reduces blood loss during open heart surgery. Circulation 1993 Nov; 88 (5 Pt 2): II432–6PubMed

126.

Miyamoto Y, Nakano S, Kaneko M, et al. Clinical evaluation of a new synthetic protease inhibitor in open heart surgery. Effect on plasma serotonin and histamine release and blood conservation. ASAIO J 1992 Jul-1992 30; 38(3): M395–8PubMedCrossRef

127.

Shimada M, Matsumata T, Shirabe K, et al. Effect of nafamostat mesilate on coagulation and fibrinolysis in hepatic resection. J Am Coll Surg 1994 May; 178(5): 498–502PubMed

128.

Kaminishi Y, Hiramatsu Y, Watanabe Y, et al. Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass. Ann Thorac Surg 2004 Feb; 77(2): 644–50PubMedCrossRef

129.

Munoz JJ, Birkmeyer NJ, Birkmeyer JD, et al. Is epsilon-aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery: a meta-analysis. Circulation 1999 Jan 5–1999; 99(1): 81–9PubMedCrossRef

130.

Xanodyne Pharmaceuticals Inc. Amicar® (aminocaproic acid) injection, syrup and tablets [prescribing information]. Florence (KY): Xanodyne Pharmaceuticals Inc, 2004 Sep

131.

Seymour BD, Rubinger M. Rhabdomyolysis induced by epsi-lon-aminocaproic acid. Ann Pharmacother 1997 Jan; 31(1): 56–8PubMed

132.

Achiron A, Gornish M, Melamed E. Cerebral sinus thrombosis as a potential hazard of antifibrinolytic treatment in menorrhagia. Stroke 1990 May; 21(5): 817–9PubMedCrossRef

133.

Fanashawe MP, Shore-Lesserson L, Reich DL. Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology 2001 Dec; 95(6): 1525–7PubMedCrossRef

134.

Aprile AE, Palmer TJ. The intraoperative use of Amicar to reduce bleeding associated with open heart surgery. AANA J 1995 Aug; 63(4): 325–31PubMed

135.

Sonntag VK, Stein BM. Arteriopathic complications during treatment of subarachnoid hemorrhage with epsilon-aminocaproic acid. J Neurosurg 1974 Apr; 40(4): 480–5PubMedCrossRef

136.

Balduini CL, Noris P, Belletti S, et al. In vitro and in vivo effects of desmopressin on platelet function. Haematologica 1999 Oct; 84(10): 891–6PubMed

137.

DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol 1990 Jan; 33(1): 39–45PubMedCrossRef

138.

Avenus Pharmaceuticals Inc. DDAVP injection (desmopressin) [prescribing information]. Kansas City (MO): Avenus Pharmaceuticals Inc., 2004

139.

Bertholini DM, Butler CS. Severe hyponatraemia secondary to desmopressin therapy in von Willebrand’s disease. Anaesth Intensive Care 2000 Apr; 28(2): 199–201PubMed

140.

Das P, Carcao M, Hitzler J. DDAVP-induced hyponatremia in young children. J Pediatr Hematol Oncol 2005 Jun; 27(6): 330–2PubMedCrossRef

141.

Garcia EB, Ruitenberg A, Madretsma GS, et al. Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von Willebrand’s disease. Haemophilia 2003 Mar; 9(2): 232–4CrossRef

142.

Garcia VV, Silva IA, Borrasca AL. Response of factor VIII/von Willebrand factor to intranasal DDAVP in healthy subjects and mild haemophiliacs (with observations in patients with combined deficiency of factors V and VIII). Thromb Haemost 1982 Aug 24; 48(1): 91–3PubMed

143.

Mannucci PM, Canciani MT, Rota L, et al. Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. Br J Haematol 1981 Feb; 47(2): 283–93PubMedCrossRef

144.

Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001 May; 21(5): 731–8PubMedCrossRef

145.

Mannucci PM, Lusher JM. Desmopressin and thrombosis [letter]. Lancet 1989 Sep 16; 2(8664): 675–6PubMedCrossRef

146.

Byrnes JJ, Larcada A, Moake JL. Thrombosis following desmopressin for uremic bleeding. Am J Hematol 1988 May; 28(1): 63–5PubMedCrossRef

147.

Franchini M, Salvagno GL, Manzato F, et al. Are thrombotic complications in patients with von Willebrand’s disease expression of a multifactorial disease? Haematologica 2005 Nov; 90 Suppl: ECR34PubMed

148.

Grainge C, Nokes T. Cerebral arterial thrombosis in a young woman following vasopressin for von Willebrand’s disease. Thromb Haemost 2005 Feb; 93(2): 380PubMed

149.

Siddiqui MA, Scott LJ. Recombinant factor VIIa (Eptacog Alfa): a review of its use in congenital or acquired haemophilia and other congenital bleeding disorders. Drugs 2005; 65(8): 1161–77PubMedCrossRef

150.

O’Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006 Jan 18; 295(3): 293–8PubMedCrossRef

151.

Roberts HR, Monroe DM, Hoffman M. Molecular biology of the coagulation factors and pathways of hemostasis. In: Beutler E, Lichtman MA, Coller BS, et al, editors. Williams hematology. 6th ed. New York: McGraw Hill, 2001: 1409–34

152.

Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004 Dec 15; 104(13): 3858–64PubMedCrossRef

153.

Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002 Dec 3; 137(11): 884–8PubMed

154.

Eikelboom JW, Bird R, Blythe D, et al. Recombinant activated factor VII for the treatment of life-threatening haemorrhage. Blood Coagul Fibrinolysis 2003 Dec; 14(8): 713–7PubMedCrossRef

155.

Hoots WK. Challenges in the therapeutic use of a “so-called” universal hemostatic agent: recombinant factor VIIa. Hematology Am Soc Hematol Educ Program 2006, 426–31

156.

Mayer SA, Brun NC, Broderick J, et al. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 2005 Jan; 36(1): 74–9PubMedCrossRef

157.

Mayer SA, Bran NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005 Feb 24; 352(8): 777–85PubMedCrossRef

158.

Uhlmann EJ, Eby CS. Recombinant activated factor VII for non-hemophiliac bleeding patients. Curr Opin Hematol 2004 May; 11(3): 198–204PubMedCrossRef

159.

Lodge JP, Jonas S, Jones RM, et al. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005 Aug; 11(8): 973–9PubMedCrossRef

160.

Planinsic RM, van der Meer J, Testa G, et al. Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl 2005 Aug; 11(8): 895–900PubMedCrossRef

161.

Shao YF, Yang JM, Chau GY, et al. Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Am J Surg 2006 Feb; 191(2): 245–9PubMedCrossRef

162.

Porte RJ, Caldwell SH. The role of recombinant factor VIIa in liver transplantation. Liver Transpl 2005 Aug; 11(8): 872–4PubMedCrossRef

163.

Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004 Jun; 2(6): 899–909PubMedCrossRef

164.

Levy JH, Fingerhut A, Brott T, et al. Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion (Paris) 2006 Jun; 46(6): 919–33CrossRef

165.

Garay RP, Chiavaroli C, Hannaert P. Therapeutic efficacy and mechanism of action of ethamsylate, a long-standing hemostatic agent. Am J Ther 2006 May-2006 30; 13(3): 236–47PubMedCrossRef

166.

Schulte J, Osbome J, Benson JW, et al. Developmental outcome of the use of etamsylate for prevention of periventricular haemorrhage in a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2005 Jan; 90(1): F31–5PubMedCrossRef

167.

Benson JW, Drayton MR, Hayward C, et al. Multicentre trial of ethamsylate for prevention of periventricular haemorrhage in very low birthweight infants. Lancet 1986 Dec 6; 2(8519): 1297–300PubMedCrossRef

168.

Livio M, Mannucci PM, Vigano G, et al. Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 1986 Sep 18; 315(12): 731–5PubMedCrossRef

169.

Seth S, Geier TM. Use of conjugated estrogens to control gastrointestinal tract bleeding in two patients with chronic renal failure. Clin Pharm 1988 Dec; 7(12): 906–9PubMed

170.

Heunisch C, Resnick DJ, Vitello JM, et al. Conjugated estrogens for the management of gastrointestinal bleeding secondary to uremia of acute renal failure. Pharmacotherapy 1998 Jan-1998 28; 18(1): 210–7PubMed

171.

Frenette L, Cox J, McArdle P, et al. Conjugated estrogen reduces transfusion and coagulation factor requirements in orthotopic liver transplantation. Anesth Analg 1998 Jun; 86(6): 1183–6PubMed

172.

Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol 2004; 190(4): 1141–67PubMedCrossRef

Title: A Benefit-Risk Review of Systemic Haemostatic Agents
Part 1: In Major Surgery
Authors: Dr Ian S. Fraser
Robert J. Porte
Peter A. Kouides
Andrea S. Lukes
Publication date: 01-03-2008
Publisher: Springer International Publishing
Published in: Drug Safety / Issue 3/2008
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI: https://doi.org/10.2165/00002018-200831030-00003

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A Benefit-Risk Review of Systemic Haemostatic Agents

Part 1: In Major Surgery

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2008

The US FDA ‘Black Box’ Warning for Topical Calcineurin Inhibitors

Post-Marketing Surveillance of Ischaemic Optic Neuropathy in Male Veterans Co-Prescribed Phosphodiesterase-5 Inhibitors with Organic Nitrates or α-Blockers

Frequency and Clinical Relevance of Drug Interactions with Lovastatin and Simvastatin

Improving the Detection of Subtle IKr-Inhibition

Use of Over-the-Counter Analgesics in Patients with Chronic Liver Disease

The Authors’ Reply