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J Thorac Cardiovasc Surg 1994;107:554-0561
© 1994 Mosby, Inc.

Cardiopulmonary Bypass, Myocardial Management, and Support Techniques

Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations

London and Etobicoke, Ontario, Canada

Supported in part by Miles Canada Inc.

Received for publication Feb. 2, 1993. Accepted for publication June 9, 1993. Address for reprints: John M. Murkin, MD, FRCPC, Department of Anaesthesia, University Hospital, 339 Windermere Rd., London, Ontario, Canada N6A 5A5.

Abstract

Background: Patients with heart disease are frequently maintained on a regimen of aspirin because of its ability to decrease thrombotic complications and reduce the prevalence of unstable angina and myocardial infarction. Aspirin-induced platelet acetylation also increases bleeding caused by impairment of platelet function during cardiac surgery. Methods: Between October 1990 and November 1991 this double-blind, randomized, placebo-controlled, parallel group interventional study examined the efficacy of high-dose aprotinin administration (up to 7 million KIU) to decrease blood loss and transfusion requirements in patients receiving aspirin within 48 hours of undergoing coronary bypass or valvular heart operations. Primary outcome measures in this study were total volume of blood loss (intraoperative blood loss plus postoperative chest tube drainage) and volume of transfusion during hospitalization. Results: Patients treated with aprotinin (n = 29) had significantly lower total blood loss (1409 ± 232 ml versus 2765 ± 248 ml; p = 0.0002), intraoperative blood loss (503 ± 53 ml versus 1055 ± 199 ml; p = 0.0001), postoperative blood loss (906 ± 204 ml versus 1710 ± 202 ml; p = 0.0074), and prevalence of transfusion (59% versus 88% of patients; p = 0.016) than the placebo group (n = 25). The prevalence of complications including myocardial infarction was similar in the two groups. Conclusions: High-dose aprotinin significantly reduces blood loss and red blood cell transfusions in patients receiving aspirin who undergo cardiac operations. (J THORAC CARDIOVASC SURG 1994;107:554-61)

Patients with ischemic heart disease are often maintained on a regimen of aspirin in addition to other antianginal medications because of the demonstrated ability of aspirin to decrease anginal symptoms. ^1-4 The antiplatelet effect of aspirin is due to irreversible acetylation of cyclooxygenase enzyme and lasts for the lifetime of the platelet. Inhibition of platelet aggregation has been shown to occur after a single dose of 2 mg · kg^-1 and lasts for 72 hours. ⁵ In patients undergoing cardiac surgery who receive aspirin therapy, bleeding and transfusion requirements ^6-9 and surgical reexploration ¹⁰ are much greater than in untreated patients.

Aprotinin, a serine protease inhibitor isolated from bovine lung, has been demonstrated to decrease bleeding after cardiac surgery by mechanisms including antifibrinolytic activity and preservation of platelet function. ^11-14 In addition, a preliminary open-label study with high-dose aprotinin reported a marked reduction in blood loss and transfusion requirements in aspirin-treated patients undergoing coronary bypass operations. ¹⁵ We therefore undertook to examine the efficacy of high-dose aprotinin using a rigorous double-blind, placebo-controlled protocol in patients receiving aspirin until within 48 hours of first-time cardiac surgery.

METHODS

This was a single-center, randomized, double-blind, placebo-controlled comparison of the efficacy of aprotinin and placebo to decrease bleeding and transfusion requirements in patients undergoing cardiac operations who had been treated with aspirin.

Patients undergoing first-time coronary bypass or valvular heart operations requiring cardiopulmonary bypass (CPB), who had received aspirin for at least 1 week, with the last dose taken within 48 hours of the operation, who were over the age of 18 years, and who weighed 40 to 120 kg were recruited for this study from the elective surgical list. Patients with impaired renal function or hepatic dysfunction, those with a known allergy to aprotinin, or patients with previous exposure to aprotinin, including any patients with a history of acute pancreatitis, were excluded from this study.

Sample size was calculated by an expected difference in blood loss between groups of 250 ml, standard deviation of 250 ml, two-tailed = 0.05, ß = 0.8, with n = 25. By means of a computer-generated random code, patients were randomized to receive aprotinin (up to 7 million kallikrein inactivator units, KIU) or an equal volume of placebo according to the following regimen: 200 ml (2 million KIU) loading dose including an initial 5 ml dose given after establishment of full monitoring and anesthesia; 200 ml (2 million KIU) added to the CPB pump prime; continuous infusion of 50 ml (500,000 KIU) every hour throughout the operation and for 1 hour after the patient had returned to the intensive care unit (ICU). The maximum dose of aprotinin was 700 ml (7 million KIU).

After establishment of all routine monitors, patients were anesthetized by high-dose narcotic anesthetic technique. After sternotomy, a heparin dose of 300 to 400 IU · kg^-1 was administered before cannulation and titrated to maintain the activated clotting time (ACT) greater than 450 seconds. Patients underwent hypothermic nonpulsatile CPB with a membrane oxygenator (Cobe CML, Cobe Laboratories, Inc., Lakewood, Colo.), primed with 2000 ml Ringer's lactate solution, and a 40 µm arterial line filter and were cooled to a nasopharyngeal temperature of 28° C. Two surgeons used crystalloid cardioplegia and the other two used blood cardioplegia to achieve myocardial preservation during aortic crossclamping. All blood shed during the period of systemic heparinization was returned to the CPB circuit. At the completion of CPB, all blood was drained from the CPB circuit and readministered to the patient as autologous blood before leaving the operating room.

Patients were returned to the ICU after the operation and their lungs were ventilated overnight according to clinical practice. Administration of fluids for volume expansion, as well as vasoactive and inotropic drug use, were according to ICU clinical protocol as indicated to maintain hemodynamic stability. Administration of packed red blood cells was at the discretion of the attending physicians, with guidelines for transfusion being a hematocrit value less than 20% or mixed venous oxygen saturation less than 60% during the operation or hemoglobin concentration less than 80 gm/L or chest tube drainage in excess of 500 ml in any 12-hour period after the operation.

Intraoperative blood loss was measured by summation of the volume of blood in suction and weight of sponges. Postoperative blood loss was measured and recorded hourly by observing the volume of drainage into volumetric chest tube drains until their removal (approximately 36 hours). The total volumes of transfusions of packed red blood cells, platelets, and fresh frozen plasma during hospitalization, plus perioperative infusions of intravenous fluids, were recorded.

Blood was drawn for complete blood count, electrolytes (sodium, potassium, chlorine), fibrinogen, urea, creatinine, and bilirubin before the operation, at the end of the operation, and 5 to 7 days after the operation (or at discharge if sooner); samples for complete blood count were additionally obtained after 60 minutes of CPB and at 24 hours after the operation.

Primary and secondary efficacy parameters were total volume of blood lost and volume of transfusion (packed red blood cells, platelets and fresh frozen plasma, respectively) and were assessed between groups by means of unpaired t tests. Additional analyses including a test for interaction of treatment with internal mammary artery usage, for blood loss, transfusion, and time to close the chest were done by means of an analysis of variance model. Fisher's exact test was used to test the difference in the proportion of patients receiving transfusion in the two treatment groups.

The prevalence of clinically recognized adverse events was compared between groups by means of ² analysis. For diagnosis of myocardial infarction, postoperative electrocardiograms were obtained within 6 hours and at 24 hours after arrival in the ICU; they were considered diagnostic of myocardial infarction if persistent new Q waves were observed. If clinically indicated, the electrocardiograms were accompanied by serial measurements of creatine kinase–myocardial band (CK-MB) isoenzymes or coronary angiography. Cerebrovascular accidents were diagnosed on the basis of clinical observations of postoperative neurologic dysfunction resulting in neurologic consultation and subsequent computed tomographic scan of the head.

Clinically significant changes in laboratory values from before to after treatment and clinical complications were used to assess the safety of high-dose aprotinin in this population. For all data, p < 0.05 was required to achieve significance.

RESULTS

Between October 1990 and November 1991, 57 patients were randomized for this study. Three of them were subsequently ineligible because of cancellation of the operation in two and nonuse of CPB in the third. All remaining 54 patients were included for analysis. Data are reported as mean ± standard error of the mean.

In the aprotinin group, 24 patients underwent coronary artery bypass grafting, 4 underwent valve operations, and 1 underwent coronary bypass plus a valve operation. In the placebo group, 21 underwent coronary bypass, 4 underwent coronary bypass plus a valve operation, and none underwent a valve operation alone. There were no significant differences in the types of surgical procedures between groups (Table I).

The treatment groups were comparable with respect to age, disease characteristics, and dose and duration of aspirin therapy (Table II). There was no difference in the mean intraoperative heparin dosage administered to the aprotinin- and placebo-treated patients, 27,889 ± 916 IU versus 28,783 ± 2,209 IU, respectively.

After heparinization and during CPB, there was a significant difference in ACT between the aprotinin and the placebo groups, with significantly more aprotinin-treated patients having ACTs of more than 1000 seconds (Fig. 1). There were no significant differences in hemoglobin concentrations either at baseline or at any other time between the aprotinin- and the placebo-treated groups (Fig. 2).

View larger version (20K): [in this window] [in a new window]   Fig. 1. Distribution of highest ACT by treatment group. Significantly more aprotinin-treated patients had ACT greater than 1000 seconds.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Mean hemoglobin concentration in aprotinin and placebo groups during their hospitalizations. There were no differences between groups at anytime. S.E., Standard error.

The prevalence of adverse events was comparable in the two groups. Three patients in each group evidenced postoperative myocardial infarction. In the aprotinin group, one myocardial infarction was reported as definite on the basis of electrocardiographic and CK-MB evidence and was later confirmed by angiography. Two infarctions were reported as possible or questionable on the basis of electrocardiographic criteria but normal CK-MB concentrations. In the placebo group, two myocardial infarctions were reported as definite on the basis of diagnostic electrocardiographic and CK-MB evidence. One additional patient in the placebo group underwent catheterization, which was unable to differentiate between a myocardium injured by surgery (stunned) and infarction. In total, three myocardial infarctions (one definite) were reported in the aprotinin group and three (two definite) in the placebo group, differences which were not significant.

One patient in the aprotinin group and four patients in the placebo group had documented neurologic events. Four events were confirmed on computed tomographic scan and considered as consistent with embolic events. These were variously reported to be in the left frontal area, bilateral hemisphere (possibly old), right hemisphere, and right cerebral and left middle cerebral artery territories. Of these patients, two had evidence of extensive calcific and atheromatous plaques within the ascending aorta as reported in the operative note, one had undergone combined aortic valve replacement and triple coronary artery bypass grafting, and the remaining two patients had had sudden onset of atrial fibrillation after the operation, which was associated with the development of new neurologic signs. One patient was left with severe impairment, three had mild residual hemiparesis, and one patient had symptoms that resolved within 72 hours.

DISCUSSION

Aspirin is frequently administered to patients with cardiovascular disease to reduce the risk of myocardial infarction and death in unstable angina. ^1-4 Aspirin administered preoperatively and continued into the postoperative period has been shown to improve early graft patency rates. ¹⁶ Patients receiving preoperative aspirin also have increased blood loss associated with cardiac surgery. ^6-10

Because preoperative aspirin use is associated with significant increases in perioperative bleeding, it has been recommended that it be stopped 1 week or more before the operation. ^{6, 8, 9, 16} Aspirin irreversibly acetylates cyclooxygenase, thereby inhibiting the formation of thromboxane A₂ and leading to platelet dysfunction with decreased capillary vasoconstriction and impaired platelet aggregation. ^{17, 18} These effects persist for a week or more, until the population of acetylated platelets is substantially replaced.

Because it is not always possible to delay cardiac operations for a week or more until the risk of bleeding caused by aspirin use is reduced, effective pharmacologic therapy can have a significant clinical impact. An open-label study with high-dose aprotinin reported a marked reduction in blood loss and blood use when aprotinin was given to patients receiving aspirin and undergoing first-time coronary bypass grafting. ¹⁵

Aprotinin (Trasylol) is a serine antiprotease isolated from bovine lung. It has been known since the 1930s ^{19, 20} and was first reported clinically in 1953 for the treatment of acute pancreatitis and later for shock syndromes and hyperfibrinolytic hemorrhage. ²¹ In 1987, Royston and Bidstrup and colleagues ²² reported that high doses of aprotinin were found to reduce blood loss and blood use associated with cardiac operations. This was confirmed in later studies both in patients undergoing coronary bypass ^11-13 and in those at risk of high blood loss, for example, reoperation or septic endocarditis. ^23-26

In the current study the placebo and aprotinin groups were comparable with respect to baseline demographics and duration and dosage of aspirin therapy. All patients entered in the study had received therapeutic doses of aspirin for a sufficient time to have produced irreversible platelet acetylation and were maintained on aspirin therapy until within 48 hours of the operation (Table II).

Aprotinin significantly reduced total blood loss by over 50% in comparison with placebo. The volumes of blood lost after the operation in the placebo group are within the ranges reported in the literature for aspirin-treated patients. ^6-9 Concomitant with this effect of aprotinin to decrease bleeding was a significant reduction in the transfusion of packed red blood cells by 60%. Intraoperative transfusions of packed red blood cells, fresh frozen plasma, or platelets were significantly reduced in the aprotinin group, an effect that persisted for the duration of hospitalization because overall transfusion of any type-specific blood products (packed red blood cells, fresh frozen plasma, or platelets) was significantly decreased from 88% in the placebo group to 59% in the aprotinin group. Hemoglobin concentration was similar between groups at 24 hours and at 7 days (Fig. 2); thus aprotinin treatment did not substitute anemia for transfusion.

Reductions in bleeding and transfusion requirements would be expected to decrease the duration of the surgical procedure because less time will be required to achieve hemostasis. Also, this will tend to reduce the potential for prolonged stay in the ICU and decrease the duration of hospitalization, outcomes associated with large-volume blood transfusions. ¹⁰ Aprotinin-treated patients had significantly shorter operative times and tended to have a shorter duration of hospitalization. If these results can be translated into the larger surgical population, the potential associated cost savings are substantial. In a study such as this, with a relatively small sample size, it is possible that results can be skewed by a few outlying patients. Support for our observations has been obtained from a review of the United Kingdom experience, however, in which similar trends for decreased operative times and associated complications were seen. ²⁷

The differences in blood loss and transfusion requirements between groups cannot be explained by differences in the prevalence of autologous blood autotransfusion as effected by transfusion of residual blood from the oxygenator circuit, because all but three patients in the aprotinin group and two patients in the placebo group received this treatment. Mediastinal shed blood was not transfused. The types of surgical procedures performed were also not significantly different between groups, nor can the differences in blood loss between the groups be explained by differences in aspirin dose, duration of therapy, or time between the last aspirin dose and the start of the operation. Similarly, there were no differences in intraoperative heparin or protamine dosages; thus limitation of heparin dose does not account for these results.

Several studies have been conducted to determine the mechanism of action of aprotinin responsible for the decreases in bleeding associated with its use. Various studies demonstrating suppression of the rise in fibrinogen degradation products, ^{11-13, 28} preservation of ₂-antiplasmin activity, ¹¹ and decreased plasmin activity ¹³ during CPB indicate that aprotinin has significant antifibrinolytic activity.

In addition, significant effects of aprotinin on platelet function have also been demonstrated. van Oeveren and colleagues ¹³ have shown that aprotinin preserves platelet membrane glycoprotein Ib and IIb/IIIa receptors, and others have shown that nonspecific platelet activation during CPB, evidenced as increases in plasma thromboxane B₂ concentration, is significantly inhibited by aprotinin. ¹¹ In addition, a study using scanning electron microscope techniques demonstrated significantly better preservation of platelet aggregation after CPB in an aprotinin-treated group in comparison with a control group. ¹⁴

The ACT was significantly (p = 0.0001) longer in the aprotinin group and reached a maximum of more than 1000 seconds in a majority of the patients who received aprotinin (Fig. 1). Although it had been suggested that heparin dosage could be reduced in the presence of aprotinin, ²⁹ this theory is erroneous. ^{30, 31} The increase in ACT seen in the presence of aprotinin is largely artifactual because of an in vitro interaction between the celite activator, heparin, and aprotinin. ^{32, 33} As such, it is not recommended that the heparin dosage be reduced below the usual 300 to 400 IU · kg^-1, and the ACT should be maintained above 750 seconds during CPB in aprotinin-treated patients. ^{31, 34} Preliminary studies have indicated that a newer bedside test, the high-dose thrombin time, which is based on a modification of the thrombin time, may be better for managing anticoagulation during CPB. ³⁵

There was no difference in the prevalence of myocardial infarction in either group. This is in contradistinction to a recent report by Cosgrove and colleagues, ³⁶ which, while similarly demonstrating significant reductions in blood loss and transfusion requirements, noted an apparent dose-related trend for increased Q-wave myocardial infarction in aprotinin-treated patients. Although the reasons for this divergence remain unclear and possibly relate to differences in patient characteristics, in our study the total heparin dosage was identical between groups. Cosgrove and associates ³⁶ have speculated that the increased ACT in their aprotinin-treated patients may have led to underanticoagulation. Bidstrup ³⁷ used magnetic resonance imaging 7 to 8 days after the operation to assess graft patency in aprotinin-treated and nontreated patients undergoing coronary artery bypass and were unable to demonstrate any difference in graft patency between groups. Aprotinin has been demonstrated to decrease intraoperative platelet aggregability to adenosine diphosphate stimulation, platelet adhesiveness to glass beads, ³⁸ and platelet thromboxane release, ¹³ all factors involved in initiation of thrombosis.

The trend for the lower prevalence of clinically apparent cerebrovascular accidents in the aprotinin-treated patients, although not statistically significant, is worthy of comment. Given the prevalence of subtle neurologic dysfunction occurring after coronary bypass grafting, variously reported as occurring in 48% to 61% of patients when assessed prospectively, ^{39, 40} as well as the reported prevalence of overt stroke or major neurologic complications of 4.8% to 5.7%, ^{39, 40} amelioration of neurologic dysfunction remains as another important area of investigation. Review of safety data from 41 centers in the United Kingdom involving 671 patients treated with aprotinin and undergoing cardiac surgery with high-risk conditions (e.g., endocarditis, reoperations, or aspirin ingestion, revealed that four patients had died of postoperative cerebrovascular accident. ²⁷ This figure is lower than expected and may reflect a potential cerebroprotective effect of aprotinin. In addition to inhibition of kallikrein, a dose-dependent decrease in complement activation, kinin generation, and other plasma protease cascades is produced by aprotinin. ²¹ Recently, the synthetic serine protease inhibitor nafamostat mesylate (FUT-175) has been shown to prevent arterial narrowing in an experimental model of subarachnoid hemorrhage. ⁴¹ Clinically, administration of FUT-175 after cerebral aneurysm operations has resulted in lower rates of cerebral ischemia and poor outcome than those obtained in historical controls. ⁴² It is possible that serine protease inhibitors prevent or ameliorate the initial inflammatory endothelial response linked to the "no-reflow" phenomenon and thus improve outcome after cerebral ischemia. As a naturally occurring serine protease inhibitor, aprotinin may be producing similar salutary effects in the presence of ischemic cerebral injury.

Acknowledgments

The assistance of K. Wannamaker in the initial stages of this investigation, the support and cooperation of the cardiovascular anesthesiologists, perfusionists, and operating room nursing staff, and the aid of J. Mukherjee, PhD, with statistical analysis made this study possible.

Footnotes

From the Department of Anaesthesia^a and Division of Cardiovascular-Thoracic Surgery,^c University Hospital, University of Western Ontario, London, Ontario, and Miles Canada Inc.,^b Etobicoke, Ontario, Canada.

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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]

				C. K. Choong, C. Gerrard, K. A. Goldsmith, H. Dunningham, and A. Vuylsteke Delayed re-exploration for bleeding after coronary artery bypass surgery results in adverse outcomes Eur. J. Cardiothorac. Surg., May 1, 2007; 31(5): 834 - 838. [Abstract] [Full Text] [PDF]

				A. Ouattara, H. Bouzguenda, Y. Le Manach, P. Leger, A. Mercadier, P. Leprince, N. Bonnet, G. Montalescot, B. Riou, and P. Coriat Impact of aspirin with or without clopidogrel on postoperative bleeding and blood transfusion in coronary surgical patients treated prophylactically with a low-dose of aprotinin Eur. Heart J., April 12, 2007; (2007) ehm049v1. [Abstract] [Full Text] [PDF]

				A. Ronald and J. Dunning Does use of aprotinin decrease the incidence of stroke and neurological complications in adult patients undergoing cardiac surgery? Interactive CardioVascular and Thoracic Surgery, December 1, 2006; 5(6): 767 - 773. [Abstract] [Full Text] [PDF]

				G. Lindvall, U. Sartipy, and J. van der Linden Aprotinin Reduces Bleeding and Blood Product Use in Patients Treated With Clopidogrel Before Coronary Artery Bypass Grafting Ann. Thorac. Surg., September 1, 2005; 80(3): 922 - 927. [Abstract] [Full Text] [PDF]

				J. van der Linden, G. Lindvall, and U. Sartipy 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, August 30, 2005; 112(9_suppl): I-276 - I-280. [Abstract] [Full Text] [PDF]

				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]

				M. W.A. Chu, S. R. Wilson, R. J. Novick, L. W. Stitt, and M. A. Quantz Does Clopidogrel Increase Blood Loss Following Coronary Artery Bypass Surgery? Ann. Thorac. Surg., November 1, 2004; 78(5): 1536 - 1541. [Abstract] [Full Text] [PDF]

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				L. Y. Lee, W. J. DeBois, K. H. Krieger, and O. W. Isom Transfusion Therapy and Blood Conservation Card. Surg. Adult, January 1, 2003; 2(2003): 389 - 400. [Full Text]

				D. C. Lee, W. Ting, and M. C. Oz Myocardial Revascularization after Acute Myocardial Infarction Card. Surg. Adult, January 1, 2003; 2(2003): 639 - 658. [Full Text]

				R. H. Hongo, J. Ley, S. E. Dick, and R. R. Yee The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting J. Am. Coll. Cardiol., July 17, 2002; 40(2): 231 - 237. [Abstract] [Full Text] [PDF]

				J. M. Murkin Adverse Central Nervous System Outcomes After Cardiopulmonary Bypass: A Beneficial Effect of Aprotinin? Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 2001; 5(4): 282 - 285. [Abstract] [PDF]

				J. M. Alvarez, L. R. Jackson, C. Chatwin, and J. J. Smolich Low-dose postoperative aprotinin reduces mediastinal drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: A prospective, randomized, double-blind, placebo-controlled trial J. Thorac. Cardiovasc. Surg., September 1, 2001; 122(3): 457 - 463. [Abstract] [Full Text] [PDF]

				R. J. Dignan, D. W. Law, P. W. Seah, C. W. Manganas, D. C. Newman, P. W. Grant, and H. D. Wolfenden Ultra-low dose aprotinin decreases transfusion requirements and is cost effective in coronary operations Ann. Thorac. Surg., January 1, 2001; 71(1): 158 - 164. [Abstract] [Full Text] [PDF]

				J.-O. Defraigne, J. Pincemail, G. Dekoster, R. Larbuisson, M. Dujardin, F. Blaffart, J.-L. David, and R. Limet SMA circuits reduce platelet consumption and platelet factor release during cardiac surgery Ann. Thorac. Surg., December 1, 2000; 70(6): 2075 - 2081. [Abstract] [Full Text] [PDF]

				V. Casati, D. Guzzon, M. Oppizzi, F. Bellotti, A. Franco, C. Gerli, M. Cossolini, G. Torri, G. Calori, S. Benussi, et al. Tranexamic acid compared with high-dose aprotinin in primary elective heart operations: Effects on perioperative bleeding and allogeneic transfusions J. Thorac. Cardiovasc. Surg., September 1, 2000; 120(3): 520 - 527. [Abstract] [Full Text] [PDF]

				S. V Moran, G. Lema, J. Medel, M. J Irarrazaval, R. Zalaquett, B. Garayar, and R. Flaskamp Comparison of two doses of aprotinin in patients receiving aspirin before coronary bypass surgery Perfusion, March 1, 2000; 15(2): 105 - 110. [Abstract] [PDF]

				B. P. Bidstrup, B. J. Hunt, S. Sheikh, R. N. Parratt, J. M. Bidstrup, and R. N. Sapsford Amelioration of the bleeding tendency of preoperative aspirin after aortocoronary bypass grafting Ann. Thorac. Surg., February 1, 2000; 69(2): 541 - 547. [Abstract] [Full Text] [PDF]

				M. Klein, P.R. Keith, H.-P. Dauben, H.D. Schulte, H. Beckmann, G. Mayer, O. Elert, and E. Gams Aprotinin counterbalances an increased risk of peri-operative haemorrhage in CABG patients pre-treated with Aspirin Eur. J. Cardiothorac. Surg., October 1, 1999; 14(4): 360 - 366. [Abstract] [Full Text] [PDF]