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Ann Thorac Surg 2001;72:521-526
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Postoperatively administered aprotinin or epsilon aminocaproic acid after cardiopulmonary bypass has limited benefit

^a Department of Haematology, The Prince Charles Hospital, Brisbane, Australia
^b Department of Cardiac Surgery, The Prince Charles Hospital, Brisbane, Australia

Accepted for publication May 3, 2001.

Address reprint requests to Dr Ray, Department of Haematology, The Prince Charles Hospital, Chermside, Brisbane, 4032, Australia
e-mail: michael_ray{at}health.qld.gov.au

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Intraoperative antifibrinolytic treatment with aprotinin and epsilon aminocaproic acid (EACA) has been shown to be effective prophylaxis in the reduction of excessive bleeding after cardiopulmonary bypass operations. This study investigated the effectiveness of both drugs when used as a postoperative treatment of patients showing early signs of increased bleeding.

Methods. In a double-blind, randomized study, 69 patients with chest drainage of 100 mL or more 1 hour after bypass were treated with aprotinin, EACA, or placebo.

Results. In the first 24 hours postoperatively, neither drug significantly reduced chest drainage or blood transfusion requirements compared with placebo. Median (interquartile) cumulative chest drainage volumes for the first 24 hours postoperatively for the aprotinin, EACA, and placebo groups were 525 (340, 750), 575 (450, 762), and 650 (550, 800) mL, respectively. Among the study patients, 4 undergoing valve operation and treated with aprotinin showed a trend toward less bleeding during the first 12 hours postoperatively compared with 5 valve operation patients who received placebo (p = 0.06). Among all patients, the treatment with aprotinin or EACA failed to reduce levels of D-dimer compared with placebo after treatment, indicating that fibrinolysis was not significantly inhibited.

Conclusions. Aprotinin or EACA administered in the early postoperative period was ineffective in reducing postoperative bleeding with the exception of a small group of patients having valve operations in whom aprotinin treatment may have shown some benefit.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
In the many years since the introduction of cardiopulmonary bypass (CPB), there has been great progress in overcoming the problems of excessive postoperative bleeding associated with the procedure. This development has included the improved design of bypass pumps and oxygenators, and the introduction of hemodilution and autotransfusion techniques [1]. One of the causes of this bleeding has been identified as activation of the fibrinolytic system with subsequent breakdown of the clots formed after bypass [2]. This role of fibrinolysis has been confirmed by the successful reduction of postoperative bleeding when antifibrinolytic agents are administered intraoperatively. Notable among these drugs have been aprotinin [3] and epsilon aminocaproic acid (EACA) [4]. Low-dose and high-dose aprotinin have been shown to be effective in reducing the frequency of urgent reoperations for bleeding [5], which otherwise occur in approximately 3% of cases [6]. This low frequency makes their occurrence difficult to predict and attempt to prevent with prophylactic antifibrinolytic therapy. This problem of determining patients who will need antifibrinolytic therapy highlights the value of being able to effectively target treatment to those who are showing early signs of excessive bleeding.

In an uncontrolled study, postoperative aprotinin was administered with apparent benefit to 6 patients who had life-threatening bleeding [7]. In another placebo-controlled study by Kallis and colleagues [8], treatment was started one to three hours after entry into the postoperative ward for 60 patients who were bleeding excessively, the aprotinin group showing significantly reduced bleeding compared with placebo. A later study by Cicek and colleagues [9] randomized 75 patients, regardless of blood loss, to high-dose intraoperative aprotinin, aprotinin administered in the operating room at the end of the operation, or placebo. Intraoperative and postoperative treatments were equally effective compared with placebo in reducing postoperative chest drainage and transfusion requirements [9].

A recent study at our institution has shown intraoperative low-dose aprotinin and EACA equally effective in reducing bleeding [10]. In the present study we investigated the benefit of administration, approximately 2 hours after bypass, of aprotinin or EACA as a treatment of CPB patients who are showing early signs of excessive postoperative bleeding.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Selection of patients at higher risk of bleeding
The historic postoperative bleeding data of 102 patients who comprised the placebo groups of two previous studies [3, 5] were analyzed. All patients were having valve replacement operation. The 44 patients with a chest drainage volume of 100 mL or more 1 hour after bypass had a median (interquartile) 24-hour chest drainage of 600 (500, 900) mL compared with 350 (300, 550) mL for the 58 patients with less than 100 mL chest drainage 1 hour after bypass (p < 0.001). Of the 44 patients draining 100 mL or more, 26 (59.1%) required postoperative transfusion of blood products within the first 24 hours postoperatively compared with 17 of the 58 (29.3%) patients draining less than 100 mL (p = 0.003).

These data provided a rationale for this study to select patients who were likely to bleed excessively. Patients with increased risk of excessive bleeding were recruited when the volume of their mediastinal chest drainage 1 hour after bypass was 100 mL or more.

Patient population
In two studies of high-dose aprotinin therapy performed at this institution, the difference between the mean chest drainage of the treated compared with placebo group at 24 hours after CPB was 240 mL (SD = 269 mL). On this basis, with p = 0.05 and a power of 80%, a significant difference could be detected with a sample size of 20 in each group.

This study was double-blind, randomized, and placebo-controlled. A total of 328 patients consented to participate. From these, based on having chest drainage of 100 mL or more, 75 were recruited into the study. Subsequent review excluded 6 patients not fully meeting the inclusion criteria. Of the 69 remaining patients, 23 received aprotinin (preservative-free Trasylol, Bayer AG, Leverkusen, Germany), 22 EACA (Amicar, Lederle Laboratories Division, Cyanamid Australia), and 24 placebo. Patients were stratified according to three surgical types; coronary artery bypass grafts (CABG), single valve operation, and valve operation plus CABG. Patients in each group were then randomly assigned to receive aprotinin, EACA, or placebo. Informed consent was obtained from all patients who were to undergo these types of operation. The study was approved by this institute’s Ethics Committee, approval number EC 9826.

Exclusion criteria included the following: intraoperative aprotinin or EACA therapy, aprotinin therapy on an earlier occasion, sepsis, renal or liver failure, insulin-dependent diabetes mellitus, history of thrombosis, refusal to receive any blood transfusion, autologous blood donation before operation, abnormal preoperative coagulation screen (other than due to anticoagulant therapy), and age of less than 18 years.

Surgical and anesthetic protocol
All patients in this study underwent similar anesthetic procedures. These consisted of induction with midazolam 0.05 mg/kg and fentanyl 10 to 15 µg/kg and maintenance with propofol infusion at a rate of 0.4 to 0.7 mg · kg^-1 · h^-1 with intermittent doses of morphine. Pancuronium 0.1 to 0.15 mg/kg was used for appropriate muscle relaxation.

The surgical technique was likewise similar throughout the study. A full median sternotomy was used as the surgical approach with the exception of one valve operation patient. This patient was in the aprotinin group and received a ministernotomy. Cardiopulmonary bypass was instituted with a membrane oxygenator and a roller pump system with mild systemic hypothermia to 32°C. Antegrade and subsequent intermittent retrograde cardioplegia, either crystalloid or blood in type, was used for myocardial protection.

Intraoperative anticoagulation was obtained with 3 mg/kg of heparin, achieving an activated clotting time using a kaolin activator of greater than 480 seconds. After CPB, heparin was neutralized with protamine sulfate.

Trial drugs administration
Aprotinin, EACA, or placebo was administered over 4 hours, after the patient had reached the postoperative intensive care ward and excessive drainage was noted, the trial drug prepared, and the test dose given. The infusion commenced at a mean (SD) time of 122 (36) minutes after the end of bypass.

Aprotinin
A test dose of 10,000 kallikrein inhibitor units (KIU) was administered through a central line at least 10 minutes before the loading dose and the patient observed for any signs of anaphylaxis. Then a loading dose of 1 x 10⁶ KIU was given over a 20-minute period followed by 0.5 x 10⁶ KIU per hour for 4 hours. This dose was used as it has previously been shown to be the most cost-efficient [5] and is the dose currently used at our institution.

Epsilon aminocaproic acid
A test dose of 250 mg was administered as for aprotinin. A loading dose of 5 g was given over a 20-minute period followed by 1.25 g per hour for 4 hours. This dose was based on that found previously to be as effective as the low-dose aprotinin noted above [10].

Perioperative measurements
The cumulative mediastinal chest drainage volume was measured at 4-hour intervals for the first 24 hours postoperatively. The volume of blood products transfused during this time was also recorded. D-dimer measurements were performed as a measure of fibrinolytic activity. In addition to recording any adverse events from the patients’ charts, cardiac troponin I levels were monitored to provide a measure of any adverse effect of either therapy with regard to myocardial damage. Blood samples were taken immediately before the administration of the trial drug/placebo, at the end of treatment 4 hours later, and 24 hours after bypass. An additional sample was taken for base line D-dimer measurement at the beginning of the operation. D-dimer was measured by enzyme-linked immunoassay, using Dimertest Gold (Agen Biomedical Ltd, Brisbane, Australia). D-dimer assays in this study were performed on serum, serum levels having been shown in our laboratory to be equivalent to those in plasma, as confirmed by others [11]. Troponin I was measured with a colorimetric immunoassay (Dade Behring Inc, Glasgow, Delaware).

Statistical analysis
The Mann–Whitney test was used to test the differences between each treatment and placebo at each of the six time points. A repeated-measures analysis was undertaken to determine any interaction between the three groups in relation to cumulative chest drainage at the six time periods. Kruskal–Wallis was used to test for any difference between the demographics of the three treatment groups. Fisher exact test was used to test for different frequencies in regard to demographic variables and transfusion.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Demographics
The aprotinin, EACA, and placebo groups were similar with regard to variables likely to affect blood loss (Table 1). The eight surgeons participating in the study had similar numbers of cases in each group. The volume of drainage 1 hour after bypass was similar in each group.

Considering the study population as a whole, the cumulative volumes of chest drainage at each 4-hour interval for the first 24 hours in intensive care were similar with either aprotinin or EACA when compared with placebo (Fig 1). There was some indication of a slight reduction in bleeding in the aprotinin group at 20 postoperative hours (p = 0.03), when the median (interquartile) drainage in the aprotinin and placebo groups was 475 (337, 712) and 625 (550, 737) mL, respectively. Repeated-measures analysis showed no reduction of chest drainage with postoperative aprotinin or EACA therapy at the six time periods.

View larger version (22K): [in this window] [in a new window]   Fig 1. Cumulative chest drainage volumes at 4-hour intervals for 24 hours postoperatively. Values in this and subsequent figures are expressed as medians and the error bars represent the 25th and 75th percentiles. *Difference between the aprotinin and placebo groups at that stage, p = 0.03. (EACA = epsilon aminocaproic acid.)

Postoperative bleeding according to type of operation
As randomization was stratified according to operation, postoperative bleeding data were analyzed separately for CABG and valve operation (± CABG) patients. Among 58 CABG patients there was no significant effect of postoperative aprotinin or EACA on blood loss. However, among the 12 patients undergoing valve operation, the 4 patients who received aprotinin exhibited a trend toward less drainage than the 5 placebo patients for the first 12 hours postoperatively (p = 0.06) (Fig 2).

View larger version (18K): [in this window] [in a new window]   Fig 2. Cumulative chest drainage at 4-hour intervals for 24 hours postoperatively in those patients having valve operations in the aprotinin (n = 4) and placebo (n = 5) groups. *Difference between the aprotinin and placebo groups at those stages, p = 0.06.

View larger version (15K): [in this window] [in a new window]   Fig 3. Serum D-dimer levels at four stages. The levels were not statistically different at any stage. (EACA = epsilon aminocaproic acid.)

Full blood count
There was no significant difference among the aprotinin, EACA, or placebo groups with regard to hemoglobin, hematocrit, red cell counts, white cell counts, or platelet counts at the commencement and completion of treatment or the next day.

Safety
No myocardial infarcts were recorded, although 1 patient who was in the aprotinin group had an infarct in the right occipital region. Troponin I was measured at the start and completion of treatment and the next day. There was a significant increase in levels of troponin I during treatment in the EACA (p = 0.001) and placebo (p = < 0.001) groups (Wilcoxon signed ranks test), but not in the aprotinin group (Fig 4). At the end of treatment, the median troponin I level was significantly lower in the aprotinin group compared with the placebo (p < 0.001).

View larger version (15K): [in this window] [in a new window]   Fig 4. Changes in troponin I levels from those at pretreatment. Median (interquartile) pretreatment values were: aprotinin 4.2 ng/mL (2.7,7.5), epsilon aminocaproic acid (EACA) 3.8 ng/mL (2.5, 5.0), and placebo 2.4 ng/mL (1.8, 5.1).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

The sample size of this study was determined based on the reductions of blood loss achieved with high-dose intraoperative aprotinin. A lesser reduction of bleeding achieved within this study of postoperative antifibrinolytic therapy may not have become statistically significant with the numbers of patients included.

Further analysis of this study according to operation type revealed that whereas the CABG patients derived no benefit from aprotinin or EACA, the small number of valve operation patients showed a trend toward less bleeding after administration of aprotinin. Although this trend did not reach statistical significance and the numbers were too few to form any conclusion, further investigation on a larger number of valve operation patients is justified. A study is currently underway at our institution to confirm or refute this trend.

The study by Kallis and coworkers [8], which was similar in design to this study, did show benefit from postoperative aprotinin. There were two main differences between the studies. One was that the rate of bleeding in the placebo group of Kallis and coworkers was considerably higher than the placebo group in the present study. Secondly, Kallis and coworkers used a higher dose of aprotinin.

Increased postoperative D-dimer levels provided evidence of fibrinolytic activity breaking down fibrin clots. Other studies have shown that this activity is inhibited by treatment with intraoperative aprotinin, as evidenced by subsequently lower D-dimer concentrations [12, 13]. In the present study, high levels of D-dimer postoperatively before treatment indicated that the fibrinolysis was active at this stage. The postoperative aprotinin and EACA administered had no effect on D-dimer levels and presumably fibrinolysis, D-dimer levels of the treated patients being no different from those of the placebo group. This lack of effect on D-dimer levels when aprotinin treatment was initiated in the postoperative ward was confirmed in the study by Kallis and colleagues [8] in which D-dimer was measured with a latex assay using the same antibody as used in this study. In the study by Cicek and colleagues [9], earlier administration of aprotinin (at the end of the operation before admission to the postoperative ward) was effective in inhibiting fibrinolysis, D-dimer levels being significantly lower in the aprotinin group compared with placebo. The mechanism of antifibrinolytic therapy involves aprotinin itself [12] or the ₂-antiplasmin released by EACA [10] binding to the plasmin formed perioperatively, thus inhibiting its digestion of the fibrin clot. This digestion may have progressed too far 2 hours after the end of bypass to be inhibited in this way.

Troponin I is specific for myocardial tissue and has been reported to have high sensitivity and specificity for perioperative myocardial damage in CPB [14, 15]. The observed increase in troponin I after CPB has been shown to be reduced in patients treated with intraoperative aprotinin [10]. In this study, postoperative aprotinin treatment also inhibited the postoperative increase in troponin I that occurred in the EACA and placebo groups. Aprotinin reduces the whole body inflammatory response, possibly through a mechanism of scavenging the free oxygen radicals by which it is induced. Although this study did not demonstrate it clinically, this mechanism may afford some protection of the myocardium from this "postperfusion syndrome."

The possibility of intraoperative aprotinin therapy being associated with increased adverse thrombotic events has not been well supported in the literature [16]. In a study of intraoperative high-dose aprotinin performed at this institution, in comparison with placebo there was no evidence of aprotinin causing an increase in prothrombin fragment 1 + 2, thrombin antithrombin III, or soluble fibrin, all of which are associated with fibrin formation [12]. However, the International Multicenter Aprotinin Graft Patency Experience study failed to totally clear aprotinin of any link with decreased graft patency [17]. Because of the small number of patients in the current study, little clinical safety data could be provided regarding postoperative antifibrinolytic therapy and adverse thrombotic events.

In conclusion, with the possible exception of patients who have undergone valve operation, aprotinin and EACA therapy given in the postoperative period was ineffective in inhibiting fibrinolysis and did not result in decreased postoperative blood loss or blood product transfusion requirements. If postoperative antifibrinolytic therapy is to be effective, it may need to be given at an earlier stage.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank The Prince Charles Hospital Foundation, The Prince Charles Hospital Private Practice Education and Research Trust Fund, and Parke Davis/Pfizer (Cardiovascular Lipid Research Grant) for their support of this project. Statistical support was provided under the ARC SPIRT Grant C 10024120 titled "Statistical methodology contributing to decision support capability for evidence based practice using two public hospitals in Brisbane as models for Australia" Pettitt AN, Wolff RL, Fleming JM, Whitby M, Morton A. We also thank the cardiac surgeons, anaesthetists and intensive care unit staff for their advice and continual support. Thanks to Dr Kerrie Mengersen, Dr Miranda Mortlock and Associate Professor Neville Marsh from Queensland University of Technology for their assistance with the statistical analysis and supervision. We are grateful to Dr Julia Potter for her advice and support. We also thank Agen Biochemical Ltd, Brisbane, Australia for their generous support.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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