Skip to main content

Aprotinin

A Review of its Pharmacology and Therapeutic Efficacy in Reducing Blood Loss Associated with Cardiac Surgery

Drugs volume 49, pages 954–983 (1995)Cite this article

Summary

Synopsis

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) experience transient haemostatic defects as a result of adverse changes to their blood components, blood cells and specific coagulation proteins. Aprotinin is a naturally occurring serine protease inhibitor isolated from bovine lung tissue which inhibits kallikrein and plasmin. A high dose aprotinin regimen (aprotinin 280mg loading dose over 20 to 30 minutes after anaesthesia induction followed by 70 mg/h for the duration of the operation and 280mg added to the priming fluid of the CPB circuit) has been used during CPB in order to reduce perioperative bleeding.

Recent clinical trials confirm the efficacy of high dose aprotinin in reducing blood loss and transfusion requirements associated with primary cardiac procedures such as coronary artery bypass graft (CABG) or heart valve replacement surgery. High dose aprotinin is also effective in procedures known to possess a high risk for excessive blood loss, such as repeat CABG or heart valve replacement surgery, cardiac surgery in patients with infective endocarditis, or in patients receiving aspirin (acetylsalicylic acid) before surgery. Studies indicate that low dose aprotinin (280mg added to CPB pump prime fluid) is effective in reducing blood loss and transfusion requirements in patients undergoing primary CABG surgery. Additionally, low dose aprotinin regimens (both 280mg added to CPB pump prime fluid and 50% of the high dose regimen) have shown some benefit in repeat CABG surgery; however, more studies are needed to confirm these results.

Data from clinical trials indicate that aprotinin is well tolerated. The types and incidences of adverse events reported with aprotinin therapy are generally consistent with those associated with major cardiac surgery, and are not significantly different from those observed in control groups. A trend towards lower graft patency rates, detected by ultrafast computerised tomography (CT), has been observed in aprotinin recipients in 2 US trials. These differences did not reach statistical significance and should be interpreted with caution since the ability of ultrafast CT to determine graft patency has not been validated. Mildly elevated plasma creatinine levels are more commonly observed in aprotinintreated patients; these changes are transient in the majority of patients.

Both high dose and low dose aprotinin regimens (280mg added to CPB pump prime fluid or 50% of the high dose regimen) have reduced blood loss and transfusion requirements in patients undergoing primary and repeat cardiac surgery. The role of aprotinin in paediatric cardiac surgery needs further clarification, while well-designed studies comparing aprotinin with other agents which inhibit fibrinolysis are also awaited with interest. Preliminary pharmacoeconomic assessments of aprotinin appear favourable, and antigenic reactions occur in only a small proportion of patients. However, the achievement of a clear consensus regarding the routine use of aprotinin for primary cardiac surgery requires further clarification of these issues. Nonetheless, it is clear that high dose aprotinin should be considered a valuable adjunct to aggressive blood conservation programmes in patients undergoing cardiac surgery with the potential for excessive blood loss, in patients for whom transfusion is unavailable or in patients who refuse homologous transfusions.

Pharmacological Properties

Aprotinin is a serine protease inhibitor with effects on a number of biochemical systems. In patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), aprotinin has been shown to inhibit plasmin- and kallikrein-mediated fibrinolysis, as indicated by reductions in the formation of fibrin degradation products. In addition to effects on contact activation and fibrinolytic pathways, aprotinin is also thought to improve haemostasis during and after CPB by preserving the platelet membrane adhesive receptor (glycoprotein Ib).

Pharmacokinetic Properties

Following single dose intravenous administration of aprotinin 70 to 280mg to patients awaiting cardiac surgery or to female patients undergoing primary elective abdominal hysterectomy, mean maximum plasma concentrations (Cmax) ranged from 8.4 to 59.6 mg/L (60.0 to 425.7 KIU/ml). Linear pharmacokinetics over this dose range were observed. Following administration of high dose aprotinin (aprotinin 280mg loading dose after anaesthesia induction followed by 70 mg/h for the duration of the operation and 280mg added to the priming fluid of the CPB circuit), mean plasma drug concentrations ranged from 37 to 47 mg/L at the beginning of CPB and 26 to 27 mg/L at the end of CPB.

Aprotinin is rapidly distributed into the extracellular compartment after intravenous administration. Plasma drug concentrations decrease biphasically, with distribution and elimination half-lives of 0.32 to 0.50 hours and 5.25 to 8.28 hours for the 2 phases, respectively.

Animal studies have shown that aprotinin is primarily accumulated within the proximal tubular epithelial cells of the kidneys. After undergoing glomerular filtration, aprotinin is actively reabsorbed by the proximal tubules, stored in phagolysosomes and then gradually metabolised by lysosomal enzymes in the kidney. Approximately 25 to 40% of a single intravenous dose of 131I-labelled aprotinin was found in the urine of healthy volunteers within the first 48 hours. However, the total urinary excretion of unchanged drug is low (range 1.1 to 8.7%), but appears to increase slightly when the infused dose is increased.

Therapeutic Efficacy

The therapeutic efficacy of aprotinin in both high and low dose regimens (mostly 50% of the high dose regimen or 280mg added to the CPB pump prime fluid) has been evaluated in patients undergoing cardiac surgery with CPB. Patients in these trials underwent primary cardiac surgery [both with and without aspirin (acetylsalicylic acid) pretreatment] or repeat cardiac operations or were patients with active infective endocarditis (high dose aprotinin only). Compared with control patients, high dose aprotinin significantly reduced postoperative blood loss (range 35 to 81%) and homologous transfusion requirements (range 35 to 97%) and markedly increased the percentage of patients who did not require homologous transfusions (range 40 to 88%). Significant reductions in blood loss and transfusion requirements and increases in the number of patients who did not require homologous transfusions were also seen in patients treated with low dose aprotinin (280mg added to the CPB pump prime fluid) who underwent primary coronary artery bypass graft (CABG) surgery. Low dose aprotinin regimens (both 50% of the high dose regimen and 280mg added to the CPB pump prime fluid) also showed encouraging results in a recent study in patients who underwent repeat CABG surgery. Although there was no clear correlation between dosage and overall efficacy, the observed reductions in the haemostatic measures of clinical efficacy were less marked in the studies that used low dose aprotinin regimens compared with those that used high dose aprotinin, particularly in patients at high risk for excessive blood loss.

Tolerability

Aprotinin was generally well tolerated in clinical trials. Adverse events associated with aprotinin usage in 4 pooled double-blind placebo-controlled US studies were generally consistent with those associated with major cardiac surgery, and no significant differences were noted between aprotinin and placebo recipients.

Although no clear pattern of serious adverse events with high dose aprotinin has emerged in clinical trials to date, there are still concerns about increased risks of graft occlusion and hypersensitivity reactions. A trend towards lower graft patency rates detected by ultrafast computerised tomography (CT) in aprotinin recipients than in placebo recipients has been observed in a 2 US studies; however, these differences did not reach statistical significance. These results should be interpreted with caution because the ability of ultrafast CT to determine internal mammary artery graft patency has not been validated.

The reported incidence of anaphylactic reactions in patients from recent placebo-controlled US studies who received aprotinin was 0.3%. In 2 large European reviews, the incidence of mild hypersensitivity reactions (skin rash, hypotension and/or bronchospasm) ranged from 0.3 to 0.6% in patients who received mostly high dose aprotinin. These reactions are more likely to occur in patients who have received prior aprotinin treatment.

Plasma creatinine concentration elevations ≥44 μmol/L (0.5 mg/dl) above baseline were more common in the aprotinin-treated patients than in those who received placebo; however, the observed renal dysfunction was mild, reversible and clinically insignificant in the majority of patients.

Dosage and Administration

The high dose regimen used in recent clinical trials is a loading dose of aprotinin 280mg infused over 20 to 30 minutes after induction of anaesthesia but before sternotomy, followed by a continuous infusion of aprotinin 70 mg/h until the surgical procedure is completed and the patient is removed from the operating room. Before initiation of CPB, aprotinin 280mg is added to the priming fluid of the CPB circuit by replacement of an aliquot of the priming fluid. Because of the risk of serious allergic reactions, test doses of 1.4mg administered by intravenous injection or 1.4 to 7mg administered as part of the initial intravenous loading dose have been recommended. Although a variety of low dose aprotinin regimens have been evaluated, the 2 most commonly used regimens include aprotinin administered as 50% of the high dose regimen and a. single dose of aprotinin 280mg added to the priming fluid of the CPB circuit.

Aprotinin prolongs the results of coagulation assays which depend on contact activation, such as the activated partial thromboplastin time (APTT) and celite activated contact time (ACT). Consequently, in patients who are receiving aprotinin, the standard method for monitoring heparinisation during CPB, i.e. maintaining the celite ACT above 400 to 450 seconds, may not provide adequate anticoagulation. Although this issue remains unresolved, the current recommendation appears to be to maintain celite ACT values at >750 seconds during CPB, to administer heparin in a fixed-dose regimen based on patient weight or to utilise other monitoring tests (e.g. kaolin ACT or assays which measure plasma heparin concentrations) which are not affected by aprotinin.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Kraut E, Frey EK, Werle E. Über die Inaktivierung des Kallikreins. Hoppe-Seyler’s Zeitschrift für Physiologische Chemie 1930; 192: 1–21.

    CAS  Google Scholar 

  2. Kunitz M, Northrup JH. Isolation rom beef pancreas of crystalline trypsinogen, trypsin, a trypsin inhibitor, and an inhibitor trypsin compound. J Gen Physiol 1936; 19: 991–1007.

    PubMed  CAS  Google Scholar 

  3. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985; 29: 236–61.

    PubMed  CAS  Google Scholar 

  4. Royston D, Bidstrup BP, Taylor KM, et al. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987 Dec 5; 2: 1289–91.

    PubMed  CAS  Google Scholar 

  5. van Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on haemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 1987; 44: 640–5.

    PubMed  Google Scholar 

  6. Royston D. High-dose aprotinin therapy: a review of the first. five years’ experience. J Cardiothorac Vasc Anesth 1992 Feb; 6: 76–100.

    Google Scholar 

  7. Edmunds LH, Addonizio VP. Extracorporeal circulation. In: Colman RW, Hirsh J, Marder VJ, et al., editors. Hemostasis and thrombosis. Basic principles and clinical practice. Philadelphia: Lippencott, 1987: 901–912.

    Google Scholar 

  8. Bick RL. Hemostasis defects associated with cardiac surgery, prosthetic devices, and other extracorporeal circuits. Semin Thromb Hemost 1985; 11: 249–80.

    PubMed  CAS  Google Scholar 

  9. Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1990; 76: 1680–97.

    PubMed  CAS  Google Scholar 

  10. Kirklin JK, Westaby S, Blackstone JW, et al. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983; 86: 845–57.

    PubMed  CAS  Google Scholar 

  11. Westaby S. Complement and the damaging effects of cardiopulmonary bypass. Thorax 1983; 38: 321–5.

    PubMed  CAS  Google Scholar 

  12. Edmunds LH, Colman RW, Niewiarowski S. Blood-surface interactions during cardiopulmonary bypass. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 27–36.

    Google Scholar 

  13. Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992; 326: 800–6.

    PubMed  CAS  Google Scholar 

  14. Kluft C. Pathomechanisms of defective hemostasis during and after extracorporeal circulation: contact phase activation. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 10–15.

    Google Scholar 

  15. Bachmann F, McKenna R, Cole ER, et al. The hemostatic mechanism after open heart surgery. I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation. J Thorac Cardiovasc Surg 1975; 70: 76–85.

    PubMed  CAS  Google Scholar 

  16. Holloway DS, Summaria L, Sandesara J, et al. Decreased platelet number and function and increased fibrinolysis contribute to postoperative bleeding in cardiopulmonary bypass patients. Thromb Haemost 1988; 59: 62–7.

    PubMed  CAS  Google Scholar 

  17. Kucuk O, Kwaan HC, Frederickson J, et al. Increased fibrinolytic activity in patients undergoing cardiopulmonary bypass operation. Am J Hematol 1986; 23: 223–9.

    PubMed  CAS  Google Scholar 

  18. Stibbe J, Kluft C, Brommer EJP, et al. Enhanced fibrinolytic activity during cardiopulmonary bypass in open-heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator. Eur J Clin Invest 1984; 14: 375–82.

    PubMed  CAS  Google Scholar 

  19. Michelson AD. Pathomechanism of defective hemostasis during and after extrcorporeal circulation: The role of platelets. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 16–26.

    Google Scholar 

  20. Shattil SJ, Hoxie JA, Cunningham M, et al. Changes in the platelet membrane glycoprotein IIb-IIIa complex during platelet activation. J Biol Chem 1985; 260: 11107–14.

    PubMed  CAS  Google Scholar 

  21. Musial J, Niewiarowski S, Hershock D, et al. Loss of fibrinogen receptors from the platelet surface during simulated extracorporeal circulation. J Lab Clin Med 1985; 105: 514–22.

    PubMed  CAS  Google Scholar 

  22. Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med 1986; 314: 1446–8.

    PubMed  CAS  Google Scholar 

  23. 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: 364–72.

    Google Scholar 

  24. Alajmo F, Calamai G, Perna AM, et al. High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg 1989 Oct; 48: 536–9.

    Google Scholar 

  25. Biagini A, Comite C, Russo V, et al. High dose aprotinin to reduce blood loss in patients undergoing redo open heart surgery. Acta Anaesthesiol Belg 1992; 43: 181–6.

    PubMed  CAS  Google Scholar 

  26. Campbell FW, Jobes DR, Ellison N. Coagulation management during and after cariopulmonary bypass. In: Hensley FA, Martin DE, editors. The practice of cardiac anesthesia. Boston/Toronto/London: Little, Brown and Company, 1990: 546–579.

    Google Scholar 

  27. Orchard MA, Goodchild CS, Prentice CRM, et al. Aprotinin reduces cardiopulmonary bypass-induced blood loss and inhibits fibrinolysis without influencing platelets. Br J Haematol 1993; 85: 533–41.

    PubMed  CAS  Google Scholar 

  28. van den Dungen JJ, Karliczek GF, Brenken U, et al. Clinical study of blood trauma during perfusion with membrane and bubble oxygenators. J Thorac Cardiovasc Surg 1982; 83: 108–16.

    PubMed  Google Scholar 

  29. Masters RG. Bubble oxygenators are outdated and no longer appropriate for cardiopulmonary bypass. Pro: the superiority of the membrane oxygenator. J Cardiothor Anesth 1989; 3: 235–7.

    CAS  Google Scholar 

  30. Adelman B, Michelson AD, Greenberg J, et al. Proteolysis of platelet glycoprotein Ib by plasmin is facilitated by plasmin lysine-binding regions. Blood 1986; 68: 1280–4.

    PubMed  CAS  Google Scholar 

  31. Stricker RB, Wong D, Shiu DT, et al. Activation of plasminogen by tissue plasminogen activator on normal and thrombasthenic platelets: Effects on surface proteins and platelet aggregation. Blood 1986; 68: 275–80.

    PubMed  CAS  Google Scholar 

  32. Wenger RK, Lukasiewicz H, Mikuta BS, et al. Loss of platelet fibrinogen receptors during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989; 97: 235–9.

    PubMed  CAS  Google Scholar 

  33. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittel Forschung 1983; 33: 479–94.

    PubMed  CAS  Google Scholar 

  34. Lu H, Soria C, Commin P-L, et al. Hemostasis in patients undergoing extracorporeal circulation: The effect of aprotinin (Trasylol). Thromb Haemost 1991; 66: 633–7.

    PubMed  CAS  Google Scholar 

  35. Havel M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J Thorac Cardiovasc Surg 1991 Jun; 101: 968–72.

    Google Scholar 

  36. Vandenvelde C, Fondu P, Dubois-Primo J. Low-dose aprotinin for reduction of blood loss after cardiopulmonary bypass [letter]. Lancet 1991 May 11; 337: 1157–8.

    PubMed  CAS  Google Scholar 

  37. Marx G, Pokar H, Reuter H, et al. The effects of aprotinin on hemostatic function during cardiac surgery. J Cardiothorac Vasc Anesth 1991 Oct; 5: 467–74.

    Google Scholar 

  38. Kawasuji M, Ueyama K, Sakakibara N, et al. Effect of low-dose aprotinin on coagulation and fibrinolysis in cardiopulmonary bypass. Ann Thorac Surg 1993; 55: 1205–9.

    PubMed  CAS  Google Scholar 

  39. Longstaff C. Studies in the mechanisms of action of aprotinin and tranexamic acid as plasmin inhibitors and antifibrinolytic agents. Blood Coagul Fibrinolysis 1994; 5: 537–42.

    PubMed  CAS  Google Scholar 

  40. Feindt P, Volkmer I, Seyfert U, et al. Activated clotting time, anticoagulation, use of heparin, and thrombin activation during extracorporeal circulation: changes under aprotinin therapy. Thorac Cardiovasc Surg 1993 Feb; 41: 9–15.

    Google Scholar 

  41. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990 Dec; 73: 1119–26.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. Mohr R, Goor DA, Lusky A, et al. Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction. A scanning electron microscope study. Circulation 1992 Nov; 86 (5 Suppl): II405–9.

    PubMed  CAS  Google Scholar 

  44. Covino E, Pepino P, Iorio D, et al. Low dose aprotinin as blood saver in open heart surgery. Eur J Cardiothorac Surg 1991; 5: 414–8.

    PubMed  CAS  Google Scholar 

  45. Lavee J, Raviv Z, Smolinsky A, et al. Platelet protection by low-dose aprotinin in cardiopulmonary bypass: electron microscopic study. Ann Thorac Surg 1993 Jan; 55: 114–9.

    Google Scholar 

  46. Liu B, Belboul A, Rådberg G, et al. Effect of reduced aprotinin dosage on blood loss and use of blood products in patients undergoing cardiopulmonary bypass. Scand J Thorac Cardiovasc Surg 1993; 27: 149–55.

    PubMed  CAS  Google Scholar 

  47. van Oeveren W, Harder MP, Roozendaal KJ, et al. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 99: 788–97.

    PubMed  Google Scholar 

  48. Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor blood transfusion in patients undergoing repeat coronary artery bypass grafting. Miles data on file.

  49. Spannagl M, Dietrich W, Beck A, et al. High dose aprotinin reduces prothrombin and fibrinogen conversion in patients undergoing extracorporeal circulation for myocardial infarction [letter]. Thromb Haemost 1994; 72: 159–60.

    PubMed  CAS  Google Scholar 

  50. Nagaoka H, Innami R, Murayama F, et al. Effects of aprotinin on prostaglandin metabolism and platelet function in open heart surgery. J Cardiovasc Surg Torino 1991 Jan-Feb; 32: 31–7.

    Google Scholar 

  51. John LCH, Rees GM, Kovacs IB. Reduction of heparin binding to and inhibition of platelets by aprotinin. Ann Thorac Surg 1993 May; 55: 1175–9.

    Google Scholar 

  52. Kestin AS, Valeri R, Shukri KF, et al. The platelet function defect of cardiopulmonary bypass. Blood 1993; 82: 107–17.

    PubMed  CAS  Google Scholar 

  53. Cramer EM, Lu H, Caen JP, et al. Differential redistribution of platelet glycoproteins Ib and IIb-IIIa after plasmin stimulation. Blood 1991; 77: 694–9.

    PubMed  CAS  Google Scholar 

  54. Wachtfogel YT, Kucich U, Hack CE, et al. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993 Jul; 106: 1–10.

    Google Scholar 

  55. Fraedrich G, Neukamm K, Schneider T, et al. Safety and risk/benefit assessment of aprotinin in primary CABG. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 221–231.

    Google Scholar 

  56. Blauhut B, Gross C, Necek S, et al. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 101: 958–67.

    PubMed  CAS  Google Scholar 

  57. Kaller H, Patzschke K, Wegner LA, et al. Pharmacokinetic observations following intravenous administration of radioactive labelled aprotinin in volunteers. Eur J Drug Metab 1978; 2: 79–85.

    Google Scholar 

  58. Levy JH, Bailey JM, Salmenperä M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994; 80: 1013–8.

    PubMed  CAS  Google Scholar 

  59. Schall R, Groenewoud G, Hundt HKL, et al. Pharmacokinetic profile of aprotinin (Trasylol) in female patients undergoing primary elective hysterectomy. Drug Invest 1992; 4 (4): 292–9.

    CAS  Google Scholar 

  60. Schall R, Müller FO, Hundt HKL, et al. Pharmacokinetic profile of high doses of aprotinin in patients undergoing primary elective hysterectomy: a meta-analysis of two clinical trials. Drug Invest 1994 Apr; 7: 200–8.

    Google Scholar 

  61. Miles. Aprotinin prescribing information. West Haven, Connecticut, USA, 1994.

  62. Jochum M, Jonáková V, Dittmer H, et al. An enzymatic assay convenient for the control of aprotinin levels during proteinase inhibitor therapy. Fresenius Z Anal Chem 1984; 317: 719–20.

    CAS  Google Scholar 

  63. Müller-Esterl W. Drugs monitored during therapy: Aprotinin, drugs and pesticides. In: Bergmeyer HU, editor. Methods of enzymatic analysis. Weinheim: VerlagsgesellschaftmbH, 1986: 246–256.

    Google Scholar 

  64. Trautschold I, Werle E, Zickgraf-Rüdel G. Trasylol. Biochem Pharmacol 1967; 16: 59–72.

    CAS  Google Scholar 

  65. Emerson TE. Pharmacology of aprotinin and efficacy during cardiopulmonary bypass. Cardiovasc Drug Rev 1989; 7: 127–40.

    Google Scholar 

  66. Clasen C, Jochum M, Mueller-Esterl W. Feasability study of very high dose aprotinin in polytrauma patients. In: Schlag G, Redl H, editors. First Vienna Shock Forum:pathophysiological role of mediators and mediator inhibitors in shock. New York: Liss, 1987: 175–183.

    Google Scholar 

  67. Lemmer JH, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: Efficacy, safety, and influence on early saphenous vein graft patency. J Thorac Cardiovasc Surg 1994; 107: 543–53.

    PubMed  Google Scholar 

  68. Baele PL, Ruiz-Gomez J, Londot C, et al. Systematic use of aprotinin in cardiac surgery: influence on total homologous exposure and hospital cost. Acta Anaesthesiol Belg 1992; 43: 103–12.

    PubMed  CAS  Google Scholar 

  69. Bidstrup BP, Underwood SR, Sapsford RN, et al. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993 Jan; 105: 147–52.

    Google Scholar 

  70. Dietrich W, Barankay A, Hähnel C, et al. High-dose aprotinin in cardiac surgery: three years’ experience in 1,784 patients. J Cardiothorac Vasc Anesth 1992 Jun; 6: 324–7.

    Google Scholar 

  71. Harder MP, Eijsman L, Roozendaal KJ, et al. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg 1991 Jun; 51: 936–41.

    Google Scholar 

  72. Swart MJ, Gordon PC, Hayse-Gregson PB, et al. High-dose aprotinin in cardiac surgery-a prospective, randomized study. Anaesth Intensive Care 1994; 22: 529–33.

    PubMed  CAS  Google Scholar 

  73. Lytle BW, Loop FD, Cosgrove DM, et al. Fifteen hundred coronary reoperations: results and determinants of early and late survival. J Thorac Cardiovasc Surg 1987; 93: 847–59.

    PubMed  CAS  Google Scholar 

  74. Chesebro JH, Clements IP, Fuster V, et al. A platelet-inhibitor drug trial in coronary artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency. N Engl J Med 1982; 307: 73–8.

    PubMed  CAS  Google Scholar 

  75. Ferraris VA, Ferraris SP, Lough FC, et al. Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting. Ann Thorac Surg 1988; 45: 71–4.

    PubMed  CAS  Google Scholar 

  76. Sethi GK, Copeland JG, Goldman S, et al. Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 1990; 15: 15–20.

    PubMed  CAS  Google Scholar 

  77. Bashein G, Nessly ML, Rice AL, et al. Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery. Arch Intern Med 1991; 151: 89–93.

    PubMed  CAS  Google Scholar 

  78. Bidstrup BP, Royston D, McGuinness C, et al. Aprotinin in aspirin-pretreated patients. Perfusion 1990; 5 Suppl.: 77–81.

    Google Scholar 

  79. Liu B, Belboul A, al-Khaja N, et al. High-dose aprotinin (Trasylol) in reducing bleeding and protecting lung function in potential bleeders undergoing cardiopulmonary bypass. Chin Med J Engl 1991; 104: 980–5.

    PubMed  CAS  Google Scholar 

  80. Murkin JM, Lux J, Shannon NA, et al. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994; 107: 554–61.

    PubMed  CAS  Google Scholar 

  81. Bertrand P, Mazzucotelli JP, Loisance D, et al. L’aprotinine en chirurgie cardiaque chez les patients sous antiagrégants plaquettaires. Arch Mal Coeur Vaiss 1993; 86: 1471–4.

    PubMed  CAS  Google Scholar 

  82. Schönberger JP, Bredee JJ, van Oeveren W, et al. Preoperative therapy of low-dose aspirin in internal mammary artery bypass operations with and without low-dose aprotinin. J Thorac Cardiovasc Surg 1993; 106: 262–7.

    PubMed  Google Scholar 

  83. Tabuchi N, van Oeveren W, Eijsman L, et al. Preserved hemostasis during the combined use of aprotinin and aspirin in CABG operations. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 245–251.

    Google Scholar 

  84. CosgroveIII DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992 Dec; 54: 1031–8.

    Google Scholar 

  85. Havel M, Grabenwöger F, Schneider J, et al. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994; 107: 807–10.

    PubMed  CAS  Google Scholar 

  86. Schönberger JP, Everts PA, Ercan H, et al. Low-dose aprotinin in internal mammary artery bypass operations contributes to important blood saving. Ann Thorac Surg 1992; 54: 1172–6.

    PubMed  Google Scholar 

  87. Schönberger JP, van Zundert A, Bredée JJ, et al. Blood loss and use of blood in internal mammary artery and saphenous vein bypass grafting with and without adding a single, low-dose of aprotinin (2 million units) to the pump prime. Acta Anaesthesiol Belg 1992; 43: 187–96.

    PubMed  Google Scholar 

  88. Lytle BW, Cosgrove DM, Loop FD, et al. Perioperative risk of bilateral internal mammary artery grafting: analysis of 500 cases from 1971 to 1984. Circulation 1986; 74 Suppl. 3: 37–41.

    Google Scholar 

  89. Henze A, Ramström J, Nyström SO. Bilateral internal mammary artery for coronary revascularization. Early experience of 100 cases. Scand J Thorac Cardiovasc Surg 1989; 23: 9–12.

    PubMed  CAS  Google Scholar 

  90. Hardy J-F, Desroches J, Belisle S, et al. Low-dose aprotinin infusion is not clinically useful to reduce bleeding and transfusion of homologous blood products in high-risk cardiac surgical patients. Can J Anaesth 1993; 40: 625–31.

    PubMed  CAS  Google Scholar 

  91. o’Regan DJ, Giannopoulos N, Mediratta N, et al. Topical aprotinin in cardiac operations. Ann Thorac Surg 1994; 58: 778–81.

    PubMed  Google Scholar 

  92. Scott DHT, Au J. The Edinburgh experience-low-dose Trasylol. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 263–265.

    Google Scholar 

  93. Tatar H, Cicek S, Demirkilic U, et al. Topical use of aprotinin in open heart operations. Ann Thorac Surg 1993 Mar; 55: 659–61.

    Google Scholar 

  94. Popov-Cenic S, Urban AE, Noë G. Studies on the cause of bleeding during and after surgery with heart-lung machine in children with cyanotic and acyanotic congenital cardiac defects and their prophylactic treatment. In: McConn R, editor. Role of chemical mediators in the pathophysiology of acute illness and injury. New York: Raven, 1982: 229–42.

    Google Scholar 

  95. Boldt J, Knothe C, Zickmann B, et al. Aprotinin in pediatric cardiac operations: platelet function, blood loss, and use of homologous blood. Ann Thorac Surg 1993 Jun; 55: 1460–6.

    Google Scholar 

  96. Boldt J, Knothe C, Zickmann B, et al. Comparison of two aprotinin dosage regimens in pediatric patients having cardiac operations. Influence on platelet function and blood loss. J Thorac Cardiovasc Surg 1993 Apr; 105: 705–11.

    Google Scholar 

  97. Dietrich W, Mossinger H, Spannagl M, et al. Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations. J Thorac Cardiovasc Surg 1993 Apr; 105: 712–20.

    Google Scholar 

  98. Herynkopf F, Lucchese F, Pereira E, et al. Aprotinin in children undergoing correction of congenital heart defects. J Thorac Cardiovasc Surg 1994; 108: 517–21.

    PubMed  CAS  Google Scholar 

  99. Müller H, Alken A, Ziemer G, et al. Aprotinin in paediatric cardiopulmonary bypass surgery. J Cardiothor Anesth 1992; 6.

  100. Bidstrup BP, Harrison J, Royston D, et al. Aprotinin therapy in cardiac operations: a report on use in 41 cardiac centers in the United Kingdom. Ann Thorac Surg 1993 Apr; 55: 971–6.

    Google Scholar 

  101. Laub GW, Riebman JB, Chen C, et al. The impact of aprotinin on coronary artery bypass graft patency. Chest 1994; 106: 1370–5.

    PubMed  CAS  Google Scholar 

  102. Jegaden O, Vedrinne C, Rossi R. Aprotinin does not compromise arterial graft patency in coronary bypass operations [letter]. J Thorac Cardiovasc Surg 1993 Jul; 106: 180–1.

    Google Scholar 

  103. Lemmer Jr. JH, Stanford W, Bonney SL, et al. Aprotinin for coronary artery bypasss grafting: effect on postoperative renal function. Ann Thorac Surg 1995; 59: 132–6.

    PubMed  Google Scholar 

  104. Sundt TM 3d, Kouchoukos NT, Saffitz JE, et al. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993 Jun; 55: 1418–24.

    Google Scholar 

  105. Smith CR, Mongero LB, DeRosa CM, et al. Safety of aprotinin in profound hypothermia and circulatory arrest. Ann Thorac Surg 1994; 58: 606–7.

    PubMed  CAS  Google Scholar 

  106. Levy JH. Antibody formation after drug administration during cardiac surgery: parameters for aprotinin use. J Heart Lung Transplant 1993 Jan-Feb; 12 (1 Pt 1): S26–33.

    PubMed  CAS  Google Scholar 

  107. Ruskowski H, Joos A, Kiefer H, et al. Untersuchungen zur antigenität von Trasylol in der offenen herzchirurgie. Thorac Cardiovasc Surg 1993; 41 Suppl. 1: 142.

    Google Scholar 

  108. Beckmann H, Mayer G. Allergic/anaphylactic reaction in patients with cardiac reoperation and Trasylol re-exposition-retrospective analysis in 2 cardiosurgical units-statistical report. Bayer data on file. 1994.

  109. Schulze K, Graeter T, Schaps D, et al. Severe anaphylactic shock due to repeated application of aprotinin in patients following intrathoracic aortic replacement. Eur J Cardiothorac Surg 1993; 7: 495–6.

    PubMed  CAS  Google Scholar 

  110. Lorenz W, Duda D, Dick W, et al. Incidence and clinical importance of perioperative histamine release: randomised study of volume loading and antihistamines after induction of anaesthesia. Lancet 1994; 343: 933–40.

    PubMed  CAS  Google Scholar 

  111. Overlack A, Stumpe KO, Küehnert M, et al. Evidence for participation of kinins in the antihypertensive effect of converting enzyme inhibition. Klin Wochenschr 1981; 59: 69–74.

    PubMed  CAS  Google Scholar 

  112. Clozel J-P, Banken L, Roux S. Aprotinin: an antidote for recombinant tissue-type plasminogen activator (rt-PA) active in vivo. J Am Coll Cardiol 1990; 16: 507–10.

    PubMed  CAS  Google Scholar 

  113. Fears R, Greenwood H, Hearn J, et al. Inhibition of the fibrinolytic and fibrinogenolytic activity of plasminogen activators in vitro by the antidotes -aminocaproic acid, tranexamic acid and aprotinin. Fibrinolysis 1992 Apr; 6: 79–86.

    Google Scholar 

  114. Hunt BJ, Segal H, Yacoub M. Aprotinin and heparin monitoring during cardiopulmonary bypass. Circulation 1992; 86 Suppl. 2: II410–2.

    PubMed  CAS  Google Scholar 

  115. Najman DM, Walenga JM, Fareed J, et al. Effects of aprotinin on anticoagulant monitoring: implications in cardiovascular surgery. Ann Thorac Surg 1993 Mar; 55: 662–6.

    Google Scholar 

  116. Wendel HP, Heller W, Gallimore MJ, et al. The prolonged activated clotting time (ACT) with aprotinin depends on the type of activator used for measurement. Blood Coagul Fibrinolysis 1993 Feb; 4: 41–5.

    Google Scholar 

  117. Wang J-S, Lin C-Y, Hung W-T, et al. Monitoring of heparin-induced anticoagulation with kaolin-activated clotting time in cardiac surgical patients treated with aprotinin. Anesthesiology 1992 Dec; 77: 1080–4.

    Google Scholar 

  118. Royston D, Bidstrup BP, Taylor KM, et al. Reduced blood loss following open heart surgery with aprotinin (Trasylol) is associated with an increase in intraoperative activated clotting time (ACT). J Cardiothorac Anesth 1989 Oct; 3 (5 Suppl 1): 80.

    PubMed  CAS  Google Scholar 

  119. de Smet AA, Joen MC, van Oeveren W, et al. Increased anticoagulation during cardiopulmonary bypass by aprotinin. J Thorac Cardiovasc Surg 1990 Oct; 100: 520–7.

    Google Scholar 

  120. Farooqi N, De Hert S, Vlaeminck A, et al. Effects of low doses of aprotinin on clotting times activated with celite and kaolin. Acta Anaesth Belg 1993; 44: 87–92.

    PubMed  CAS  Google Scholar 

  121. Marggraf G, Schax H, Trübenbach H, et al. Evolutin of requirements to replace blood and plasma in cardiac surgery. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 78–83.

    Google Scholar 

  122. Bhattacharya SK, Sharma GP, Polimeni PI, et al. Intraoperative blood conservation using cell-saver. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 178–18.

    Google Scholar 

  123. von der Emde J, Mahmoud FO, Esperer HD. Retransfusion of postoperative drainage blood. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 129–132.

    Google Scholar 

  124. Sons H, Schulte HD, Bircks W. Preoperative autologous blood donation to minimize homologous blood transfusions. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 160–163.

    Google Scholar 

  125. Donauer E, Babik B, Mészáros E, et al. Use of predonated autologous blood in cardiac surgery. In: Friedel N, Hetzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1991: 164–170.

    Google Scholar 

  126. Daily PO, Lamphere JA, Dembitsky WP, et al. Effect of prophylactic epsilon-aminocaproic acid on blood loss and transfusion requirements in patients undergoing first-time coronary artery bypass grafting. Arandomized, prospective, double-blind study. J Thorac Cardiovasc Surg 1994; 108: 99–108.

    PubMed  CAS  Google Scholar 

  127. Horrow JC, Hlavacek J, Strong MD, et al. Prophylactic tranexamic acid decreases bleeding after cardiac operations. J Thorac Cardiovasc Surg 1990; 99: 70–4.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  129. Vander Salm TJ, Ansell JE, Okike ON, et al. The role of epsilon-aminocaproic acid in reducing bleeding after cardiac operation: a double blind randomised study. J Thorac Cardiovasc Surg 1988; 95: 538–40.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  131. Hardy JF, Desroches J. Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anaesth 1992 Apr; 39: 353–65.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Rick Davis & Ruth Whittington

Authors
  1. Rick Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruth Whittington
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Various sections of the manuscript reviewed by: P.L. Baele, Department of Anesthesiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; C.R. Bailey, Department of Anaesthetics, Guy’s Hospital, London, England; B.P. Bidstrup, Director of Cardiothoracic Surgery, North Queensland Clinical School, University of Queensland, Townsville, Queensland, Australia; W. Dietrich, German Heart Center Munich, Institute for Anesthesiology, Munich, Germany; L.H. Edmunds, Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA; M. Kawasuji, Department of Surgery, Kanazawa University School of Medicine, Kanazawa, Japan; J.H. Lemmer, Cardiothoracic Surgeon, Northwest Surgical Associates, Good Samaritan Hospital, Portland, Oregon, USA; J.H. Levy, Associate Professor of Anesthesiology, Division of Cardiothoracic Anesthesiology and Critical Care, Emory University School of Medicine, Atlanta, Georgia/USA; B. Liu, Department of Thoracic and Cardiovascular Surgery, University of Göteborg, Göteborg, Sweden; A.D. Michelson, Department of Pediatrics and Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA; J.M. Murkin, Department of Anaesthesia, University Hospital, University of Western Ontario, London, Ontario, Canada; D. Roberts, Department of Thoracic and Cardiovascular Surgery, University of Göteborg, Göteborg, Sweden; K.M. Taylor, Cardiothoracic Surgery Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, England; J.P.A.M. Schönberger, Department of Cardiopulmonary Surgery, Catharina Hospital, Eindhoven, The Netherlands; D.S. Watermeyer, Staff Anesthesiologist, St. Joseph Medical Center, Tacoma, Washington, USA.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Davis, R., Whittington, R. Aprotinin. Drugs 49, 954–983 (1995). https://doi.org/10.2165/00003495-199549060-00008

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199549060-00008

Keywords

  • Aprotinin
  • Transfusion Requirement
  • Graft Patency
  • High Dose Regimen
  • Postoperative Blood Loss