Does use of aprotinin decrease the incidence of stroke and neurological complications in adult patients undergoing cardiac surgery
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《血管的通路杂志》
a Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZN, UK
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether aprotinin use was associated with a lower incidence of stroke and neurological complications in adult patients undergoing cardiac surgery. Using the reported search 224 papers were identified on Medline, 722 on Embase and 12 by hand-searching reference lists. Eight papers represented the best evidence on the subject and the author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study comments and weaknesses were tabulated. We conclude that there is evidence from three meta-analyses and two more recent RCTs that the use of aprotinin is associated with a decreased incidence of stroke and neurological complications in some patients undergoing cardiac surgery. However, many single studies within these meta-analyses are small and designed to look at other outcomes so are underpowered for neurological outcome. In contrast, however, a recent cohort study has raised concerns about aprotinin, suggesting that its use is associated with a significant increased risk of stroke in uncomplicated CABG surgery. Ideally further large well-constructed RCTs are required to give a definitive answer to this question and determine the most appropriate dose but given recent concerns, data may have to be obtained from large better controlled cohort studies.
Key Words: Cardiac surgery; Aprotinin; Brain ischaemia; Cerebrovascular disorder; Postoperative complications
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You are about to perform CABG and aortic valve replacement surgery on a 75-year-old man with a history of diabetes, hypertension, carotid disease and transient ischaemic attacks. Your colleague suggests that you should give your patient aprotinin to minimise the risk of cerebrovascular complications but given recent controversies you decide to review the literature to investigate what evidence there is to suggest aprotinin has neuroprotective properties.
3. Three-part question
In [adult patients undergoing cardiac surgery], does [Aprotinin use] decrease [risk of stroke and neurological dysfunction].
4. Search strategy
Medline 1966 to May Week 4 2006 using OVID interface EMBASE 1980 to 2006 Week 21 [exp Cardiopulmonary Bypass/OR CABG.mp. OR exp Thoracic Surgery/OR Coronary art$ bypass.mp. OR Cardiopulmonary bypass.mp. OR exp Cardiopulmonary Bypass/OR exp Cardiovascular Surgical Procedures/OR exp Thoracic Surgical Procedures/OR exp Coronary Artery Bypass/OR cardiac transplantation.mp. OR exp Heart Transplantation/] AND [Aprotinin.mp. OR exp APROTININ/OR Trasylol.mp. OR exp Aprotinin/OR Serine protease inhibitors.mp. OR exp Serine Proteinase Inhibitors/] AND [cerebrovascular disorders.mp. OR exp Cerebrovascular Disorders/OR brain ischemia.mp. OR Brain Ischemia/OR brain hypoxia.mp. OR Hypoxia, Brain/OR confusional state.mp. OR Confusion/OR postoperative complications.mp. OR Postoperative Complications/OR postoperative neurological complications.mp. OR coma.mp. OR exp Coma/OR encephalopathy.mp. OR cerebrovascular accident.mp. OR Cerebrovascular Accident/OR stroke.mp.].
5. Search outcome
Using the reported search 224 papers were identified on Medline, 722 on Embase and 12 by hand-searching reference lists. Eight papers provided the best evidence to answer the question (Table 1).
6. Results
In the past 10 years, three meta-analyses have reported decreased postoperative stroke incidence in patients receiving perioperative aprotinin by bolus and infusion [2–4]. Those by Murkin et al. [2] and Smith et al. [3] analyse essentially the same studies [5–9] and include unpublished data from the manufacturers Bayer. However, whilst Murkin et al. only analysed studies using the so-called ‘Hammer-smith’ or ‘full-dose’ aprotinin regime, Smith et al. also studied data from ‘half-dose’ and ‘pump-prime only’ studies. Whilst both showed a lower incidence of stroke in aprotinin-treated patients, Smith's group demonstrated that this only occurred with ‘full-dose’ techniques and raised safety concerns about use of ‘half-dose’ and ‘prime only’ techniques [3].
The most recent meta-analysis by Sedrakyan et al. assessed 2976 patients in 18 trials [4]. However, this included 2179 patients from 9 trials in which additional stroke/neurological dysfunction data were obtained from personal communication with the primary investigator and so cannot always be verified in the original paper [5,6,8–14]. The remaining patients came from 9 trials in which ‘neurological outcomes’ were reported [7,15–22]. Unfortunately most are small studies underpowered to identify significant differences in stroke incidence with only two of the latter group having study populations of over 50 in each limb. Nevertheless, Levy et al. did find a significantly lower incidence of stroke in patients receiving ‘full-dose’ or ‘half-dose’ aprotinin compared to placebo [7] although the stroke incidence in their placebo group seems extraordinarily high at 7.69% compared to similar studies. In contrast, Dignan et al. noted comparable incidences of temporary and permanent neurological dysfunction in 101 patients receiving a non-standard ultra-low dose of aprotinin [19]. Even larger ‘Investigator Reported’ studies by Lemmer et al. and Alderman et al. with 704 and 850 patients, respectively, failed to show significant differences in stroke incidence between aprotinin and placebo groups with stroke incidences of 0.85% vs.1.12% (Lemmer et al. [8]) and 1.15% vs. 1.84% (Alderman et al. [9]). In addition, Lemmer's group could find no difference in stroke incidence between ‘full-dose’, ‘half-dose’ and ‘pump-prime only’ regimes [8]. However, in their meta-analysis, Sedrakayan et al. concluded that the use of intraoperative prophylactic aprotinin decreased the incidence of postoperative stroke by 47% with a 10-event risk difference per 1000 patients treated although they did not differentiate between ‘full-dose’ and ‘half-dose’ data. They also confirmed the decreased transfusion requirements seen in many other aprotinin studies with no excess of myocardial infarction, renal failure or mortality [4].
Subsequent more recent studies support aprotinin's neuroprotective actions. Frumento et al. recognised a lower stroke risk with ‘full-dose’ rather than ‘half-dose’ aprotinin in a patient group at high risk of stroke [23] although their cohort was not randomised and may contain inherent surgical bias. Harmon et al. demonstrated lower incidence of cognitive dysfunction 4 days and 6 weeks postoperatively in a small group of CABG patients given high dose aprotinin [24].
In contrast, Mangano et al. [25] reported significantly increased adverse outcomes in 1295 patients who received aprotinin within a cohort of 4374 patients undergoing ‘primary’ (CABG or angioplasty only) or ‘complex’ (all other) surgery. Using logistic regression analysis and propensity scoring techniques they reported that the risk of stroke was increased by 181% and the risk of MI by 55% in ‘primary’ surgery, and the incidence of renal failure doubled in both ‘primary’ and ‘complex’ surgery. They also noted dose-response aprotinin effects and commented that as other anti-fibrinolytic such as tranexamic acid and aminocaproic acid had the same blood-sparing effects without adverse effects, continued use of aprotinin was ‘not prudent’. However, whilst this study has several weaknesses, including a risk of bias from systemic sampling across multiple institutions with inherently embedded practices, and higher risk factors for some adverse outcomes within the aprotinin group, it has resulted in considerable debate and may lead to some reappraisal of aprotinin's use particularly in uncomplicated ‘primary’ surgery.
7. Clinical bottom line
There is evidence from three meta-analyses and two more recent RCTs that the use of aprotinin is associated with decreased incidence of stroke and neurological complications in some patients undergoing cardiac surgery. However many single studies within these meta-analyses are small, designed to look at other outcomes, and underpowered to assess neurological differences. In contrast, a recent cohort study has suggested that aprotinin use is associated with a significant increased risk of stroke in uncomplicated CABG surgery.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003; 2:405–409.
Murkin JM, Maurer J, Niemcryk S. Full dose aprotinin is associated with a significant decrease in perioperative stroke in patients undergoing elective cardiac surgery. A meta-analysis. Ann Thorac Surg 2002; 73:S374.
Smith PK, Muhlbaier LH. Aprotinin: safe and effective only with the full-dose regimen. Ann Thorac Surg 1996; 62:1575–1577.
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 controlled trials. J Thorac Cardiovasc Surg 2004; 128:442–448.
Cosgrove DM 3rd, Heric B, Lytle BW, Taylor PC, Novoa R, Golding LA, Stewart RW, McCarthy PM, Loop FD. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992; 54:1031–1036.
Lemmer JH Jr, Stanford W, Bonney SL, Breen JF, Chomka EV, Eldredge WJ, Holt WW, Karp RB, Laub GW, Lipton MJ, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994; 107:543–551.
Levy JH, Pifarre R, Schaff HV, Horrow JC, Albus R, Spiess B, Rosengart TK, Murray J, Clark RE, Smith PA. 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; 92:2236–2244.
Lemmer JH Jr, Dilling EW, Morton JR, Rich JB, Robicsek F, Bricker DL, Hantler CB, Copeland JG 3rd, Ochsner JL, Daily PO, Whitten CW, Noon GP, Maddi R. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996; 62:1659–1667.
Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998; 116:716–730.
Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989; 97:364–372.
Harig F, Feyrer R, Mahmoud FO, Blum U, von der Emde J. Reducing the post-pump syndrome by using heparin-coated circuits, steroids, or aprotinin. Thorac Cardiovasc Surg 1999; 47:111–118.
Kalangos A, Tayyareci G, Pretre R, Di Dio P, Sezerman O. Influence of aprotinin on early graft thrombosis in patients undergoing myocardial revascularization. Eur J Cardio-Thorac 1994; 8:651–656.
Klein M, Keith PR, Dauben HP, Schulte HD, Beckmann H, Mayer G, Elert O, Gams E. Aprotinin counterbalances an increased risk of peri-operative hemorrhage in CABG patients pre-treated with aspirin. Eur J Cardio-Thorac 1998; 14:360–366.
Wahba A, Black G, Koksch M, Rothe G, Preuner J, Schmitz G, Birnbaum DE. Aprotinin has no effect on platelet activation and adhesion during cardiopulmonary bypass. Thromb Haemost 1996; 75:844–848.
Asimakopoulos G, Kohn A, Stefanou DC, Haskard DO, Landis RC, Taylor KM. Leukocyte integrin expression in patients undergoing cardiopulmonary bypass. Ann Thorac Surg 2000; 69:1192–1197.
Bidstrup BP, Underwood SR, Sapsford RN, Streets EM. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993; 105:147–152.
Bidstrup BP, Hunt BJ, Sheikh S, Parratt RN, Bidstrup JM, Sapsford RN. Amelioration of the bleeding tendency of preoperative aspirin after aortocoronary bypass grafting. Ann Thorac Surg 2000; 69:541–547.
Blauhut B, Harringer W, Bettelheim P, Doran JE, Spath P, Lundsgaard-Hansen P. Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994; 108:1083–1091.
Dignan RJ, Law DW, Seah PW, Manganas CW, Newman DC, Grant PW, Wolfenden HD. Ultra-low dose aprotinin decreases transfusion requirements and is cost effective in coronary operations. Ann Thorac Surg 2001; 71:158–163.
Moran SV, Lema G, Medel J, Irarrazaval MJ, Zalaquett R, Garayar B, Flaskamp R. Comparison of two doses of aprotinin in patients receiving aspirin before coronary bypass surgery. Perfusion 2000; 15:105–110.
Murkin JM, Lux J, Shannon NA, Guiraudon GM, Menkis AH, McKenzie FN, Novick RJ. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994; 107:554–561.
Santamaria A, Mateo J, Oliver A, Litvan H, Murillo J, Souto JC, Fontcuberta J. The effect of two different doses of aprotinin on haemostasis in cardiopulmonary bypass surgery: similar transfusion requirements and blood loss. Haematologica 2000; 85:1277–1284.
Frumento RJ, O'Malley CM, Bennett-Guerrero E. Stroke after cardiac surgery: a retrospective analysis of the effect of aprotinin dosing regimens. Ann Thorac Surg 2003; 75:479–483.
Harmon DC, Ghori KG, Eustace NP, O'Callaghan SJ, O'Donnell AP, Shorten GD. Aprotinin decreases the incidence of cognitive deficit following CABG and cardiopulmonary bypass: a pilot randomized controlled study. Can J Anaesth 2004; 51:1002–1009.
Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. New Engl J Med 2006; 354:353–365.(Andrew Ronald, and Joel D)
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether aprotinin use was associated with a lower incidence of stroke and neurological complications in adult patients undergoing cardiac surgery. Using the reported search 224 papers were identified on Medline, 722 on Embase and 12 by hand-searching reference lists. Eight papers represented the best evidence on the subject and the author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study comments and weaknesses were tabulated. We conclude that there is evidence from three meta-analyses and two more recent RCTs that the use of aprotinin is associated with a decreased incidence of stroke and neurological complications in some patients undergoing cardiac surgery. However, many single studies within these meta-analyses are small and designed to look at other outcomes so are underpowered for neurological outcome. In contrast, however, a recent cohort study has raised concerns about aprotinin, suggesting that its use is associated with a significant increased risk of stroke in uncomplicated CABG surgery. Ideally further large well-constructed RCTs are required to give a definitive answer to this question and determine the most appropriate dose but given recent concerns, data may have to be obtained from large better controlled cohort studies.
Key Words: Cardiac surgery; Aprotinin; Brain ischaemia; Cerebrovascular disorder; Postoperative complications
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You are about to perform CABG and aortic valve replacement surgery on a 75-year-old man with a history of diabetes, hypertension, carotid disease and transient ischaemic attacks. Your colleague suggests that you should give your patient aprotinin to minimise the risk of cerebrovascular complications but given recent controversies you decide to review the literature to investigate what evidence there is to suggest aprotinin has neuroprotective properties.
3. Three-part question
In [adult patients undergoing cardiac surgery], does [Aprotinin use] decrease [risk of stroke and neurological dysfunction].
4. Search strategy
Medline 1966 to May Week 4 2006 using OVID interface EMBASE 1980 to 2006 Week 21 [exp Cardiopulmonary Bypass/OR CABG.mp. OR exp Thoracic Surgery/OR Coronary art$ bypass.mp. OR Cardiopulmonary bypass.mp. OR exp Cardiopulmonary Bypass/OR exp Cardiovascular Surgical Procedures/OR exp Thoracic Surgical Procedures/OR exp Coronary Artery Bypass/OR cardiac transplantation.mp. OR exp Heart Transplantation/] AND [Aprotinin.mp. OR exp APROTININ/OR Trasylol.mp. OR exp Aprotinin/OR Serine protease inhibitors.mp. OR exp Serine Proteinase Inhibitors/] AND [cerebrovascular disorders.mp. OR exp Cerebrovascular Disorders/OR brain ischemia.mp. OR Brain Ischemia/OR brain hypoxia.mp. OR Hypoxia, Brain/OR confusional state.mp. OR Confusion/OR postoperative complications.mp. OR Postoperative Complications/OR postoperative neurological complications.mp. OR coma.mp. OR exp Coma/OR encephalopathy.mp. OR cerebrovascular accident.mp. OR Cerebrovascular Accident/OR stroke.mp.].
5. Search outcome
Using the reported search 224 papers were identified on Medline, 722 on Embase and 12 by hand-searching reference lists. Eight papers provided the best evidence to answer the question (Table 1).
6. Results
In the past 10 years, three meta-analyses have reported decreased postoperative stroke incidence in patients receiving perioperative aprotinin by bolus and infusion [2–4]. Those by Murkin et al. [2] and Smith et al. [3] analyse essentially the same studies [5–9] and include unpublished data from the manufacturers Bayer. However, whilst Murkin et al. only analysed studies using the so-called ‘Hammer-smith’ or ‘full-dose’ aprotinin regime, Smith et al. also studied data from ‘half-dose’ and ‘pump-prime only’ studies. Whilst both showed a lower incidence of stroke in aprotinin-treated patients, Smith's group demonstrated that this only occurred with ‘full-dose’ techniques and raised safety concerns about use of ‘half-dose’ and ‘prime only’ techniques [3].
The most recent meta-analysis by Sedrakyan et al. assessed 2976 patients in 18 trials [4]. However, this included 2179 patients from 9 trials in which additional stroke/neurological dysfunction data were obtained from personal communication with the primary investigator and so cannot always be verified in the original paper [5,6,8–14]. The remaining patients came from 9 trials in which ‘neurological outcomes’ were reported [7,15–22]. Unfortunately most are small studies underpowered to identify significant differences in stroke incidence with only two of the latter group having study populations of over 50 in each limb. Nevertheless, Levy et al. did find a significantly lower incidence of stroke in patients receiving ‘full-dose’ or ‘half-dose’ aprotinin compared to placebo [7] although the stroke incidence in their placebo group seems extraordinarily high at 7.69% compared to similar studies. In contrast, Dignan et al. noted comparable incidences of temporary and permanent neurological dysfunction in 101 patients receiving a non-standard ultra-low dose of aprotinin [19]. Even larger ‘Investigator Reported’ studies by Lemmer et al. and Alderman et al. with 704 and 850 patients, respectively, failed to show significant differences in stroke incidence between aprotinin and placebo groups with stroke incidences of 0.85% vs.1.12% (Lemmer et al. [8]) and 1.15% vs. 1.84% (Alderman et al. [9]). In addition, Lemmer's group could find no difference in stroke incidence between ‘full-dose’, ‘half-dose’ and ‘pump-prime only’ regimes [8]. However, in their meta-analysis, Sedrakayan et al. concluded that the use of intraoperative prophylactic aprotinin decreased the incidence of postoperative stroke by 47% with a 10-event risk difference per 1000 patients treated although they did not differentiate between ‘full-dose’ and ‘half-dose’ data. They also confirmed the decreased transfusion requirements seen in many other aprotinin studies with no excess of myocardial infarction, renal failure or mortality [4].
Subsequent more recent studies support aprotinin's neuroprotective actions. Frumento et al. recognised a lower stroke risk with ‘full-dose’ rather than ‘half-dose’ aprotinin in a patient group at high risk of stroke [23] although their cohort was not randomised and may contain inherent surgical bias. Harmon et al. demonstrated lower incidence of cognitive dysfunction 4 days and 6 weeks postoperatively in a small group of CABG patients given high dose aprotinin [24].
In contrast, Mangano et al. [25] reported significantly increased adverse outcomes in 1295 patients who received aprotinin within a cohort of 4374 patients undergoing ‘primary’ (CABG or angioplasty only) or ‘complex’ (all other) surgery. Using logistic regression analysis and propensity scoring techniques they reported that the risk of stroke was increased by 181% and the risk of MI by 55% in ‘primary’ surgery, and the incidence of renal failure doubled in both ‘primary’ and ‘complex’ surgery. They also noted dose-response aprotinin effects and commented that as other anti-fibrinolytic such as tranexamic acid and aminocaproic acid had the same blood-sparing effects without adverse effects, continued use of aprotinin was ‘not prudent’. However, whilst this study has several weaknesses, including a risk of bias from systemic sampling across multiple institutions with inherently embedded practices, and higher risk factors for some adverse outcomes within the aprotinin group, it has resulted in considerable debate and may lead to some reappraisal of aprotinin's use particularly in uncomplicated ‘primary’ surgery.
7. Clinical bottom line
There is evidence from three meta-analyses and two more recent RCTs that the use of aprotinin is associated with decreased incidence of stroke and neurological complications in some patients undergoing cardiac surgery. However many single studies within these meta-analyses are small, designed to look at other outcomes, and underpowered to assess neurological differences. In contrast, a recent cohort study has suggested that aprotinin use is associated with a significant increased risk of stroke in uncomplicated CABG surgery.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003; 2:405–409.
Murkin JM, Maurer J, Niemcryk S. Full dose aprotinin is associated with a significant decrease in perioperative stroke in patients undergoing elective cardiac surgery. A meta-analysis. Ann Thorac Surg 2002; 73:S374.
Smith PK, Muhlbaier LH. Aprotinin: safe and effective only with the full-dose regimen. Ann Thorac Surg 1996; 62:1575–1577.
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 controlled trials. J Thorac Cardiovasc Surg 2004; 128:442–448.
Cosgrove DM 3rd, Heric B, Lytle BW, Taylor PC, Novoa R, Golding LA, Stewart RW, McCarthy PM, Loop FD. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992; 54:1031–1036.
Lemmer JH Jr, Stanford W, Bonney SL, Breen JF, Chomka EV, Eldredge WJ, Holt WW, Karp RB, Laub GW, Lipton MJ, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994; 107:543–551.
Levy JH, Pifarre R, Schaff HV, Horrow JC, Albus R, Spiess B, Rosengart TK, Murray J, Clark RE, Smith PA. 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; 92:2236–2244.
Lemmer JH Jr, Dilling EW, Morton JR, Rich JB, Robicsek F, Bricker DL, Hantler CB, Copeland JG 3rd, Ochsner JL, Daily PO, Whitten CW, Noon GP, Maddi R. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996; 62:1659–1667.
Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998; 116:716–730.
Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989; 97:364–372.
Harig F, Feyrer R, Mahmoud FO, Blum U, von der Emde J. Reducing the post-pump syndrome by using heparin-coated circuits, steroids, or aprotinin. Thorac Cardiovasc Surg 1999; 47:111–118.
Kalangos A, Tayyareci G, Pretre R, Di Dio P, Sezerman O. Influence of aprotinin on early graft thrombosis in patients undergoing myocardial revascularization. Eur J Cardio-Thorac 1994; 8:651–656.
Klein M, Keith PR, Dauben HP, Schulte HD, Beckmann H, Mayer G, Elert O, Gams E. Aprotinin counterbalances an increased risk of peri-operative hemorrhage in CABG patients pre-treated with aspirin. Eur J Cardio-Thorac 1998; 14:360–366.
Wahba A, Black G, Koksch M, Rothe G, Preuner J, Schmitz G, Birnbaum DE. Aprotinin has no effect on platelet activation and adhesion during cardiopulmonary bypass. Thromb Haemost 1996; 75:844–848.
Asimakopoulos G, Kohn A, Stefanou DC, Haskard DO, Landis RC, Taylor KM. Leukocyte integrin expression in patients undergoing cardiopulmonary bypass. Ann Thorac Surg 2000; 69:1192–1197.
Bidstrup BP, Underwood SR, Sapsford RN, Streets EM. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993; 105:147–152.
Bidstrup BP, Hunt BJ, Sheikh S, Parratt RN, Bidstrup JM, Sapsford RN. Amelioration of the bleeding tendency of preoperative aspirin after aortocoronary bypass grafting. Ann Thorac Surg 2000; 69:541–547.
Blauhut B, Harringer W, Bettelheim P, Doran JE, Spath P, Lundsgaard-Hansen P. Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994; 108:1083–1091.
Dignan RJ, Law DW, Seah PW, Manganas CW, Newman DC, Grant PW, Wolfenden HD. Ultra-low dose aprotinin decreases transfusion requirements and is cost effective in coronary operations. Ann Thorac Surg 2001; 71:158–163.
Moran SV, Lema G, Medel J, Irarrazaval MJ, Zalaquett R, Garayar B, Flaskamp R. Comparison of two doses of aprotinin in patients receiving aspirin before coronary bypass surgery. Perfusion 2000; 15:105–110.
Murkin JM, Lux J, Shannon NA, Guiraudon GM, Menkis AH, McKenzie FN, Novick RJ. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994; 107:554–561.
Santamaria A, Mateo J, Oliver A, Litvan H, Murillo J, Souto JC, Fontcuberta J. The effect of two different doses of aprotinin on haemostasis in cardiopulmonary bypass surgery: similar transfusion requirements and blood loss. Haematologica 2000; 85:1277–1284.
Frumento RJ, O'Malley CM, Bennett-Guerrero E. Stroke after cardiac surgery: a retrospective analysis of the effect of aprotinin dosing regimens. Ann Thorac Surg 2003; 75:479–483.
Harmon DC, Ghori KG, Eustace NP, O'Callaghan SJ, O'Donnell AP, Shorten GD. Aprotinin decreases the incidence of cognitive deficit following CABG and cardiopulmonary bypass: a pilot randomized controlled study. Can J Anaesth 2004; 51:1002–1009.
Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. New Engl J Med 2006; 354:353–365.(Andrew Ronald, and Joel D)