Aprotinin: 1 Year on

Current Opinion in Anaesthesiology

Volumn 22, Issue 1, 2009, Pages 121-127

  Dietrich, Wulf ^a  

^a UNIVERSITY OF MUNICH   (Germany)

Author keywords

Aprotinin; Blood loss; Dialysis; Hypersensitivity; Renal; Safety; Side effect; Transfusion

Indexed keywords

AMINOCAPROIC ACID; APROTININ; TRANEXAMIC ACID;

BLOOD TRANSFUSION; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CORONARY ARTERY BYPASS GRAFT; DRUG APPROVAL; DRUG EFFICACY; DRUG EXCRETION; DRUG MEGADOSE; DRUG SAFETY; HIGH RISK PATIENT; HUMAN; KIDNEY DISEASE; KIDNEY FAILURE; LOW DRUG DOSE; META ANALYSIS; MORTALITY; POSTOPERATIVE HEMORRHAGE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REVIEW; SIDE EFFECT; SYSTEMATIC REVIEW;

ANTIFIBRINOLYTIC AGENTS; APROTININ; BLOOD LOSS, SURGICAL; CARDIAC SURGICAL PROCEDURES; HEMOSTATICS; HUMANS; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 62249196771     PISSN: 09527907     EISSN: None     Source Type: Journal    
DOI: 10.1097/ACO.0b013e32831c833f     Document Type: Review

References (57)

1. Kraut E, Frey EK, Werte E. About the inactivation of Kallikrein [in German], Hoppe-Seyler Zeitschr. Physiol Chem 1930; 192:1-21.
2. Kunitz M, Nrothrop JH. Isolation from beef pancreas of crystalline trypsinogen, trypsin, a trypsin inhibitor and an inhibitor trypsin compound. J Gen Physiol 1936; 19:991-1007.
3. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung 1983; 33:479-494.
4. Dietrich W. Reducing thrombin formation during cardiopulmonary bypass: is there a benefit of the additional anticoagulant action of aprotinin? J Cardiovasc Pharmacol 1996; 27:S50-S57.
5. Landis RC, Haskard DO, Taylor KM. New antiinflammatory and plateletpreserving effects of aprotinin. Ann Thorac Surg 2001; 72:S1808-S1813.
6. Royston D. High-dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vase Anesth 1992; 6:76-100.
7. Royston D, Taylor KM, Bidstrup BP, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; ii:1289-1291.
8. Fergusson D, Glass KC, Mutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clin Trials 2005; 2:218-229.
9. 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.
10. Henry DA, Carless P, Moxey A, et al. Antifibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007:CD001886. The latest Cochrane report about antifibrinolytics with no sign of severe side effects from aprotinin in the literature.
11. Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization - a placebo-controlled study. Ann Thorac Surg 1992; 54:1031-1038.
12. Sundt TM, Kouchoukos NT, Saffitz JE, et al. Renal dysfunction and intravascular coagulation with aprotinin and hypothermie circulatory arrest. Ann Thorac Surg 1993; 55:1418-1424.
13. Dietrich W, Spath P, Ebell A, Richter JA. Prevalence of anaphylactic reactions to aprotinin: analysis of two hundred forty-eight reexposures to aprotinin in heart operations. J Thorac Cardiovasc Surg 1997; 113:194-201.
14. Westaby S. Aprotinin: twenty-five years of claim and counterclaim [editorial]. J Thorac Cardiovasc Surg 2008; 135:487-491. This editorial is the summary of an investigator who followed the use of aprotinin in cardiac surgery over the past 25 years.
15. Horl WH. Aprotinin and renal function in patients undergoing cardiac surgery. Br J Anaesth 2000; 84:3-5.
16. DAmbra MN, Akins CW, Blackstone EH, et al. Aprotinin in primary valve replacement and reconstruction: a multicenter, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 1996; 112:1081-1089.
17. 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; 101:958-967.
18. Lemmer JH, Stanford W, Bonney SL, et al. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg 1995; 59:132-136.
19. Henry DA, Moxey AJ, Carless PA, et al. Antifibrinolytic use for minimising perioperative allogeneic blood transfusion (Cochrane Review). The Cochrane Library 2003:CD001886.
20. Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007; 115:2801-2813. The latest metaanalysis on the use of aprotinin in cardiac surgery. There were signals that aprotinin is associated with higher renal impairment but not with a higher incidence of renal insufficiency.
21. Dietrich W, Späth P, Zühlsdorf M, et al. Anaphylactic reactions to aprotinin reexposure in cardiac surgery - relation to antiaprotinin immunoglobulin G and E antibodies. Anesthesiology 2001; 95:64-71.
22. Dietrich W, Ebell A, Busley R, Boulesteix AL. Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery. Ann Thorac Surg 2007; 84:1144-1150.
23. 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 2006; 46:327-338.
24. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354:353-365.
25. Kulier AMD, Levin JMD, Moser RMD, et al. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation 2007; 116:471-479. An analysis of the same dataset that was used by Mangano et al. This analysis demonstrated a close association of blood transfusion and adverse outcome.
26. Royston D, van Haaften N, De Vooght P. Aprotinin; friend or foe? A review of recent medical literature. Eur J Anaesthesiol 2007; 24:6-14. A detailed analysis of the first Mangano study with an in-depth criticism of the applied statistical methods.
27. 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.
28. Brown JR, Birkmeyer NJ, O'Connor GT. Aprotinin in cardiac surgery [letter to the editor]. N Engl J Med 2006; 354:1953-1957.
29. D'Ambra MN. Aprotinin in cardiac surgery [letter to the editor]. N Engl J Med 2006; 354:1953-1957.
30. Ferraris VA, Bridges CR, Anderson RP. Aprotinin in cardiac surgery [letter to the editor]. N Engl J Med 2006; 354:1953-1957.
31. Levy JH, Ramsay JG, Guyton RA. Aprotinin in cardiac surgery [letter to the editor], N Engl J Med 2006; 354:1953-1957.
32. Sedrakyan A, Atkins D, Treasure T. The risk of aprotinin: a conflict of evidence [letter to the editor]. Lancet 2006; 367:1376-1377.
33. Shaw AD, Stafford-Smith M, White WD, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008; 358:784-793. This study is an analysis of a single-center database. Out of 10 000 patients, 1300 received aprotinin between 1996 and 2005. In a risk-adjusted model, survival was worse in aprotinin-treated patients, and the incidence of renal impairment and failure was also higher; however, aprotinin was used in highly selected high-risk patients and, thus, a selection bias cannot be excluded. 34 Koch CG, Li L, Duncan Al, et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronaty artery bypass grafting. Crit Care Med 2006; 34:1608-1616.
34. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of apratinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358:2319-2331. This is the analysis and interpretation of the results of the BART study. This study finally turned the balance against aprotinin. To understand the data, the reader should also refer to the appendix of the manuscript.
35. Bittner HB, Lemke J, Lange M, et al. The impact of aprotinin on blood loss and blood transfusion in off-pump coronary artery bypass grafting. Ann Thorac Surg 2008; 85:1662-1668. It was showed that aprotinin was effective in off-pump cardiac surgery without adverse side effects.
36. Dietrich W, Busley R, Boulesteix AL. Effects of aprotinin dosage on renal function: an analysis of 8,548 cardiac surgical patients treated with different dosages of aprotinin. Anesthesiology 2008; 108:189-198. This retrospective study investigated the influence of aprotinin dosage on renal function and could not find a detrimental effect of higher dosages on renal function, if the dosage was adjusted for body weight and length of operation. In contrast, higher dosages were more effective in reducing bleeding tendency.
37. Kluth M, Lueth JU, Zittermann A, et al. Safety of low-dose aprotinin in coronary artery bypass graft surgery: a single-centre investigation in 2,436 patients in Germany. Drug Saf 2008; 31:617-626.
38. Lindvall G, Sartipy U, Ivert T, van der Linden J. Aprotinin is not associated with postoperative renal impairment after primary coronary surgery. Ann Thorac Surg 2008; 86:13-19. This study is a matched cohort study without association between aprotinin and impaired renal function in comparison with tranexamic acid.
39. Mouton R, Finch D, Davies I, et al. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 2008; 371:475-482. A retrospective study of more than 9000 patients analyzes the incidence of renal dysfunction in patients receiving aprotinin, tranexamic acid or no antifibrinolytic treatment in the presence or absence of preoperative angiotensin-converting enzyme (ACE) inhibitor treatment. Aprotinin was not associated with renal dysfunction in patients without ACE inhibitor treatment. However, in patients with off-pump surgery and ACE inhibitor treatment, the risk was significantly higher with aprotinin treatment.
40. Olenchock SA Jr, Lee PH, Yehoshua T, et al. Impact of aprotinin on adverse clinical outcomes and mortality up to 12 years in a registry of 3,337 patients. Ann Thorac Surg 2008; 86:560-566. It was shown that, in more than 3000 patients, aprotinin treatment was associated with greater renal impairment.
41. Pagano D, Howell NJ, Freemantle N, et al. Bleeding in cardiac surgery: the use of aprotinin does not affect survival. J Thorac Cardiovasc Surg 2008; 135:495-502. A retrospective study of almost 8000 patients, 44% treated with aprotinin. Aprotinin was effective in risk reduction for reoperation for bleeding and need for blood transfusion, whereas there was no detrimental effect on renal function.
42. Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary artery bypass grafting and risk of death. N Engl J Med 2008; 358:771 -783. An analysis of an administrative database with no clinical data. The reader can find all the strengths and weaknesses of the analysis of administrative databases.
43. Van der Linden PJ, Hardy JF, Daper A, et al. Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome? Br J Anaesth 2007; 99:646-652.
44. Furnary AP, Wu Y, Hiratzka LF, et al. Aprotinin does not increase the risk of renal failure in cardiac surgery patients. Circulation 2007; 116:1127-1133. A multicenter analysis of 11 000 cardiac surgical patients. Adverse outcome was associated with the amount of blood transfusion but not with the use of aprotinin.
45. Braitman LE, Rosenbaum PR. Rare outcomes, common treatments: analytic strategies using propensity scores. Ann Intern Med 2002; 137:693-695.
46. Austin PC. Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement. J Thorac Cardiovasc Surg 2007; 134:1128-1135.
47. Ott E, Mazer CD, Tudor IC, et al. Coronary artery bypass graft surgery-care globalization: the impact of national care on fatal and nonfatal outcome. J Thorac Cardiovasc Surg 2007; 133:1242-1251.
48. Romano PS, Schembri ME, Rainwater JA. Can administrative data be used to ascertain clinically significant postoperative complications? Am J Med Qual 2002; 17:145-154.
49. Bridges CR. Valid comparisons of antifibrinolytic agents used in cardiac surgery. Circulation 2007; 115:2790-2792.
50. Hausenloy DJ, Pagano D, Keogh B. Aprotinin - still courting controversy. Lancet 2008; 371:449-450. An editorial reviewing the aprotinin discussion with a critical appraisal of the withdrawal of aprotinin.
51. Karkouti K, Seattle WS. Letter by Karkouti and Seattle regarding article 'Aprotinin does not increase the risk of renal failure in cardiac surgery patients'. Circulation 2008; 117:472.
52. Landis RC, Taylor KM, Poston RS. Letter by Landis et al. regarding article 'Aprotinin does not increase the risk of renal failure in cardiac surgery patients'. Circulation 2008; 117:e473.
53. Ray WA. Learning from aprotinin - mandatory trials of comparative efficacy and safety needed. N Engl J Med 2008; 358:840-842. An editorial that reinforces the requirement of independent phase 4 safety studies.
54. Ray WA, Stein CM. The aprotinin story - is BART the final chapter? N Engl J Med 2008; 358:2398-2400. The editorial accompanying the publication of the BART results.
55. Sundt TM. The demise of aprotinin: our share of the blame. J Thorac Cardiovasc Surg 2008; 135:729-731. An editorial and summary of an early investigator of aprotinin.
56. Vlahakes GJ. The value of phase 4 clinical testing. N Engl J Med 2006; 354:413-415.
57. Murugesan C, Banakal SK, Garg R, et al. The efficacy of aprotinin in arterial switch operations in infants. Anesth Analg 2008; 107:783-787.