Drug Safety

, Volume 30, Issue 9, pp 731–740 | Cite as

Is There Still a Role for Aprotinin in Cardiac Surgery?

  • Neel R. Sodha
  • Munir Boodhwani
  • Frank W. Sellke
Current Opinion

Abstract

Cardiac surgery is associated with a systemic inflammatory response and systemic coagulopathy, which can result in significant organ dysfunction and bleeding. Aprotinin, a serine protease inhibitor, can limit systemic inflammation, and has been associated with myocardial, pulmonary and cerebral protection in addition to its proven haemostatic efficacy. Data are currently conflicting regarding the haemostatic efficacy of aprotinin relative to alternative agents including tranexamic acid. Recent studies have demonstrated aprotinin usage is associated with increased rates of thrombotic and renal complications, but these findings are at odds with the majority of studies relating to aprotinin safety to date. The lack of adequately powered, randomised studies evaluating aprotinin and alternative agents limits drawing conclusions about the complete use or disuse of aprotinin presently and requires individualised patient selection based on bleeding risk and co-morbidities for its usage.

References

  1. 1.
    Ramlawi B, Feng J, Mieno S, et al. Indices of apoptosis activation after blood cardioplegia and cardiopulmonary bypass. Circulation 2006; 114 (1 Suppl.): I257–63PubMedCrossRefGoogle Scholar
  2. 2.
    Saldanha C, Hearse DJ. Cardioplegia and vascular injury: dissociation of the effects of ischemia from those of the cardioplegic solution. J Thorac Cardiovasc Surg 1994; 108: 279–90PubMedGoogle Scholar
  3. 3.
    Anselmi A, Abbate A, Girola F, et al. Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence. Eur J Cardiothorac Surg 2004; 25: 304–11PubMedCrossRefGoogle Scholar
  4. 4.
    Biglioli P, Cannata A, Alamanni F, et al. Biological effects of off-pump vs. on-pump coronary artery surgery: focus on inflammation, hemostasis and oxidative stress. Eur J Cardiothorac Surg 2003; 24: 260–9PubMedCrossRefGoogle Scholar
  5. 5.
    de Vroege R, te Meerman F, Eijsman L, et al. Induction and detection of disturbed homeostasis in cardiopulmonary bypass. Perfusion 2004; 19: 267–76PubMedCrossRefGoogle Scholar
  6. 6.
    Pintar T, Collard CD. The systemic inflammatory response to cardiopulmonary bypass. Anesthesiol Clin North America 2003; 21: 453–64PubMedCrossRefGoogle Scholar
  7. 7.
    Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg 2001; 71: 745–54PubMedCrossRefGoogle Scholar
  8. 8.
    Gomes WJ, Erlichman MR, Batista-Filho ML, et al. Vasoplegic syndrome after off-pump coronary artery bypass surgery. Eur J Cardiothorac Surg 2003; 23: 165–9PubMedCrossRefGoogle Scholar
  9. 9.
    Hazama S, Eishi K, Yamachika S, et al. Inflammatory response after coronary revascularization: off-pump versus on-pump (heparin-coated circuits and poly2methoxyethylacrylate-coated circuits). Ann Thorac Cardiovasc Surg 2004; 10: 90–6PubMedGoogle Scholar
  10. 10.
    Lazar HL, Bao Y, Rivers S. Does off-pump revascularization reduce coronary endothelial dysfunction? J Card Surg 2004; 19: 440–3PubMedCrossRefGoogle Scholar
  11. 11.
    Aljassim O, Karlsson M, Wiklund L, et al. Inflammatory response and platelet activation after off-pump coronary artery bypass surgery. Scand Cardiovasc J 2006; 40: 43–8PubMedCrossRefGoogle Scholar
  12. 12.
    Goodnough LT, Brecher ME, Kanter MH, et al. Transfusion medicine. First of two parts: blood transfusion. N Engl J Med 1999; 340: 438–47PubMedCrossRefGoogle Scholar
  13. 13.
    Moulton MJ, Creswell LL, Mackey ME, et al. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg 1996; 111: 1037–46PubMedCrossRefGoogle Scholar
  14. 14.
    Spiess BD. Transfusion of blood products affects outcome in cardiac surgery. Semin Cardiothorac Vasc Anesth 2004; 8: 267–81PubMedCrossRefGoogle Scholar
  15. 15.
    Karkouti K, Wijeysundera DN, Yau TM, et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion 2004; 44: 1453–62PubMedCrossRefGoogle Scholar
  16. 16.
    Spiess BD, Royston D, Levy JH, et al. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion 2004; 44: 1143–8PubMedCrossRefGoogle Scholar
  17. 17.
    Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353–65PubMedCrossRefGoogle Scholar
  18. 18.
    Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007; 297: 471–9PubMedCrossRefGoogle Scholar
  19. 19.
    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: 327–38PubMedCrossRefGoogle Scholar
  20. 20.
    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: 716–30PubMedCrossRefGoogle Scholar
  21. 21.
    Royston D, Bidstrup BP, Taylor KM, et al. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; 2: 1289–91PubMedCrossRefGoogle Scholar
  22. 22.
    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; 107: 543–51; discussion 551–3PubMedGoogle Scholar
  23. 23.
    Lemmer Jr JH, Dilling EW, Morton JR, et al. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996; 62(6): 1659–67; discussion 1667–8PubMedCrossRefGoogle Scholar
  24. 24.
    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. Circulation 1995; 92(8): 2236–44PubMedCrossRefGoogle Scholar
  25. 25.
    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; 55: 971–6PubMedCrossRefGoogle Scholar
  26. 26.
    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: 442–8PubMedCrossRefGoogle Scholar
  27. 27.
    Henry DA, Moxey A, Carless J, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 1999; (4): CD001886Google Scholar
  28. 28.
    Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung 1983; 33: 479–94PubMedGoogle Scholar
  29. 29.
    Mahdy AM, Webster NR. Perioperative systemic haemostatic agents. Br J Anaesth 2004; 93: 842–58PubMedCrossRefGoogle Scholar
  30. 30.
    Khan TA, Bianchi C, Voisine P, et al. Aprotinin inhibits protease-dependent platelet aggregation and thrombosis. Ann Thorac Surg 2005; 79: 1545–50PubMedCrossRefGoogle Scholar
  31. 31.
    Poullis M, Manning R, Laffan M, et al. The antithrombotic effect of aprotinin: actions mediated via the protease activated receptor 1. J Thorac Cardiovasc Surg 2000; 120: 370–8PubMedCrossRefGoogle Scholar
  32. 32.
    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: 788–96; discussion 796–7PubMedGoogle Scholar
  33. 33.
    Coughlin SR, Vu TK, Hung DT, et al. Expression cloning and characterization of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Semin Thromb Hemost 1992; 18: 161–6PubMedCrossRefGoogle Scholar
  34. 34.
    Coughlin SR, Vu TK, Hung DT, et al. Characterization of a functional thrombin receptor: issues and opportunities. J Clin Invest 1992; 89: 351–5PubMedCrossRefGoogle Scholar
  35. 35.
    Landis RC, Haskard DO, Taylor KM. New antiinflammatory and platelet-preserving effects of aprotinin. Ann Thorac Surg 2001; 72: S1808–13PubMedCrossRefGoogle Scholar
  36. 36.
    Ferraris VA, Ferraris SP, Singh A, et al. The platelet thrombin receptor and postoperative bleeding. Ann Thorac Surg 1998; 65: 352–8PubMedCrossRefGoogle Scholar
  37. 37.
    Day JR, Punjabi PP, Randi AM, et al. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation 2004; 110: 2597–600PubMedCrossRefGoogle Scholar
  38. 38.
    Maquelin KN, Nieuwland R, Lentjes EG, et al. Aprotinin administration in the pericardial cavity does not prevent platelet activation. J Thorac Cardiovasc Surg 2000; 120: 552–7PubMedCrossRefGoogle Scholar
  39. 39.
    Day JR, Taylor KM, Lidington EA, et al. Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1. J Thorac Cardiovasc Surg 2006; 131: 21–7 739PubMedCrossRefGoogle Scholar
  40. 40.
    Sellke FW. Organ protection in cardiac surgery. In: Sellke FW, editor. Improving outcomes in open heart surgery. Boston (MA): Interactive Communications, 2005Google Scholar
  41. 41.
    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: 104–10; discussion 110–1PubMedCrossRefGoogle Scholar
  42. 42.
    Bradfield JF, Bode AP. Aprotinin restores the adhesive capacity of dysfunctional platelets. Thromb Res 2003; 109: 181–8PubMedCrossRefGoogle Scholar
  43. 43.
    Carr Jr ME, Carr SL, Roa V, et al. Aprotinin counteracts heparin-induced inhibition of platelet contractile force. Thromb Res 2002; 108: 161–8PubMedCrossRefGoogle Scholar
  44. 44.
    Dietrich W. Reducing thrombin formation during cardiopulmonary bypass: is there a benefit of the additional anticoagulant action of aprotinin? J Cardiovasc Pharmacol 1996; 27 Suppl. 1: S50-7Google Scholar
  45. 45.
    Alston TA. Aprotinin. Int Anesthesiol Clin 2004; 42: 81–91PubMedCrossRefGoogle Scholar
  46. 46.
    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; 97: 364–72PubMedGoogle Scholar
  47. 47.
    Hongo RH, Ley J, Dick SE, et al. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002; 40: 231–7PubMedCrossRefGoogle Scholar
  48. 48.
    Akowuah E, Shrivastava V, Jamnadas B, et al. Comparison of two strategies for the management of antiplatelet therapy during urgent surgery. Ann Thorac Surg 2005; 80: 149–52PubMedCrossRefGoogle Scholar
  49. 49.
    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 (9 Suppl.): I276–80PubMedGoogle Scholar
  50. 50.
    Lindvall G, Sartipy U, van der Linden J. Aprotinin reduces bleeding and blood product use in patients treated with clopidogrel before coronary artery bypass grafting. Ann Thorac Surg 2005; 80: 922–7PubMedCrossRefGoogle Scholar
  51. 51.
    Nader ND, Davidson BA, Tait AR, et al. Serine antiproteinase administration preserves innate superoxide dismutase levels after acid aspiration and hyperoxia but does not decrease lung injury. Anesth Analg 2005; 101: 213–9PubMedCrossRefGoogle Scholar
  52. 52.
    Erdogan M, Kalaycioglu S, Iriz E. Protective effect of aprotinin against lung damage in patients undergoing CABG surgery. Acta Cardiol 2005; 60: 367–72PubMedCrossRefGoogle Scholar
  53. 53.
    Ege T, Arar C, Canbaz S, et al. The importance of aprotinin and pentoxifylline in preventing leukocyte sequestration and lung injury caused by protamine at the end of cardiopulmonary bypass surgery. Thorac Cardiovasc Surg 2004; 52: 10–5PubMedCrossRefGoogle Scholar
  54. 54.
    Lazar HL, Bao Y, Tanzillo L, et al. Aprotinin decreases ischemic damage during coronary revascularization. J Card Surg 2005; 20: 519–23PubMedCrossRefGoogle Scholar
  55. 55.
    Yun TJ, Rho JR. Aprotinin attenuates the elevation of pulmonary vascular resistance after cardiopulmonary bypass. J Korean Med Sci 2006; 21: 25–9PubMedCrossRefGoogle Scholar
  56. 56.
    Olivencia-Yurvati AH, Wallace WE, Wallace N, et al. Intraoperative treatment strategy to reduce the incidence of post-cardiopulmonary bypass atrial fibrillation. Perfusion 2002; (17 Suppl.): 35–9Google Scholar
  57. 57.
    Gillespie EL, Gryskiewicz KA, White CM, et al. Effect of aprotinin on the frequency of postoperative atrial fibrillation or flutter. Am J Health Syst Pharm 2005; 62: 1370–4PubMedCrossRefGoogle Scholar
  58. 58.
    Khan TA, Bianchi C, Voisine P, et al. Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest. J Thorac Cardiovasc Surg 2004; 128: 602–8PubMedCrossRefGoogle Scholar
  59. 59.
    Bull DA, Maurer J. Aprotinin and preservation of myocardial function after ischemia-reperfusion injury. Ann Thorac Surg 2003; 75: S735–9PubMedCrossRefGoogle Scholar
  60. 60.
    Karaca P, Konuralp C, Enc Y, et al. Cardioprotective effect of aprotinin on myocardial ischemia/reperfusion injury during cardiopulmonary bypass. Circ J 2006; 70: 1432–6PubMedCrossRefGoogle Scholar
  61. 61.
    Royston D, Levy JH, Fitch J, et al. Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes. Anesth Analg 2006; 103: 1082–8PubMedCrossRefGoogle Scholar
  62. 62.
    Ulker S, Cinar MG, Bayraktutan U, et al. Aprotinin impairs endothelium-dependent relaxation in rat aorta and inhibits nitric oxide release from rat coronary endothelial cells. Cardiovasc Res 2001 Jun; 50(3): 589–96PubMedCrossRefGoogle Scholar
  63. 63.
    Fischer JH, Steinhoff M. Effects of aprotinin on endothelium-dependent relaxation of large coronary arteries. Eur J Cardiothorac Surg 2005; 28: 801–4PubMedCrossRefGoogle Scholar
  64. 64.
    Khan TA, Bianchi C, Araujo E, et al. Aprotinin preserves cellular junctions and reduces myocardial edema after regional ischemia and cardioplegic arrest. Circulation 2005; 112 (9 Suppl.): I196–201PubMedGoogle Scholar
  65. 65.
    Wachtfogel YT, Hack CE, Nuijens JH, et al. Selective kallikrein inhibitors alter human neutrophil elastase release during extracorporeal circulation. Am J Physiol 1995 Mar; 268 (3 Pt 2): H1352–7PubMedGoogle Scholar
  66. 66.
    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: 545–51PubMedCrossRefGoogle Scholar
  67. 67.
    Cugno M, Nussberger J, Biglioli P, et al. Increase of bradykinin in plasma of patients undergoing cardiopulmonary bypass: the importance of lung exclusion. Chest 2001; 120: 1776–82PubMedCrossRefGoogle Scholar
  68. 68.
    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; 106: 1–9; discussion 9–10PubMedGoogle Scholar
  69. 69.
    Hill GE, Alonso A, Spurzem JR, et al. Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass-induced inflammation in humans. J Thorac Cardiovasc Surg 1995; 110: 1658–62PubMedCrossRefGoogle Scholar
  70. 70.
    Pruefer D, Makowski J, Dahm M, et al. Aprotinin inhibits leukocyte-endothelial cell interactions after hemorrhage and reperfusion. Ann Thorac Surg 2003; 75: 210–5; discussion 215–6PubMedCrossRefGoogle Scholar
  71. 71.
    Harmon D, Lan W, Shorten G. The effect of aprotinin on hypoxia-reoxygenation-induced changes in neutrophil and endothelial function. Eur J Anaesthesiol 2004; 21: 973–9PubMedGoogle Scholar
  72. 72.
    Kalangos A, Tayyareci G, Pretre R, et al. Influence of aprotinin on early graft thrombosis in patients undergoing myocardial revascularization. Eur J Cardiothorac Surg 1994; 8: 651–6PubMedCrossRefGoogle Scholar
  73. 73.
    Havel M, Grabenwoger 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: 807–10PubMedGoogle Scholar
  74. 74.
    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: 206–10PubMedCrossRefGoogle Scholar
  75. 75.
    Wendel HP, Heller W, Michel J, et al. Lower cardiac troponin T levels in patients undergoing cardiopulmonary bypass and receiving high-dose aprotinin therapy indicate reduction of perioperative myocardial damage. J Thorac Cardiovasc Surg 1995; 109: 1164–72PubMedCrossRefGoogle Scholar
  76. 76.
    Taggart DP, Djapardy V, Naik M, et al. 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: 1087–94PubMedCrossRefGoogle Scholar
  77. 77.
    Anttila V, Hagino I, Iwata Y, et al. Aprotinin improves cerebral protection: evidence from a survival porcine model. J Thorac Cardiovasc Surg 2006; 132: 948–53PubMedCrossRefGoogle Scholar
  78. 78.
    Heikkinen J, Kaakinen T, Dahlbacka S, et al. Aprotinin to improve cerebral outcome after hypothermic circulatory arrest: 740 a study in a surviving porcine model. Heart Surg Forum 2006; 9: E719–24PubMedCrossRefGoogle Scholar
  79. 79.
    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: 1002–9PubMedCrossRefGoogle Scholar
  80. 80.
    Buziashvili YI, Ambat’ello SG, Aleksakhina YA, et al. Influence of cardiopulmonary bypass on the state of cognitive functions in patients with ischemic heart disease. Neurosci Behav Physiol 2006; 36: 107–13PubMedCrossRefGoogle Scholar
  81. 81.
    Buziashvili YI, Aleksakhina YA, Ambat’ello SG, et al. Use of p300 cognitive evoked potentials in the diagnosis of impairments of higher mental functions after cardiac surgery in conditions of cardiopulmonary bypass. Neurosci Behav Physiol 2006; 36: 115–8PubMedCrossRefGoogle Scholar
  82. 82.
    Levy JH, Sypniewski E. Aprotinin: a pharmacologic overview. Orthopedics 2004; 27: s653–8PubMedGoogle Scholar
  83. 83.
    Asimakopoulos G, Thompson R, Nourshargh S, et al. An antiinflammatory property of aprotinin detected at the level of leukocyte extravasation. J Thorac Cardiovasc Surg 2000; 120: 361–9PubMedCrossRefGoogle Scholar
  84. 84.
    Junge CE, Sugawara T, Mannaioni G, et al. The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci USA 2003; 100: 13019–24PubMedCrossRefGoogle Scholar
  85. 85.
    Jurk K, Jahn UR, Van Aken H, et al. Platelets in patients with acute ischemic stroke are exhausted and refractory to thrombin, due to cleavage of the seven-transmembrane thrombin receptor (PAR-1). Thromb Haemost 2004; 91: 334–44PubMedGoogle Scholar
  86. 86.
    D’Ambra 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: 1081–9PubMedCrossRefGoogle Scholar
  87. 87.
    Feindt PR, Walcher S, Volkmer I, et al. Effects of high-dose aprotinin on renal function in aortocoronary bypass grafting. Ann Thorac Surg 1995; 60: 1076–80PubMedCrossRefGoogle Scholar
  88. 88.
    Mora Mangano CT, Neville MJ, Hsu PH, et al. Aprotinin, blood loss, and renal dysfunction in deep hypothermic circulatory arrest. Circulation 2001; 104 (12 Suppl. 1): I276-81Google Scholar
  89. 89.
    Fauli A, Gomar C, Campistol JM, et al. Kidney-specific proteins in patients receiving aprotinin at high-and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass. Eur J Anaesthesiol 2005; 22: 666–71PubMedCrossRefGoogle Scholar
  90. 90.
    Kincaid EH, Ashburn DA, Hoyle JR, et al. Does the combination of aprotinin and angiotensin-converting enzyme inhibitor cause renal failure after cardiac surgery? Ann Thorac Surg 2005; 80: 1388–93; discussion 1393PubMedCrossRefGoogle Scholar
  91. 91.
    Kikura M, Levy JH, Tanaka KA, et al. 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: 216–22; quiz A44-5PubMedCrossRefGoogle Scholar
  92. 92.
    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: 271–8PubMedCrossRefGoogle Scholar
  93. 93.
    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 Cardiovasc Disord 2005; 5: 19PubMedCrossRefGoogle Scholar
  94. 94.
    Nuttall GA, Oliver WC, Ereth MH, et al. Comparison of blood-conservation strategies in cardiac surgery patients at high risk for bleeding. Anesthesiology 2000; 92: 674–82PubMedCrossRefGoogle Scholar
  95. 95.
    Byar DP. Problems with using observational databases to compare treatments. Stat Med 1991; 10: 663–6PubMedCrossRefGoogle Scholar
  96. 96.
    Hiatt WR. Observational studies of drug safety: aprotinin and the absence of transparency. N Engl J Med 2006; 355: 2171–3PubMedCrossRefGoogle Scholar
  97. 97.
    Mazer D, Fergusson D, Hebert P, et al. Incidence of massive bleeding in a blinded controlled trial of antifibrinolytic drugs [abstract]. Anesth Analg 2006; 102: SCA1–95Google Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Neel R. Sodha
    • 1
  • Munir Boodhwani
    • 2
  • Frank W. Sellke
    • 1
  1. 1.Division of Cardiothoracic SurgeryBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA
  2. 2.Division of Cardiac SurgeryUniversity of Ottawa Heart InstituteOttawaCanada
  3. 3.Beth Israel Deaconess Medical CenterBostonUSA

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