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Circulation. 1995;92:2236-2244

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(Circulation. 1995;92:2236-2244.)
© 1995 American Heart Association, Inc.

Articles

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

Jerrold H. Levy, MD; Roque Pifarre, MD; Hartzell V. Schaff, MD; Jan C. Horrow, MD; Robert Albus, MD; Bruce Spiess, MD; Todd K. Rosengart, MD; Jeffrey Murray, MD; Richard E. Clark, MD; Peter Smith, MD; Andrea Nadel, PhD; Sharon L. Bonney, MD; Robert Kleinfield, PhD

From the Department of Anesthesiology, Emory University Hospital, Atlanta, Ga (J.H.L.); the Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Maywood, Ill (R.P.); the Section of Cardiovascular Surgery, Mayo Clinic, Rochester, Minn (H.V.S.); the Department of Anesthesiology, Hahnemann University, Philadelphia, Pa (J.C.H.); Virginia Heart Surgery Associates, Fairfax (R.A.); the Department of Anesthesiology, University of Washington Medical Center, Seattle (B.S.); the Division of Cardiothoracic Surgery, Cornell Medical Center, New York, NY (T.K.R.); the Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor (J.M.); the Division of Cardiothoracic Surgery, Duke University Medical Center, Durham, NC (P.S.); the Department of Surgery, Allegheny General Hospital, Pittsburgh, Pa. (R.E.C.); and Miles Inc Pharmaceutical Division, West Haven, Conn (A.N., S.L.B., R.K.).


*    Abstract
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 *Abstract
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Background Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when administered prophylactically to cardiac surgical patients. To examine the safety and dose-related efficacy of aprotinin, a prospective, multicenter, placebo-controlled trial was conducted in patients undergoing repeat coronary artery bypass graft (CABG) surgery.

Methods and Results Two hundred eighty-seven patients were randomly assigned to receive either high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume. The percentage of patients requiring donor–red-blood-cell (RBC) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and placebo, 75%; overall P=.001). The number of units of donor RBCs transfused was significantly lower in the aprotinin-treated patients compared with placebo (high-dose aprotinin, 1.6±0.2 U; low-dose aprotinin, 1.6±0.3 U; pump-prime-only, 2.5±0.3 U; and placebo, 3.4±0.5 U; P=.0001). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin, 2.2±0.4 U; low-dose aprotinin, 3.4±0.9 U; pump-prime-only, 5.1±0.9 U; placebo, 10.3±1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction (MI).

Conclusions This study demonstrates that high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI.


Key Words: cardiopulmonary bypass • aprotinin • bleeding • fibrinolysis • surgery


*    Introduction
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 *Introduction
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down arrowDiscussion
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Patients undergoing cardiac surgery with CPB are at significant risk for serious postoperative bleeding.1 2 This bleeding tendency is related both to the surgical procedure itself and to acquired defects in hemostasis resulting from extracorporeal circulation.1 2 3 4 A number of different pharmacological approaches have been taken to reduce bleeding and the need for donor-blood transfusion in cardiac surgical patients.5 6 7 8 9 10 11 12 One of the most effective agents tested to date, aprotinin, is a serine protease inhibitor that has both antifibrinolytic and platelet-preserving activities.13 14 15 16 17 18 Approved for use in Europe, aprotinin has been shown to be particularly effective in complex surgical procedures in which there is a high risk of postoperative bleeding.19 20 21 22 Administration of aprotinin in a high-dose regimen (2x106 KIU loading dose, 2x106 KIU into the CPB circuit, and 5x105 KIU/h continuous infusion during surgery) has been shown to reduce blood loss by 40% to 50% and to reduce the need for donor-blood transfusion by 40% to 80% in a variety of cardiac surgical procedures.23 24 25 26 27

In addition to a high-dose regimen, aprotinin has also been administered in a low-dose regimen (1x106 KIU loading dose, 1x106 KIU into the CPB circuit, and 2.5x105 KIU/h continuous infusion during surgery),28 29 30 31 and to the prime volume of the CPB circuit alone (2x106 KIU).32 In many of these studies, lower doses of aprotinin have also been shown to be effective at reducing blood loss and the requirement for donor-blood transfusion.28 29 30 31 These lower doses are of particular interest given the concern that agents that prevent blood loss may also increase the risk of thrombotic complications.27 Although there have been no reports of increased incidence of perioperative MI or graft occlusion in the large numbers of patients who received aprotinin in Europe,23 24 25 26 a recent study in the United States suggested a trend toward an increased incidence of MI in aprotinin-treated repeat CABG patients.27 In this study, after administration of a loading dose of heparin, additional heparin was given to maintain the whole-blood ACT >400 seconds. It is now known, however, that aprotinin artificially prolongs ACT (as measured with a celite activator) in patients undergoing CPB.33 34 35 36 37 Therefore, it has been suggested that the increased incidence of MI observed among aprotinin-treated patients in this study may have been a consequence of administration of inadequate anticoagulation therapy.

The present study was designed to evaluate the safety and efficacy of aprotinin administered in three different dosage regimens (high, low, and pump-prime-only) to patients undergoing repeat CABG surgery. In this study, the administration of heparin was carefully monitored by a method independent of whole-blood ACT, and the occurrence of perioperative MI was evaluated on a blinded basis by a central core laboratory.


*    Methods
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Study Design
This was a multicenter, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of aprotinin (Bayer AG) administered in three different dosage regimens to adult patients undergoing repeat CABG surgery. The study protocol was approved by an institutional review board at each of the 11 participating medical centers, and informed consent was obtained for all patients. A total of 287 patients were randomly assigned, by center, to one of the four treatment groups. The four treatment groups were: (1) high-dose aprotinin, consisting of 2x106 KIU aprotinin loading dose, 2x106 KIU added to the CPB circuit prime, and a continuous infusion of 5x105 KIU/h during surgery; (2) low-dose aprotinin consisting of 1x106 KIU aprotinin loading dose, 1x106 KIU added to the CPB circuit prime, and a continuous infusion of 2.5x105 KIU/h during surgery; (3) pump-prime aprotinin only, consisting of 2x106 KIU aprotinin added to CPB circuit prime; and (4) placebo.

Patient Characteristics
Male and female patients more than 18 years of age requiring repeat CABG through a previous median sternotomy were eligible for enrollment in the study. Patients requiring concomitant noncoronary procedures, patients with known or suspected allergy to aprotinin, patients with a history of bleeding diathesis or known coagulation factor deficiency, patients refusing to receive donor-blood products if necessary, and patients with a low preoperative hematocrit requiring the inclusion of donor blood in the bypass circuit prime were excluded from the study before surgery.

All 287 patients who received the study drug were eligible for the safety analysis, and 254 were eligible for the efficacy analysis. The criteria for exclusion of 33 patients from the efficacy analysis include: additional procedures before or during surgery (9 patients) including aortic (3 patients), pulmonary artery (1 patient), or mitral valve repair or replacement (2 patients), LVAD placement (2 patients), and IABP placement before surgery (1 patient); blood received in the pump prime (7 patients); reexploration due to surgical bleed (4 patients); random code unblinded (5 patients); aprotinin dosed improperly (4 patients); death within 6 hours after surgery (2 patients); additional procedures after surgery (1 patient); and reaction to test dose (1 patient). Exclusion from the efficacy analysis was decided before the random code was broken. Of the 287 patients eligible for the safety analysis, 73 were randomized to the high-dose group, 70 to the low-dose group, 72 to the pump-prime-only group, and 72 to the placebo group. Of the 254 patients eligible for the efficacy analysis, 61 were randomized to the high-dose group, 60 to the low-dose group, 68 to the pump-prime-only group, and 65 to the placebo group.

Administration of Study Drug
Aprotinin was supplied in 50-mL vials at a concentration of 1.4 mg/mL (10 000 KIU/mL) in 0.9% saline, with no additional preservatives or additives. An identically appearing placebo (0.9% saline) was supplied to all study centers. To maintain blinding, patients in all treatment groups received identical volumes of solution for the loading dose, for the pump-prime dose, and for the continuous infusion, irrespective of their treatment-group assignment. After induction of anesthesia but before administration of study drug, a test dose (0.05 mL) was given intravenously, and the patient was observed for evidence of hypersensitivity. After 10 minutes of observation, the patients were given the loading dose and started on a continuous infusion at a rate of 50 mL/h. The infusion was discontinued upon completion of surgery.

Control of Anticoagulation
Before cannulation of the heart, a heparin loading dose of at least 350 U/kg was administered to each patient. Additional heparin was administered to maintain the heparin concentration >=2.7 U/mL during CPB using a heparin/protamine titration performed with the Hepcon heparin monitoring system (Medtronic Hemotec).

Blood Conservation Techniques and Blood Replacement Policy
During surgery, blood from the operative field was salvaged, processed, and reinfused. After the termination of CPB the contents of the oxygenator were returned to the patient. Blood shed from the operative site was filtered, collected in the cardiotomy reservoir, and reinfused at specific intervals if the quantity of shed blood was sufficient.

During CPB, homologous donor RBCs were transfused if the patient's hematocrit was <18%. After surgery, homologous RBCs were transfused if the patient's hematocrit was <21%. Filling pressures were maintained by use of an appropriate plasma expander if the patient's hematocrit was above this critical threshold. These guidelines did not preclude transfusion of RBCs or other blood products if, in the opinion of the clinician, the patient's condition required it.

Efficacy and Safety Assessment
The primary measure of study-drug efficacy was reduction in the requirement for donor-RBC transfusion up to and including postoperative day 12. This criterion was analyzed in terms of the percentage of patients requiring any donor-RBC transfusions (primary analysis) and in terms of the units of donor RBCs required analyzed on a per-patient basis. The total number of units and the volume (in milliliters) of donor RBCs transfused during and after surgery were recorded. All blood products given during the first 24 hours after surgery, during postoperative days 2 through 12, and from day 13 through discharge were measured, including the number of units of RBCs, fresh frozen plasma, platelets, and cryoprecipitate administered. The thoracic-drainage volume (milliliters) and thoracic-drainage rate (milliliters per hour) were recorded for the first 6 hours after surgery. The thoracic-drainage volume was also measured in the interval from the sixth hour after surgery until removal of the thoracic drains.

Patients who were known prospectively to require donor RBCs or blood products in the priming volume for the CPB circuit were excluded from entry into the study. If RBCs or blood products were subsequently included in the priming fluid, the patients were treated as if they were transfused before surgery and were excluded from the efficacy analysis.

All adverse clinical events or laboratory abnormalities were recorded and assessed by the principal investigator with regard to relationship to the study drug and severity of the event. ECGs, SGOT levels, and LDH and CPK-MB values were evaluated on a blinded basis by the Core ECG Laboratory (CEL) at St Louis University Medical Center, headed by Bernard R. Chaitman, MD, to assess the incidence of perioperative MI. MI was defined by the appearance of diagnostic changes in the ECG or elevation in the CPK-MB activity in the postoperative period.38 Specifically, probable or definite perioperative MI was indicated by the presence of a new two-step Q-wave change in the Minnesota code as compared with the preoperative ECG, the new development of a persistent left bundle-branch block, or CPK-MB values >120 ng/mol at 6, 12, and 18 hours after surgery.39

Statistical Methods
All statistical tests for treatment effect were two-tailed and performed at the .05 level of significance. The primary efficacy variable was the percentage of patients requiring donor-RBC transfusions through postoperative day 12. Secondary efficacy variables were the number of units and the number of milliliters of donor RBCs required over the same period. The primary comparison was that of low-dose aprotinin to placebo. The study was designed to have 90% power to detect a 39% difference between low-dose aprotinin and placebo groups for the percentage of patients requiring donor blood under the null hypothesis of no-treatment difference. The primary efficacy variable and all other categorical variables (excluding incidence rates of adverse events and laboratory abnormalities) were analyzed using a Mantel-Haenszel test adjusting for center. {chi}2 tests were used to analyze laboratory abnormalities. For adverse events, Fisher's exact tests were used if at least one fourth of the cells had expected values of <5; otherwise {chi}2 tests were used. For patients to be included in the analyses of incidence rates of laboratory abnormalities, values must have been obtained baseline and postbaseline, and the abnormality must not have been present at baseline. In the laboratory and adverse-event analyses, probability values were used mainly as flags to indicate possible safety issues; adjustments for the multiplicity of tests done were not made.

Because of gross departures from normality, all variables accounting for the number of units or milliliters of donor RBCs or other blood products required were analyzed nonparametrically. These variables were ranked over all centers, with ties receiving the average rank. Ranked variables, as well as other continuous variables, were then analyzed by a standard two-way ANOVA model. The initial ANOVA model included the effects of drug, center, and drug-by-center interaction. For a center to be included in the interaction model, there had to be data for at least two patients per drug group. If there was no significant interaction, the main-effects model was used. For continuous variables that were analyzed nonparametrically, the arithmetic by drug-group means and standard errors on the nonranked data are presented in the tables for descriptive purposes. For all other continuous variables, the means and standard errors tabulated are the least-squares means with their associated standard errors.

Many of the efficacy analyses were repeated after one patient was excluded from the analysis. This patient received much more donor blood and blood product than other patients due to suspected protamine reaction and incomplete heparin reversal. As the continuous donor-blood-requirement variables were analyzed nonparametrically, this exclusion had little effect on the statistical evaluation of drug effect. The patient was removed primarily because of the effect on descriptive statistics, ie, means and standard errors. The patient was excluded from the analyses subsequent to unblinding of the random code. Although this study was not designed to have power to detect differences between high-dose and low-dose groups, retrospective analysis indicates the study had {approx}55% power to detect a 20% difference between full- and half-dose groups for the percentage of patients requiring donor blood.


*    Results
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*Results
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Treatment-Group Comparability
The demographic and surgical variables for the 254 patients eligible for efficacy analysis are shown in Table 1Down. There were no significant differences among treatment groups with respect to age, sex, morphometric variables, or disease severity. The patients ranged in age from 40 to 83 years, with the majority (90%) white men (95%) undergoing reoperative myocardial revascularization involving from two to four grafts. In most patients, reversed saphenous vein was used for one or more grafts, with in-situ internal mammary arteries used in 65% to 70% of patients. Other factors, such as percentage of patients with a history of unstable angina or MI, preoperative aspirin/NSAID use, and preoperative treatment with thrombolytic therapy, were similar among treatment groups.


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  		Table 1. Demographic and Surgical Variables of Patients Valid for Efficacy

There were no significant differences among treatment groups for most baseline hematologic variables including platelet count, prothrombin time, and partial thromboplastin time (data not shown). Although preoperative hemoglobin level and RBC count were lower at baseline in aprotinin treatment groups (high-dose and pump-prime) than placebo, these groups nevertheless had decreased requirements for donor RBCs and other blood products (see below).

Differences among treatment groups were noted for a number of surgical and intraoperative variables. Both the duration of surgery and the time required for chest closure were significantly reduced in the high- and low-dose aprotinin groups relative to placebo (Table 1Up). Fifteen of 254 patients received hemostatic agents (either desmopressin or {varepsilon}-aminocaproic acid) in addition to the study drug to control intraoperative or postoperative bleeding; 8 were in the placebo group, 4 in the pump-prime-only group, and 3 in the low-dose group. No patients in the high-dose group received either desmopressin or {varepsilon}-aminocaproic acid; pairwise comparisons between the high-dose group and the placebo group indicate that this difference is statistically significant (P=.003).

The amount of heparin administered during surgery was comparable among treatment groups; although less heparin was administered to the high-dose aprotinin group than the placebo group, this result was not statistically significant (Table 1Up). There was a statistically significant difference between the pump-prime-only and placebo groups in the amount of protamine used for heparin reversal (P=.046). Otherwise, the treatment groups were comparable in the amount of protamine administered for heparin reversal.

Transfusions of Donor RBCs
The percentage of patients requiring donor RBCs up to and including postoperative day 12 is shown in Table 2Down. Treatment with high-dose and low-dose aprotinin resulted in significant reductions in the percentage of patients requiring donor RBCs of 28% and 39%, respectively. There were also highly significant differences between treatment groups with respect to the mean number of units of donor RBCs required as analyzed on a per-patient basis, with high- and low-dose aprotinin groups requiring significantly less donor RBCs than the placebo group (Table 2Down). Although aprotinin administered as a pump-prime-only dose did not decrease the percentage of patients that required transfusion, in those patients requiring transfusion, it decreased the amount transfused from a mean of 3.4 units in the placebo group to 2.5 units in the pump-prime-only group. Due to extensive bleeding of a single patient in the low-dose group who suffered a suspected protamine reaction and did not receive complete heparin reversal, the mean number of units of donor RBCs transfused in this group would be significantly larger than in the high-dose group (2.3 units versus 1.6 units, respectively). However, by excluding this patient from the analysis, the low-dose and high-dose groups were similar, both in the percentage of patients requiring donor RBCs and the mean number of units required for transfusion (Table 2Down). Since this patient was considered to be well outside the remainder of the patient population, in all subsequent discussions of the study results this patient has been excluded from the analysis.


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  		Table 2. Donor-Blood Transfusion Requirement Up To and Including Postoperative Day 12

Transfusion of Other Donor-Blood Products
The percentage of patients requiring transfusions of any donor-blood products (RBCs, platelets, fresh frozen plasma, and cryoprecipitate) and the mean number of units transfused in each of the treatment groups are shown in Table 2Up. For each of these efficacy variables, aprotinin-treated patients utilized significantly fewer units of donor-blood products than the placebo group. Although there was no prospectively defined threshold for the transfusion of blood products other than RBCs, the largest reduction in blood-product utilization was in platelet transfusions, with a mean of 4.8 units in the placebo group, 2.1 units in the pump-prime group, 1.2 units in the low-dose group, and 0.5 units in the high-dose group.

Total Blood-Product Exposures
The total number of blood-product exposures for each of the treatment groups is compared in Table 2Up. The total number of exposures was calculated as the sum of the number of units of donor RBCs, platelets, fresh frozen plasma, and cryoprecipitate administered to each patient. Again, there are striking differences between treatment groups, with all aprotinin-treated patients having a significantly reduced exposure to blood products compared with placebo. Administration of aprotinin in high-dose or low-dose regimens resulted in an average reduction of seven to eight donor exposures relative to the placebo group.

Postoperative Thoracic Drainage
In addition to the reduced transfusion requirement in the aprotinin treatment groups, these groups also exhibited a substantially reduced blood loss (Table 3Down). Thoracic-drainage rate and thoracic-drainage volume during the first 6 hours were reduced in all aprotinin groups compared with the placebo group, with the greatest reductions noted in the high- and low-dose groups. These groups also had significantly less total thoracic drainage, as measured from the time of insertion until removal of the drains, with reductions in drainage volume of 47% and 38.5% relative to placebo in the high- and low-dose groups, respectively (patients undergoing reoperations were excluded from this analysis). The mean decrease in hemoglobin levels from baseline to discharge was also significantly lower in the high-dose group relative to placebo (Table 3Down).


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  		Table 3. Postoperative Thoracic Drainage and Mean Decrease in Hemoglobin

Incidence of MI
Based on the blinded analysis of data for MI, there were no statistically significant differences among treatment groups in the incidence of definite MI based on ECG or in the more inclusive category of definite, probable, or possible MI based on all of the available data (ECG, enzyme, and autopsy data) (see Table 4Down).


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  		Table 4. Incidence of MI as Evaluated on a Blinded Basis

Cardiovascular Complications
Complications affecting the cardiovascular system were reported with equal frequency in the overall comparisons between treatment groups for all categories except ventricular tachycardia, with a frequency of 13% (9 of 70 patients) in the low-dose group, compared with 1% (1 of 72) in the placebo group and 3% (2 of 73) in the high-dose group. In the subset of adverse events reported by the clinician as related to study-drug administration, however, the incidence of ventricular tachycardia was not statistically different among treatment groups.

There were no statistically significant differences between groups in the incidence of atrial fibrillation and flutter, ventricular fibrillation, hypotension, and heart failure. Placement of an IABP or LVAD during or after surgery was required in 22 of 189 aprotinin-treated patients (11.6%) and in 9 of 65 placebo-treated patients (14%). In the high-dose group, 4 of 61 patients (7%) required insertion of an IABP or LVAD for ventricular insufficiency.

Renal Dysfunction
The incidence of clinically significant postoperative renal insufficiency or failure was similar among treatment groups. As reported by the attending clinician, 19 of 215 aprotinin-treated patients (8.8%) and 6 of 72 placebo-treated patients (8.3%) were reported as suffering from renal failure, acute renal failure, or abnormal renal function in the postoperative period. There were no significant differences reported in the incidence of patients having peak increases in postoperative serum creatinine levels >44.2 µmol/L (0.5 mg/dL) and >176.8 µmol/L (2.0 mg/dL) over baseline levels (Table 5Down). In all treatment groups there was a transient decrease in serum creatinine levels in the immediate postoperative period, after which the creatinine levels increased above baseline levels and subsequently normalized. Among the aprotinin groups there was a trend toward a prolongation of the time required for creatinine levels to return to baseline. This difference was statistically significant only on postoperative day 5 for the low-dose group as compared with placebo (P=.0277). Although the mean change in final serum potassium levels was higher in all three aprotinin groups compared with placebo (0.30 mEq/dL, 0.20 mEq/dL, 0.19 mEq/dL, and -0.06 mEq/dL for the high-dose, low-dose, pump-prime-only, and placebo groups, respectively), there was no difference between groups in the incidence of hyperkalemia (defined as levels >5.5 mEq/L) (Table 5Down).


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  		Table 5. Laboratory Indexes of Kidney Function

Allergic Reaction
Out of the 215 patients administered active drug in this study, 1 patient in the high-dose group suffered from an allergic reaction characterized by a rash over the chest and neck area (incidence of 0.5%). There were no reports of anaphylactic shock in any of the patients enrolled in this study.

Incidence of Stroke
The incidence of stroke was reduced in the high- and low-dose aprotinin groups relative to placebo. Six of 287 patients (incidence of 2.1%) were reported by the attending clinician as suffering stroke; 5 were in the placebo group, and 1 was in the pump-prime-only group. There were no instances of stroke reported for either high- or low-dose aprotinin groups (overall P=.01).

Incidence of Reexploration
Seven of 254 patients (2.8%) valid for the efficacy analysis required reoperations for bleeding; 5 were in the placebo group, and 2 were in the pump-prime-only group. Four patients were not included in the efficacy analysis due to bleeding that was correctable by surgery; 1 was in the high-dose group, 2 were in the low-dose group, and 1 was in the pump-prime-only group. Five patients valid for the efficacy analysis suffered from bleeding that was not correctable by surgery (ie, diffuse bleeding); 3 of 65 (5%) were in the placebo group, and 2 of 68 (3%) were in the pump-prime-only group. There were no patients in either the high- or low-dose aprotinin groups who required reoperation for bleeding that was not of surgical origin.

Mortality
Twenty of 287 patients (overall incidence of 7%) enrolled in the study died during or after surgery; 15 of 215 patients (7%) were in the aprotinin treatment groups, and 5 of 72 patients (7%) were in the placebo group. There was no statistical difference in the incidence rates of death between treatment groups (overall P=.252), although the incidence was higher, 8 of 70 (11%), in the low-dose group.


*    Discussion
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*Discussion
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Excessive bleeding is one of the major complications of cardiac surgery with CPB. It has been estimated that 5% to 25% of patients undergoing cardiac surgery suffer life-threatening hemorrhage in the perioperative period, with {approx}3% of these patients requiring a return to the operating room for reexploration.40 41 A substantial fraction of these patients require donor-blood transfusion. Transfusion is associated with a number of risks.42 43 44 45 46 47 48 The most common serious side effects are infectious disease transmission and nonhemolytic transfusion reactions.42 43 44 In addition, transfusion may be associated with graft-versus-host disease46 and a decreased resistance to postoperative infection.47 48 Although the risks of transfusion have considerably diminished with the routine use of sensitive assays for viral detection, the cost of transfusion and limitations in the supply of banked blood have generated further interest in reducing transfusion requirements during cardiac surgical procedures.

In recent years, the use of a number of mechanical and physical techniques has resulted in significant reductions in the requirement for donor-blood transfusion. These techniques include the use of nonblood prime for the oxygenator system, normovolemic hemodilution before bypass, retransfusion after bypass, and salvage and reinfusion of blood from the operative field and blood shed postoperatively from the mediastinum.49 50 51 Until recently, most pharmacological methods to reduce bleeding have produced disappointing results.7 8 9 10 However, aprotinin, a serine protease inhibitor with a broad spectrum of activity, has been shown to be substantially effective in reducing the need for transfusion.19 20 21 22 52 Aprotinin is now routinely administered prophylactically in a high-dose regimen, with considerable success in cardiac surgical patients at a number of European centers.

The present study was undertaken to define further the dosage regimens at which aprotinin is effective at reducing blood loss and the requirement for donor-blood transfusion in repeat CABG patients. Due to recent concerns about the safety of administering aprotinin to coronary artery bypass patients,27 the safety profile at each dosage regimen was carefully evaluated. Particular attention was paid to assessing the incidence of MI. MI was defined prospectively using an algorithm based on ECGs, CPK-MB levels, operative reports, and autopsy reports.39 These data were evaluated on a blinded basis by an outside consultant, with MI classified as definite, definite/probable, definite/probable/possible, or no indication for MI on the basis of this outside evaluation.

In terms of efficacy, this study demonstrates that aprotinin in high- and low-dose regimens significantly reduces blood loss and the requirement for donor-blood transfusion. Both dosages were effective, conferring approximately a 40% to 50% reduction in blood loss and a 30% to 40% reduction in the percentage of patients requiring donor-RBC transfusions. Total donor exposures (RBCs, platelets, fresh frozen plasma, cryoprecipitate) were substantially reduced in all aprotinin treatment groups, with the most dramatic effects evident in the high- and low-dose groups, in which there was a mean decrease of seven to eight donor exposures per patient relative to the placebo group. The largest reductions in blood use were in the transfusions of RBCs and in transfusions of platelets, with the high-dose group utilizing 50% fewer units of RBCs and 85% fewer units of platelets than placebo. There was no indication for efficacy of the pump-prime-only dose with respect to either blood loss or transfusion requirement.

Additional support for efficacy is indicated by an analysis of the distribution of patients who received the hemostatic agents {varepsilon}-aminocaproic acid or desmopressin due to excessive blood loss in the postoperative period. The use of such agents was permitted in the protocol in those cases in which the patient's postoperative bleeding could not be controlled by other means and in which these agents were felt to be of potential benefit. There were no cases in which {varepsilon}-aminocaproic acid or desmopressin were administered to patients who received high-dose aprotinin. In the remaining three treatment groups, these agents were administered, with the number of patients correlated with the dose of aprotinin (low-dose, 3 patients; pump-prime, 5 patients; and placebo, 9 patients). Since these drugs were specifically given to reduce bleeding, their administration may have resulted in reduced thoracic drainage and transfusion, resulting in a potential underestimation of the efficacy of aprotinin.

Aprotinin treatment was also associated with reductions in the incidence of mediastinal reexploration due to nonsurgical bleeding (ie, diffuse bleeding) and with reductions in the incidence of stroke. Although the total number of patients represented in these groups is small, the results are statistically significant. A recent study of high-dose aprotinin in aspirin-pretreated CABG patients also reported a decreased incidence of stroke in the aprotinin-treated patients.53 Since stroke represents a major source of postoperative morbidity and mortality in cardiac surgical patients, this finding is of some clinical importance if supported by a larger, prospective analysis in which a uniform definition of stroke is used.

One of the principal safety concerns associated with the use of aprotinin is the potential for an increased risk of thrombotic complications and perioperative MI. A number of studies have demonstrated that administration of aprotinin to patients undergoing CPB surgery is consistently associated with a decreased level of fibrinolysis.15 16 17 18 21 It has been suggested that this reduction in the normally increased levels of fibrinolysis observed during and after CPB may result in more stable clot formation and consequently less bleeding in the perioperative period. However, the use of such antifibrinolytic agents could conceivably increase the risk of thrombus formation and perioperative MI.

In the extensive experience with aprotinin in Europe, however, there have been no indications of increased mortality or graft occlusion in cardiac surgical patients.6 19 20 21 22 23 Bidstrup et al,26 using magnetic resonance imaging to assess early saphenous-vein-graft patency, found no difference in the incidence of graft occlusion in 90 patients evaluated 7 to 10 days after surgery. Of 269 vein grafts analyzed, 126 (96.2%) of 131 grafts were patent in aprotinin-treated patients, and 134 (97.1%) of 138 in the placebo-treated control subjects. More recently, Lemmer et al,52 using ultrafast computed tomography to evaluate graft patency 7 to 60 days (mean, 27 days) after surgery, reported 162 (92%) of 176 grafts patent in aprotinin-treated patients compared with 155 (95.1%) of 163 grafts patent in the placebo group. Analysis of graft patency by Havel et al,54 using coronary angiography, also failed to reveal any difference between aprotinin-treated patients and placebo-treated control subjects.

Recently, however, Cosgrove et al27 reported a trend toward an increased incidence of MI in aprotinin-treated repeat CABG patients. Although the results were not statistically significant, the incidence of Q-wave infarction in the high-dose group was 17.5%, compared with 14.3% and 8.9% in the low-dose and placebo groups, respectively. Postmortem examinations from seven patients who died during the course of the study indicated thrombi in 6 of 12 vein grafts in aprotinin-treated patients, compared with 0 of 5 grafts in the placebo control subjects.

A potential explanation for the increased incidence of MI and graft occlusion reported in the Cosgrove study in the aprotinin-treated patients is the administration of inadequate anticoagulation during surgery. The extent of anticoagulation achieved during surgery was determined by measurement of ACT values, with additional heparin administered if the ACT fell to <400 seconds. However, it is now known that aprotinin interferes with the measurement of ACT values.32 33 34 35 36 37 55 56 When celite is used as a contact-activating agent (Hemochron, International Technodyne Corp), there is an artifactual prolongation of ACT that is independent of heparin concentration. Therefore, heparin administration based on celite ACT values may result in inadequate anticoagulation and consequent thrombotic complications in aprotinin-treated patients.

To avoid such complications in the present study, heparin levels were measured directly by titration with protamine (Hepcon, Medtronic Hemotec); additional heparin was administered to patients during surgery to maintain their heparin concentration >=2.7 U/mL. When heparin was monitored in this fashion, all treatment groups received comparable amounts of heparin. This consistency in heparin dosing among treatment groups is an important factor to consider when the risk for MI between aprotinin- and placebo-treated patients is compared.

Furthermore, evaluation of the occurrence of perioperative MI should be based on uniform criteria, since there is a high degree of variability among physicians in the clinical determination of MI. Because this study was designed to investigate rigorously the incidence of this complication, the occurrence of MI was evaluated on a blinded basis by a central core laboratory by use of a predetermined algorithm. The core laboratory was provided with ECGs and CPK-MB enzyme levels at regular timed intervals, copies of the operative report, and documentation of clinical events relevant to a determination of perioperative MI. The results of this blinded analysis indicate no significant differences in the incidence of MI in any of the three aprotinin groups when compared with placebo.

Since aprotinin accumulates in the renal tubular epithelium, it might be expected to have adverse effects on renal function.57 58 However, previous clinical experience with aprotinin has yielded no clear answers regarding the effect of aprotinin on renal function; in some studies aprotinin was found to have no effect, whereas in others it was found to be associated with elevations in postoperative serum creatinine levels. In any case, there have been no indications that aprotinin is associated with clinically significant postoperative renal insufficiency or failure.15 23 25 26 27

In this study, the incidence of postoperative serum creatinine elevations >=0.5 mg/dL above baseline was comparable with placebo for each of the three aprotinin groups. The incidence of clinically significant postoperative renal insufficiency, defined as abnormal kidney function, kidney failure, or acute kidney failure, was not different among treatment groups. Therefore, although aprotinin may have a transient and small effect on renal function, the clinical relevance of this effect is unclear.

In conclusion, aprotinin administered prophylactically to repeat CABG patients in high- and low-dose regimens effectively reduces blood loss and donor-blood requirement. Despite its potent antifibrinolytic properties, aprotinin does not increase the risk of MI nor does it increase the incidence of renal dysfunction in our study. Potential benefits of aprotinin include reductions in the incidence of stroke and reexploration due to nonsurgical bleeding. Given the risks associated with transfusion, the limitations in the supply of banked blood, and the cost of donor blood and blood products, aprotinin represents an important and, with the available clinical experience, safe new approach to blood conservation.


*    Selected Abbreviations and Acronyms
 
ACT = activated clotting time
CABG = coronary artery bypass graft
CPB = cardiopulmonary bypass
CPK-MB = creatine phosphokinase MB isozyme
IABP = intra-aortic balloon pump
KIU = kallikrein inactivator units
LVAD = left ventricular–assist device
MI = myocardial infarction
RBC = red blood cell


*    Acknowledgments
 
This work was supported by a research grant from Miles Inc Pharmaceutical Division, West Haven, Conn. The authors wish to acknowledge the following for their participation in the study: Rebecca Safon, RN; Marcy Steinberg, RN, CRNA; James J. Morris, MD; Charles J. Mullany, MB, MS; William O. Oliver, MD; Thomas A. Orszulak, MD; Jane Fitch, MD; M. Louise Soltow; G. Michael Deeb, MD; Louis F. Brunsting III, MD; Steven F. Bolling, MD; Joyce A. Water, MD; and Kay Smith, BSN, RN.


*    Footnotes
 
Reprint requests to Jerrold H. Levy, MD, Emory University Hospital, 1364 Clifton Rd NE, Atlanta, GA 30322.

Received March 1, 1995; revision received April 24, 1995; accepted May 3, 1995.


*    References
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*References
 

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