(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
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.).
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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
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Introduction |
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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.
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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. 
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 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 
55% power to detect a 20% difference between full- and
half-dose groups for the percentage of patients requiring donor
blood.
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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 1
. 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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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 1
).
Fifteen of 254 patients received hemostatic agents (either desmopressin
or 
-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 -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 1). 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 2.
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 2).
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 2).
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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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 2. 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 2. 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 3). 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 3).
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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 4).
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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 5). 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 5).
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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.
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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
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
-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
-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.
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Selected Abbreviations and Acronyms |
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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 |
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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.
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References |
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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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W. Beierlein, A. M. Scheule, W. Dietrich, and G. Ziemer Forty Years of Clinical Aprotinin Use: A Review of 124 Hypersensitivity Reactions Ann. Thorac. Surg., February 1, 2005; 79(2): 741 - 748. [Abstract] [Full Text] [PDF]
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 A. M. Mahdy and N. R. Webster Perioperative systemic haemostatic agents Br. J. Anaesth., December 1, 2004; 93(6): 842 - 858. [Abstract] [Full Text] [PDF]
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A. Sedrakyan, T. Treasure, and J. A. Elefteriades Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: A systematic review and meta-analysis of randomized clinical trials J. Thorac. Cardiovasc. Surg., September 1, 2004; 128(3): 442 - 448. [Abstract] [Full Text] [PDF]
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P. K. Smith, S. K. Datta, L. H. Muhlbaier, G. Samsa, A. Nadel, and J. Lipscomb Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials Ann. Thorac. Surg., February 1, 2004; 77(2): 635 - 642. [Abstract] [Full Text] [PDF]
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L. Shore-Lesserson, D. L. Reich, and D. H. Adams Invited commentary Ann. Thorac. Surg., February 1, 2004; 77(2): 642 - 643. [Full Text] [PDF]
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 S. Vernon and G. M. Pfeifer Blood Management Strategies for Critical Care Patients Crit. Care Nurse, December 1, 2003; 23(6): 34 - 41. [Full Text] [PDF]
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D. P. Taggart, V. Djapardy, M. Naik, and A. Davies A randomized trial of aprotinin (Trasylol) on blood loss, blood product requirement, and myocardial injury in total arterial grafting J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1087 - 1094. [Abstract] [Full Text] [PDF]
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N. A. Nussmeier, C. B. Probert, D. Hirsch, J. R. Cooper Jr., I. D. Gregoric, T. J. Myers, and O. H. Frazier Anesthetic Management for Implantation of the Jarvik 2000TM Left Ventricular Assist System Anesth. Analg., October 1, 2003; 97(4): 964 - 971. [Abstract] [Full Text] [PDF]
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J. M. Costello, C. L. Backer, A. de Hoyos, H. J. Binns, and C. Mavroudis Aprotinin reduces operative closure time and blood product use after pediatric bypass Ann. Thorac. Surg., April 1, 2003; 75(4): 1261 - 1266. [Abstract] [Full Text] [PDF]
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R. J. Frumento, C. M.N. O'Malley, and E. Bennett-Guerrero Stroke after cardiac surgery: a retrospective analysis of the effect of aprotinin dosing regimens Ann. Thorac. Surg., February 1, 2003; 75(2): 479 - 483. [Abstract] [Full Text] [PDF]
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J. H. Levy Invited commentary Ann. Thorac. Surg., February 1, 2003; 75(2): 483 - 484. [Full Text] [PDF]
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J. H. Levy and K. A. Tanaka Inflammatory response to cardiopulmonary bypass Ann. Thorac. Surg., February 1, 2003; 75(2): S715 - 720. [Abstract] [Full Text] [PDF]
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J. M. Bailey, K. A. Tanaka, and J. H. Levy Cardiac Surgical Pharmacology Card. Surg. Adult, January 1, 2003; 2(2003): 85 - 118. [Full Text]
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B. W. Lytle Coronary Artery Reoperations Card. Surg. Adult, January 1, 2003; 2(2003): 659 - 679. [Full Text]
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 L. Englberger, P. Markart, F.S. Eckstein, F.F. Immer, P.A. Berdat, and T.P. Carrel Aprotinin reduces blood loss in off-pump coronary artery bypass (OPCAB) surgery Eur. J. Cardiothorac. Surg., October 1, 2002; 22(4): 545 - 551. [Abstract] [Full Text] [PDF]
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J. S. Tweddell, G. M. Hoffman, K. A. Mussatto, R. T. Fedderly, S. Berger, R. D. B. Jaquiss, N. S. Ghanayem, S. J. Frisbee, and S. B. Litwin Improved Survival of Patients Undergoing Palliation of Hypoplastic Left Heart Syndrome: Lessons Learned From 115 Consecutive Patients Circulation, September 24, 2002; 106(12_suppl_1): I-82 - I-89. [Abstract] [Full Text] [PDF]
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L. Englberger, B. Kipfer, P. A. Berdat, U. E. Nydegger, and T. P. Carrel Aprotinin in coronary operation with cardiopulmonary bypass: does "low-dose" aprotinin inhibit the inflammatory response? Ann. Thorac. Surg., June 1, 2002; 73(6): 1897 - 1904. [Abstract] [Full Text] [PDF]
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I. Q. Molenaar, R. J. Porte, M. G. Fitzsimons, and R. A. Peterfreund Aprotinin and Thromboembolism in Liver Transplantation: Is There Really a Causal Effect? * Response Anesth. Analg., May 1, 2002; 94(5): 1367 - 1368. [Full Text] [PDF]
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G. A. Nuttall, D. N. Fass, L. J. Oyen, W. C. Oliver Jr., and M. H. Ereth A Study of a Weight-Adjusted Aprotinin Dosing Schedule During Cardiac Surgery Anesth. Analg., February 1, 2002; 94(2): 283 - 289. [Abstract] [Full Text] [PDF]
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J. M. Murkin, J. Maurer, and S. Niemcryk Full dose aprotinin administration is associated with a significant decrease in perioperative stroke in patients undergoing elective cardiac surgery: a meta-analysis Ann. Thorac. Surg., January 1, 2002; 73(1): S374 - 374. [Full Text] [PDF]
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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]
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J. H. Levy Pharmacologic preservation of the hemostatic system during cardiac surgery Ann. Thorac. Surg., November 1, 2001; 72(5): S1814 - 1820. [Abstract] [Full Text] [PDF]
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G. J. Despotis, M. S. Avidan, and C. W. Hogue Jr Mechanisms and attenuation of hemostatic activation during extracorporeal circulation Ann. Thorac. Surg., November 1, 2001; 72(5): S1821 - 1831. [Abstract] [Full Text] [PDF]
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J. M. Murkin Attenuation of neurologic injury during cardiac surgery Ann. Thorac. Surg., November 1, 2001; 72(5): S1838 - 1844. [Abstract] [Full Text] [PDF]
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C. T. Mora Mangano, M. J. Neville, P. H. Hsu, I. Mignea, J. King, and D. C. Miller Aprotinin, Blood Loss, and Renal Dysfunction in Deep Hypothermic Circulatory Arrest Circulation, September 18, 2001; 104 (2009): I-276 - I-281. [Abstract] [Full Text] [PDF]
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H. A. Hennein Inflammation After Cardiopulmonary Bypass: Therapy for the Postpump Syndrome Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 236 - 255. [Abstract] [PDF]
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J. Tatoulis, B. F. Buxton, and J. A. Fuller The radial artery in coronary re-operations Eur. J. Cardiothorac. Surg., March 1, 2001; 19(3): 266 - 273. [Abstract] [Full Text] [PDF]
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 J. P. Gott Leukodepletion and aprotinin improve clinical outcome after extracorporeal circulation Perfusion, January 1, 2001; 16(1_suppl): 5 - 9. [Abstract] [PDF]
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D. M. McMullan, E. A.K. Beyer, I. Gregoric, B. Radovancevic, and O.H. Frazier Left ventricular reduction in a Jehovah's Witness Ann. Thorac. Surg., September 1, 2000; 70(3): 958 - 960. [Abstract] [Full Text] [PDF]
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J. H. Levy Platelet inhibitors and bleeding in cardiac surgical patients Ann. Thorac. Surg., August 1, 2000; 70(2): S9 - 11. [Abstract] [Full Text] [PDF]
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S. M. Beath, G. A. Nuttall, D. N. Fass, W. C. Oliver Jr., M. H. Ereth, and L. J. Oyen Plasma Aprotinin Concentrations During Cardiac Surgery: Full- Versus Half-Dose Regimens Anesth. Analg., August 1, 2000; 91(2): 257 - 264. [Abstract] [Full Text] [PDF]
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L. H. Edmunds Jr The quill passes Ann. Thorac. Surg., July 1, 2000; 70(1): 1 - 2. [Full Text] [PDF]
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S. J. Mitchell, T. Willcox, F. Paget Milsom, and D. F. Gorman Physical and Pharmacological Neuroprotection in Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 2000; 4(2): 80 - 85. [Abstract] [PDF]
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R. John, A. F. Choudhri, A. D. Weinberg, W. Ting, E. A. Rose, C. R. Smith, and M. C. Oz Multicenter review of preoperative risk factors for stroke after coronary artery bypass grafting Ann. Thorac. Surg., January 1, 2000; 69(1): 30 - 35. [Abstract] [Full Text] [PDF]
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P. B. Berger, E. L. Alderman, A. Nadel, and H. V. Schaff Frequency of Early Occlusion and Stenosis in a Left Internal Mammary Artery to Left Anterior Descending Artery Bypass Graft After Surgery Through a Median Sternotomy on Conventional Bypass : Benchmark for Minimally Invasive Direct Coronary Artery Bypass Circulation, December 7, 1999; 100(23): 2353 - 2358. [Abstract] [Full Text] [PDF]
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C. J. O’Connor, D. V. Brown, M. Avramov, S. Barnes, H. N. O’Connor, and K. J. Tuman The Impact of Renal Dysfunction on Aprotinin Pharmacokinetics During Cardiopulmonary Bypass Anesth. Analg., November 1, 1999; 89(5): 1101 - 1101. [Abstract] [Full Text] [PDF]
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 K. A. Eagle, R. A. Guyton, R. Davidoff, G. A. Ewy, J. Fonger, T. J. Gardner, J. P. Gott, H. C. Herrmann, R. A. Marlow, W. C. Nugent, et al. ACC/AHA guidelines for coronary artery bypass graft surgery: A report of the American College of Cardiology/ American Heart Association task force on Practice Guidelines (Committee to revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery) J. Am. Coll. Cardiol., October 1, 1999; 34(4): 1262 - 1347. [Full Text] [PDF]
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A. Graham and H. O’Kane Is a high hematocrit value an independent risk factor for adverse outcome after coronary artery bypass grafting? J. Thorac. Cardiovasc. Surg., October 1, 1999; 118(4): 765 - 765. [Full Text]
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M. M.H. Khan, N. Gikakis, S. Miyamoto, A. K. Rao, S. L. Cooper, L. H. Edmunds Jr, and R. W. Colman Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass Ann. Thorac. Surg., August 1, 1999; 68(2): 473 - 478. [Abstract] [Full Text] [PDF]
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A. Alonso, C. W. Whitten, and G. E. Hill Pump prime only aprotinin inhibits cardiopulmonary bypass-induced neutrophil CD11b up-regulation Ann. Thorac. Surg., February 1, 1999; 67(2): 392 - 395. [Abstract] [Full Text] [PDF]
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L. Shore-Lesserson, H. E. Manspeizer, M. DePerio, S. Francis, F. Vela-Cantos, and M. A. Ergin Thromboelastography-Guided Transfusion Algorithm Reduces Transfusions in Complex Cardiac Surgery Anesth. Analg., February 1, 1999; 88(2): 312 - 312. [Abstract] [Full Text] [PDF]
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J. J. Munoz, N. J. O. Birkmeyer, J. D. Birkmeyer, G. T. O'Connor, and L. J. Dacey Is {epsilon}-Aminocaproic Acid as Effective as Aprotinin in Reducing Bleeding With Cardiac Surgery? : A Meta-Analysis Circulation, January 12, 1999; 99(1): 81 - 89. [Abstract] [Full Text] [PDF]
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H. P. Grocott, H. Sheng, Y. Miura, S. Sarraf-Yazdi, G. B. Mackensen, R. D. Pearlstein, and D. S. Warner The Effects of Aprotinin on Outcome from Cerebral Ischemia in the Rat Anesth. Analg., January 1, 1999; 88(1): 1 - 7. [Abstract] [Full Text] [PDF]
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J. B. Rich The efficacy and safety of aprotinin use in cardiac surgery Ann. Thorac. Surg., November 1, 1998; 66(90050): S6 - 11. [Abstract] [Full Text] [PDF]
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J. P. Gott, W. A. Cooper, F. E. Schmidt Jr, W. M. Brown III, C. E. Wright, J. D. Merlino, J. D. Fortenberry, W. S. Clark, and R. A. Guyton Modifying risk for extracorporeal circulation: trial of four antiinflammatory strategies Ann. Thorac. Surg., September 1, 1998; 66(3): 747 - 754. [Abstract] [Full Text] [PDF]
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M. Misfeld, S. Dubbert, S. Eleftheriadis, H.-J. Siemens, T. Wagner, and H.-H. Sievers Fibrinolysis-adjusted perioperative low-dose aprotinin reduces blood loss in bypass operations Ann. Thorac. Surg., September 1, 1998; 66(3): 792 - 799. [Abstract] [Full Text] [PDF]
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B. E. Miller, S. R. Tosone, V. K.H. Tam, K. R. Kanter, N. A. Guzzetta, J. M. Bailey, and J. H. Levy Hematologic and economic impact of aprotinin in reoperative pediatric cardiac operations Ann. Thorac. Surg., August 1, 1998; 66(2): 535 - 540. [Abstract] [Full Text] [PDF]
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P. M. Mannucci Hemostatic Drugs N. Engl. J. Med., July 23, 1998; 339(4): 245 - 253. [Full Text] [PDF]
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W. Dietrich Incidence of Hypersensitivity Reactions Ann. Thorac. Surg., June 1, 1998; 65(90060): S60 - 64. [Abstract] [Full Text] [PDF]
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M. P. Pelletier, S. Solymoss, A. Lee, and R. C.-J. Chiu Negative Reexploration for Cardiac Postoperative Bleeding: Can It Be Therapeutic? Ann. Thorac. Surg., April 1, 1998; 65(4): 999 - 1002. [Abstract] [Full Text] [PDF]
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 R. Pifarre Use of Aprotinin in the Control of Bleeding During Cardiopulmonary Bypass Surgery: Current Status Clinical and Applied Thrombosis/Hemostasis, January 1, 1998; 4(1): 2 - 6. [Abstract] [PDF]
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W. Dietrich, K. Schopf, M. Spannagl, M. Jochum, S. L. Braun, and H. Meisner Influence of High- and Low-Dose Aprotinin on Activation of Hemostasis in Open Heart Operations Ann. Thorac. Surg., January 1, 1998; 65(1): 70 - 77. [Abstract] [Full Text] [PDF]
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R. E. Helm, T. K. Rosengart, M. Gomez, J. D. Klemperer, W. J. DeBois CPP, F. Velasco, J. P. Gold, N. K. Altorki, S. Lang, S. Thomas, et al. Comprehensive Multimodality Blood Conservation: 100 Consecutive CABG Operations Without Transfusion Ann. Thorac. Surg., January 1, 1998; 65(1): 125 - 136. [Abstract] [Full Text] [PDF]
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S. Westaby Aprotinin Fifteen Years Later Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 1997; 1(4): 366 - 375. [Abstract] [PDF]
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N. Hayashida, T. Isomura, T. Sato, H. Maruyama, K. Kosuga, and S. Aoyagi EFFECTS OF MINIMAL-DOSE APROTININ ON CORONARY ARTERY BYPASS GRAFTING J. Thorac. Cardiovasc. Surg., August 1, 1997; 114(2): 261 - 269. [Abstract] [Full Text]
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 R. R. Lazzara, F. E. Kidwell, M. F. Kraemer, J. A. Wood, and A. Starr Reduction in Costs, Blood Products, and Operating Time in Patients Undergoing Open Heart Surgery Arch Surg, August 1, 1997; 132(8): 858 - 861. [Abstract] [PDF]
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W. Dietrich, P. Spath, A. Ebell, and J. A. Richter PREVALENCE OF ANAPHYLACTIC REACTIONS TO APROTININ: ANALYSIS OF TWO HUNDRED FORTY-EIGHT REEXPOSURES TO APROTININ IN HEART OPERATIONS J. Thorac. Cardiovasc. Surg., January 1, 1997; 113(1): 194 - 201. [Abstract] [Full Text]
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P. K. Smith and L. H. Muhlbaier Aprotinin: Safe and Effective Only With the Full-Dose Regimen Ann. Thorac. Surg., December 1, 1996; 62(6): 1575 - 1577. [Full Text]
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J. H. Lemmer Jr, E. W. Dilling, J. R. Morton, J. B. Rich, F. Robicsek, D. L. Bricker, C. B. Hantler, J. G. Copeland III, J. L. Ochsner, P. O. Daily, et al. Aprotinin for Primary Coronary Artery Bypass Grafting: A Multicenter Trial of Three Dose Regimens Ann. Thorac. Surg., December 1, 1996; 62(6): 1659 - 1668. [Abstract] [Full Text]
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M. R. Terrell, J. M. Walenga, M. J. Koza, and R. Pifarre Efficacy of Aprotinin With Various Anticoagulant Agents in Cardiopulmonary Bypass Ann. Thorac. Surg., August 1, 1996; 62(2): 506 - 511. [Abstract] [Full Text]
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J. H. Lemmer Jr., M. T. Metzdorff, A. H. Krause, J. E. Okies, T. A. Molloy, J. G. Hill, W. B. Long, T. R. Winkler, and U. S. Page APROTININ USE IN PATIENTS WITH DIALYSIS-DEPENDENT RENAL FAILURE UNDERGOING CARDIAC OPERATIONS J. Thorac. Cardiovasc. Surg., July 1, 1996; 112(1): 192 - 194. [Full Text]
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