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J Thorac Cardiovasc Surg 2001;122:457-463
© 2001 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology (CPS) |
From the Cardiothoracic Surgery Unit, Monash Medical Centre, and the Centre for Heart and Chest Research, Departments of Medicine and Surgery, Monash University, Clayton, Victoria, Australia.
Presented at the Forty-seventh Annual Scientific Meeting, Cardiac Society of Australia and New Zealand, Wellington, New Zealand, August 1999.
Received for publication Nov 6, 2000. Revisions requested Jan 8, 2001; revisions received Feb 28, 2001. Accepted for publication March 5, 2001. Address for reprints: J. M. Alvarez, MBBS, FRACS, Cardiothoracic Surgery Unit, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia (Email: john.alvarez{at}health.wa.gov.au).
Abstract
Background: Although low-dose aprotinin administered after cardiopulmonary bypass has been reported to reduce mediastinal blood loss and blood product requirements in patients not taking aspirin, it is unknown whether low-dose postoperative aprotinin has any beneficial effects in patients undergoing coronary artery bypass operations who are at high risk of excessive postoperative bleeding and increased transfusion requirements because of aspirin use until just before the operation.
Methods: Fifty-five patients undergoing primary coronary artery operations with cardiopulmonary bypass who continued taking aspirin (150 mg/d) until the day before the operation were enrolled in a prospective, randomized, double-blind trial to receive a single dose of either placebo (n = 29) or 2 x 106 kallikrein inhibiting units of aprotinin (n = 26) at the time of sternal skin closure.
Results: Patients in the aprotinin group had a lower rate (28 ± 18 vs 43 ± 21 mL/h [mean ± standard deviation], P < .005) and total volume of mediastinal drainage (955 ± 615 vs 1570 ± 955 mL, P < .007), as well as a shorter duration of mediastinal drain tube insertion (24.4 ± 13.8 vs 31.3 ± 16.5 hours, P < .05). In addition, a smaller proportion of patients receiving aprotinin required a blood product (31% vs 62%, P = .03), resulting in a reduction in the use of packed cells by 47% (P = .05), platelets by 77% (P = .01), fresh frozen plasma by 88% (P = .03), and total blood products by 68% (P = .01) in this group.
Conclusions: These results suggest that postoperative administration of low-dose aprotinin in patients taking aspirin until just before primary coronary artery operations with cardiopulmonary bypass not only reduces the rate and total amount of postoperative mediastinal blood loss but also lowers postoperative blood product use.
Cardiopulmonary bypass (CPB) is associated with the induction of a transient hemostatic defect that appears to be related to a variety of factors, including platelet dysfunction caused by reduced surface expression of glycoproteins Ib and IIb-IIIa, activation of coagulation pathways with consumption of clotting factors, and increases in fibrinolytic activity.
1 By increasing the risk of excessive postoperative bleeding, this hemostatic defect predisposes to increased blood product use and reoperation for bleeding and thus makes a major contribution to postoperative morbidity and mortality after cardiac operations. 2 Meta-analysis of a large number of randomized controlled trials has established that prophylactic administration of the serine protease inhibitor aprotinin before and during CPB not only reduces postoperative blood loss 3,4 but also lowers transfusion requirements, 3-5 the frequency of surgical re-exploration for bleeding, 4,5 and overall operative mortality. 4
Aprotinin is, however, quite expensive, with a calculated cost of approximately $1000 in US currency per procedure for the commonly used high-dose perioperative regimen. 3 Moreover, concerns have also been raised about this regimen with respect to an increased risk of acute myocardial infarction, renal dysfunction, and graft occlusion. 1,6,7 For these reasons, several prospective, placebo-controlled studies have examined the effect of administering low-dose aprotinin on discontinuation of CPB. 8-10 Such studies have shown that in patients who were not taking aspirin or who discontinued aspirin for at least 7 days before the operation, low-dose postoperative aprotinin reduces postoperative mediastinal blood loss with 9,10 or without 8 a significant reduction in the use of blood products. It is unknown, however, whether low-dose aprotinin administered after CPB has any beneficial effects in patients taking aspirin until just before the cardiac operation, a subgroup that is known to be at high risk of excessive postoperative bleeding and increased transfusion requirements. 11-13
Accordingly, the purpose of this single-center, prospective, double-blind, placebo-controlled study was to determine whether a single low-dose bolus of aprotinin given at the end of CPB reduced mediastinal drainage or blood product use in patients undergoing primary coronary artery bypass grafting (CABG) who had been receiving aspirin therapy until just before the operation.
Patients and methods
Patient selection
The study was performed in accordance with the guidelines of the National Health and Medical Research Council of Australia and approved by the Human Research and Ethics Committee at Monash Medical Center. Of the 64 consecutive patients referred to one surgeon (J.M.A.) for primary elective or urgent CABG with CPB between February and July 1998 who were considered suitable for enrollment in the study, 4 declined to participate; a further 5 were deemed ineligible for inclusion because of a preoperative bleeding diathesis (n = 1), extensive pericardial adhesions detected at the time of the operation (n = 1), or incomplete postoperative data sets (n = 3). The study cohort therefore comprised 55 patients who gave informed consent to participate in the study and who continued aspirin (150 mg/d) as part of medical management of their coronary vascular disease until the day before the operation but did not receive any other preoperative antiplatelet medication. The sample size of the aprotinin and placebo groups (n > 23) was calculated on the basis of an expected difference in mediastinal blood loss between groups of 400 mL (standard deviation [SD], 400 mL), a 2-tailed 
value of less than .05, and a ß value of .9.
Patients were randomized by a computer-generated random number sequence into an aprotinin (n = 26) and a placebo (n = 29) group. All clinical participants were double-blinded until the completion of the trial. A designated pharmacy liaison officer was responsible for the randomization, as well as for the preparation of placebo and treatment solutions, which were identical in their appearance and packaging. Patients initially received a test dose of aprotinin or placebo in the operating theater after the completion of sternal skin closure. If no adverse reaction occurred to the test, then either a total of 2 x 106 kallikrein inhibiting units (KIU) of aprotinin (Trasylol; Bayer AG, Leverkusen, Germany) or an equal volume of placebo (normal saline solution) was infused over approximately 20 minutes.
Operative procedure
Anesthetic and CPB management were standardized for all study patients. CPB was performed with a hollow-fiber membrane oxygenator (Cobe Duo, Arvada, Colo) and a vortex centrifugal pump (Medtronic BioMedicus, Eden Prairie, Minn). Hypothermia to 32°C was used in all cases. Cardioplegic arrest was induced by using antegrade and retrograde blood cardioplegia (Viaflex; Baxter, Toongabbie, New South Wales, Australia). On completion of each distal anastomosis, a further bolus of cold blood cardioplegic solution was given. After completion of the last distal anastomosis, warm substrate-enriched cardioplegic solution was delivered, and the aorta-coronary anastomoses were completed by means of a side-biting aortic clamp. With the exception of 1 patient in whom a saphenous vein graft was used, the left internal thoracic artery was used to graft the left anterior descending coronary artery, and radial artery and saphenous vein grafts were used as required. After discontinuation of CPB, all blood in the CPB circuit was returned to the patient in the operating theater.
Anticoagulation was achieved with sodium heparin (300 IU/kg) and monitored with serial measurements of the activated clotting time (ACT) performed with a kaolin-activated Hemotec device (Medtronic Hemotec Inc, Englewood, Colo). The ACT was maintained above 450 seconds at all times during CPB. At completion of CPB, heparin was reversed with protamine sulfate given in a 1:1 ratio. After this dose, a further 100 mg of protamine was given if the ACT remained above 140 seconds, whereas an additional 50 mg of protamine was administered if the ACT was between 120 and 140 seconds.
Postoperative measurements
Hemoglobin concentration, platelet count, fibrinogen level, and serum creatinine level were measured before the operation, on arrival of patients into the intensive care unit (ICU), and on days 1 and 5 after the operation, whereas the activated partial thromboplastin time (APTT) and international normalized ratio were measured before and immediately after the operation. Mediastinal drainage was measured at hourly intervals in the ICU, and mediastinal drains were removed when blood loss was less than 100 mL over 4 hours.
All patients had an electrocardiogram immediately after the operation and on postoperative days 1, 2, and 5, whereas serial creatine kinase (CK) MB isoenzyme measurements were performed on days 1 and 2. The diagnosis of myocardial infarction was made if the CK-MB level was greater than 5% of the total CK level and/or if new Q waves, a new left bundle branch block, or ST-segment elevation of greater than 2 mm in 2 consecutive leads were present on the electrocardiogram.
Blood product transfusion policy
Clear criteria for transfusion of blood products were established before the start of the trial. No patient received any blood product unless prior approval was given by either the cardiac surgeon or a delegated surgical trainee, barring an emergency. Blood products were administered after clinical consideration of the rate and total amount of blood loss, and the type of blood product used was based on the results of hematologic tests. Thus, homologous packed red cells were given if the hemoglobin concentration was less than 80 g/L, platelets were given if the platelet count was less than 90 x 109/L, fresh frozen plasma was given if the international normalized ratio was greater than 1.5, and cryoprecipitate was given if the serum fibrinogen level was less than 1 g/L. No drug other than aprotinin was administered to reduce postoperative bleeding. Return to the operating theater was considered if mediastinal blood loss exceeded 500 mL in 1 hour or 400 mL over 2 hours or was greater than 100 mL/h for 3 consecutive hours.
Statistical analyses
Statistical analyses were performed with the Statistical Package for the Social Sciences, Version 9.0.1 (SPSS Inc, Chicago, Ill). Statistical comparisons were performed with the Student t test for normally distributed variables, a Mann-Whitney test for nonnormally distributed data, and the 
2 test for discrete variables. On the basis of the visual impression that a linear relationship existed between cumulative blood loss and time in the initial postoperative period, 8,10 postoperative mediastinal drainage patterns were evaluated with mediastinal drainage-time relationships, which were constructed by plotting the cumulative drainage at 2-hour intervals for the initial 14 to 20 hours after the operation and analyzed with linear regression. The average regression line for each group was determined with the average slope method of Colquhoun, 14 in which the average slope and intercept were obtained from the weighted individual values. Results are expressed as means ± SD.
Results
The placebo and aprotinin groups were well matched with respect to their demographic features, CPB times, and heparin and protamine doses, as well as the number and type of vascular conduits used for grafting (Table 1). Apart from a higher serum creatinine level and APTT in the aprotinin group after arrival in the ICU, no significant differences in hematologic and biochemical variables were evident between the 2 groups before or after the operation (Table 2). Moreover, no deaths, perioperative myocardial infarctions, strokes, or acute renal failure occurred in either group, and no patient was returned to the operating theater for any reason.
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, C). Furthermore, the average slope of the relationship (ie, the rate of drainage) in the aprotinin group (28 ± 18 mL/h) was 65% of that of the placebo group (43 ± 21 mL/h, P < .005;Figure 2, D).
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The main finding of this single-center, prospective, randomized, double-blind, placebo-controlled study was that low-dose aprotinin given postoperatively had a significant benefit in patients undergoing primary CABG and continuing with aspirin therapy until just before cardiac operations. Specifically, the administration of a single dose of 2 x 106 KIU of aprotinin at the time of sternal skin closure in such patients not only reduced postoperative mediastinal blood loss by approximately 40% but also halved the number of patients requiring blood product transfusion in the immediate postoperative period.
When used prophylactically before CPB, during CPB, or both, aprotinin is generally given in a high-dose regimen as a bolus of 2 x 106 KIU before CPB, as a similar dose in the pump prime, and as a continuous infusion or repeat boluses during CPB. 1,7,15-17 The rationale underlying this regimen is the attainment of a stable plasma concentration of aprotinin during CPB that inhibits both the coagulation and fibrinolytic pathways. 1 A low-dose prophylactic approach, which consists of the addition of 2 x 106 KIU of aprotinin to the pump prime, has also been used. 17,18 The high-dose aprotinin regimen has been shown to be effective in reducing both mediastinal blood loss and homologous transfusion requirements in the absence or presence of pretreatment with aspirin before cardiac operations, 1,16 whereas the low-dose protocol appears to decrease blood loss but not transfusion requirements in patients pretreated with aspirin. 17,18
The proposition that administration of aprotinin confined to the period after cessation of CPB might also have a beneficial effect on postoperative bleeding was initially raised by the study of Angelini and colleagues, 19 which demonstrated that a bolus of 2 x 106 KIU of aprotinin followed by an infusion of 0.5 x 106 KIU/h had a profound hemostatic effect in 6 patients exhibiting a life-threatening bleeding diathesis after CPB. Subsequently, a randomized trial of a similar aprotinin dosage regimen starting 3 hours after cardiac operations reported a significant reduction in mediastinal blood loss but not in blood product use. 8 More recent studies have reported that a single 2 x 106 KIU bolus of aprotinin given to patients on arrival in the ICU after the operation not only reduced mediastinal blood loss and blood product use 9,10 but was as efficacious as high-dose aprotinin given before and during CPB. 9
The effectiveness of low-dose postoperative aprotinin has only been established in patients who were not taking aspirin or who had discontinued aspirin for 7 or more days before the operation. 9,10 The question of whether low-dose postoperative aprotinin has any benefit in patients in whom aspirin therapy is continued until the day before the operation has considerable clinical relevance, however, because low-dose aspirin is normally prescribed as part of routine medical management in patients with coronary artery disease to reduce anginal symptoms and the risk of thromboembolic episodes, myocardial infarction, and death. 20,21 Because aspirin use up until just before the operation increases the risk of excessive postoperative bleeding, 11,12 the likelihood of reoperation for bleeding, 13 and the use of homologous blood and blood products, 11,13 aspirin therapy is usually discontinued 5 to 10 days before an elective coronary vascular operation to reduce the risk of perioperative blood loss. 16,22 It is not always feasible, however, to delay cardiac operations until the risk of aspirin-induced bleeding is reduced, particularly in patients undergoing urgent operations, nor is it desirable, such as in patients with unstable angina and critical high-grade left main stenosis (>95%) or triple-vessel disease. Indeed, the proportion of patients taking aspirin before cardiac operations in published series is typically in the order of 35%. 7
In our study the aprotinin and placebo groups were comparable with respect to baseline characteristics and postoperative biochemical and hematologic measures, with 2 exceptions. First, the serum creatinine level was transiently higher by approximately 15% in the aprotinin group in the initial hours after drug administration, which is consistent with previous findings suggesting that aprotinin use may be associated with reversible renal dysfunction related to its active reabsorption by the proximal tubules and its gradual metabolism by renal lysosomal enzymes. 1 Second, the APTT of the aprotinin group was prolonged in the initial ICU sample, which is in accord with in vitro data 23 and the recognized inhibitory action of aprotinin on contact activation of the intrinsic clotting system. 1
The postoperative blood loss in the placebo group of our study (1570 mL) was within the range of 1515 to 1710 mL reported in the literature for aspirin-treated patients. 16,17 Administration of low-dose aprotinin after CPB had 2 beneficial effects on mediastinal drainage. First, mediastinal drainage was reduced in the aprotinin group, with the magnitude of the reduction in total drainage (approximately 40%) being within the range of 35% to 49% reported in patients in whom aspirin was discontinued 7 or more days before the operation. 9,10 In conjunction with this reduced mediastinal drainage, removal of mediastinal drain tubes occurred, on average, approximately 7 hours earlier in the group receiving low-dose postoperative aprotinin.
Use of linear regression analysis to examine the mediastinal blood loss pattern in greater detail indicated that the decrease in blood loss after aprotinin in our study was associated with a reduction in both the intercept and slope of cumulative blood loss–time relationship. These findings suggest that the reduced overall mediastinal drainage associated with aprotinin administration constituted a combination of 2 effects, namely an initial fall in drainage occurring in conjunction with drug administration followed by a persistent reduction in the subsequent rate of drainage over the first postoperative day. These results are also in accord with the graphic representation of data presented in previous studies in patients not taking aspirin and undergoing cardiac operations. 8,10
The reduction in mediastinal drainage associated with the use of low-dose postoperative aprotinin in our study had an additional clinical benefit because it was accompanied by a reduced use of total blood products, with significant differences evident in the need for packed cells, platelets, and fresh frozen plasma. Furthermore, the major factor contributing to this lesser blood product use was a marked fall in the proportion of patients requiring transfusion after CPB from 62% in the placebo group to 31% in the aprotinin group, which is similar to the corresponding values of 60% to 65% and 32% to 37% reported in patients not receiving aspirin therapy. 9,10 Importantly, however, there was no significant difference in the amount of blood products given to those patients in the placebo and aprotinin groups requiring transfusion. Taken together, our observations therefore imply that the fall in blood product use associated with administration of low-dose postoperative aprotinin in our study was principally related to a profound hemostatic effect of this agent in approximately 30% of patients undergoing CPB, in whom the need for blood products after the operation was avoided.
When given before and after CPB in a high-dose regimen, aprotinin ameliorates the hemostatic defect produced by CPB through a prophylactic action mediated by means of inhibition of plasmin- and kallikrein-mediated fibrinolysis 1 and preservation of the platelet membrane glycoprotein 1b adhesion receptor function. 24 However, although the results of our study and those of others 8-10 suggest that postoperative low-dose aprotinin reduces mediastinal blood loss and blood product use, the precise mechanisms that underpin the beneficial effect of this regimen still remain to be defined. Future studies will be needed to establish the relative extent to which reversals in the abnormalities of coagulation activity, fibrinolysis, and platelet function produced by CPB 1 contribute to this beneficial effect of postoperative low-dose aprotinin.
Despite its widespread use, one issue that is still not entirely resolved relates to the optimal manner of aprotinin administration in the setting of a CPB procedure. It has been suggested that many patients treated with aprotinin are unnecessarily exposed to the potential adverse effects of this agent and that it may therefore be more prudent to limit use of this drug to patients exhibiting evidence of excessive bleeding after CPB. 9,10 This proposition was recently examined by Forestier and colleagues 25 in patients who demonstrated active bleeding during the first 3 hours after arrival in the ICU after CPB and was shown not to be of any benefit compared with placebo. However, it is likely that this negative outcome was influenced by at least 2 factors. First, the timing of postoperative aprotinin dose appears to be important because administration up to 3 hours after patient arrival in the ICU produces only a 25% reduction in mediastinal blood loss without any fall in blood product use, 8 whereas aprotinin administration at the time of sternal skin closure (present study) or on patient arrival in the ICU 9,10 results in a larger fall in mediastinal blood loss (35%-49%), as well as a reduction in blood product use. Second, the dosing schedule of Forestier and colleagues26 (0.2 x 106 KIU bolus followed by an infusion of 0.1 x 106 KIU/h for 8 hours) was estimated to have produced a plasma aprotinin concentration of 45 to 50 KIU/mL, which is considerably lower than the thresholds of 125 and 250 KIU/mL reported to be required for inhibition of fibrinolysis and coagulation processes, respectively. 1
References
This article has been cited by other articles:
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  D. R. McIlroy, P. S. Myles, L. E. Phillips, and J. A. Smith Antifibrinolytics in cardiac surgical patients receiving aspirin: a systematic review and meta-analysis Br. J. Anaesth., February 1, 2009; 102(2): 168 - 178. [Abstract] [Full Text] [PDF]
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 J. R. Brown, N. J.O. Birkmeyer, and G. T. O'Connor Meta-Analysis Comparing the Effectiveness and Adverse Outcomes of Antifibrinolytic Agents in Cardiac Surgery Circulation, June 5, 2007; 115(22): 2801 - 2813. [Abstract] [Full Text] [PDF]
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 C. P. Cannon, S. R. Mehta, and S. F. Aranki Balancing the Benefit and Risk of Oral Antiplatelet Agents in Coronary Artery Bypass Surgery Ann. Thorac. Surg., August 1, 2005; 80(2): 768 - 779. [Abstract] [Full Text] [PDF]
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 D. Fergusson, K. C. Glass, B. Hutton, and S. Shapiro Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clinical Trials, June 1, 2005; 2(3): 218 - 232. [Abstract] [PDF]
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V. A. Ferraris, S. P. Ferraris, D. J. Moliterno, P. Camp, J. M. Walenga, H. L. Messmore, W. P. Jeske, F. H. Edwards, D. Royston, D. M. Shahian, et al. The Society of Thoracic Surgeons Practice Guideline Series: Aspirin and Other Antiplatelet Agents During Operative Coronary Revascularization (Executive Summary) Ann. Thorac. Surg., April 1, 2005; 79(4): 1454 - 1461. [Full Text] [PDF]
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 E. Akowuah, V. Shrivastava, and G. Cooper Coronary artery bypass graft surgery in patients with recent exposure to clopidogrel and aspirin therapy J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1425 - 1426. [Full Text] [PDF]
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