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Ann Thorac Surg 2001;71:838-843
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Comparison of epsilon aminocaproic acid and low-dose aprotinin in cardiopulmonary bypass: efficiency, safety and cost

^a Department of Haematology, Queensland Health Pathology Service, Brisbane, Australia
^b Department of Cardiac Surgery, The Prince Charles Hospital, Brisbane, Australia

Accepted for publication July 29, 2000.

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

	Abstract

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Background. In this study we compared the clinical efficiency, safety, and economic benefit of low-dose aprotinin with epsilon aminocaproic acid (EACA) in reducing bleeding after cardiopulmonary bypass operation.

Methods. In a double-blind, randomized study, 100 patients received low-dose aprotinin (2 x 10⁶ kallikrein inhibitor units) or EACA (20 g). The surgical procedure was single- or double-valve replacement with or without coronary artery bypass grafts.

Results. Mediastinal chest drainage and transfusion requirements with both therapies were similar. There were no urgent reoperations to secure hemostasis in either group. Similar levels of D-dimer with both therapies indicate a similar inhibition of fibrinolysis. Release of troponin I was less in the low-dose aprotinin group 1 and 4 hours after bypass, although electrocardiographic measurements did not reflect this difference. Levels of S-100ß and neuron-specific enolase were similar with both therapies, confirming that there was no difference in the occurrence of any adverse neurologic events in either group.

Conclusions. Low-dose aprotinin and EACA showed similar effects on the reduction of intraoperative and postoperative bleeding. The lower cost of EACA with no change in safety outcome suggests it is the preferred treatment.

	Introduction

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Excessive bleeding after cardiopulmonary bypass (CPB) operation is a common, but often preventable complication. The cause may relate to preoperative variables such as platelet dysfunction [1], or oral anticoagulant therapy [2]. The type of operation is also a factor. Patients undergoing valve replacement operation, especially with coronary artery bypass grafts (CABG), bleed more than CABG alone [3].

Many studies have proved that significant alterations in hemostatic mechanisms are induced by the nonbiological surfaces of the extracorporeal circulation. Activation of fibrinolysis during CPB has been established [4] and its relevance to postoperative bleeding confirmed by the effectiveness of intraoperative antifibrinolytic therapy with aprotinin and epsilon aminocaproic acid (EACA) in reducing mediastinal drainage, transfusion requirements and the frequency of urgent reoperations to secure hemostasis [5]. As therapy is considerably more costly with aprotinin than with EACA, it is important to compare the clinical and economic effectiveness of both drugs. Five studies compared the clinical efficiency of high-dose aprotinin with a variety of doses of EACA. Two of these reported no significant difference in mediastinal drainage at 24 hours postoperatively [6, 7]. Three studies found high-dose aprotinin to be significantly more effective than EACA at reducing this mediastinal drainage, but did not demonstrate any significant difference in the frequency of transfusion [8–10].

Low-dose aprotinin is often used in preference to high-dose aprotinin because of the considerable economic savings with little loss in efficiency [11]. The present study compared the effectiveness of prophylactically administered low-dose aprotinin and EACA in reducing perioperative CPB bleeding.

	Material and methods

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Patient population
A prospective, double-blind, randomized study was performed. The patient population studied was undergoing single- or double-valve replacement operation with or without CABG. This specific surgical group was selected as they are more likely to have increased postoperative bleeding and need more blood product transfusions. The sample size was 100, based on demonstrating a difference of 150 mL in the 24-hour chest drainage, with a confidence level of 0.95 and power of 0.8. Following approval from the Institution’s Ethics Committee (EC 9615), patients who consented to participate were randomized into two treatment arms, 49 receiving low-dose aprotinin and 51 receiving EACA. This randomization was stratified according to two operation types: (1) single-valve replacement (aortic or mitral) or (2) single-valve replacement plus CABG, or double-valve replacement. As the surgeons often require prophylactic antifibrinolytic therapy, a placebo arm was not included. Exclusion criteria were previous exposure to aprotinin, previous thrombotic episodes, insulin-dependent diabetes mellitus, refusal to receive blood transfusion, autologous blood taken for subsequent reinfusion, less than 18 years of age, abnormal liver or renal function, abnormal preoperative coagulation profile (other than due to anticoagulant therapy), and urgent operation cases. These criteria also ensured a homogeneous population.

Surgical and anesthetic protocol
Surgical and anesthetic techniques were constant for all study patients. Anesthesia was induced with midazolam (0.05 mg/kg) and fentanyl (10 to 15 mg/kg) and maintained with propofol infusion at 0.4 to 0.7 mg · kg^-1 · h^-1 and intermittent doses of morphine. Muscle relaxation was achieved with pancuronium 0.1 to 0.15 mg/kg. The surgical techniques included full median sternotomy approach. Cardiopulmonary bypass was conducted with a membrane oxygenator, roller pump system, and mild system hypothermia to 32°C. Myocardial protection was achieved with cold crystalloid cardioplegia with antegrade and most often retrograde cannulation. Delivery of retrograde cardioplegia was intermittent, being repeated every 20 to 25 minutes. Coronary ostial cannulation was rarely required. Anticoagulation was achieved with 3 mg/kg heparin to maintain an activated clotting time (using a kaolin activator) of more than 480 seconds. Heparin neutralization with protamine sulfate was confirmed with the return to the base line activated clotting time (ACT).

Trial drug administration
For the aprotinin (preservative-free Trasylol, Bayer AG, Leverkusen, Germany), a test dose of 10,000 kallikrein inhibitor units (KIU) was administered through a central line at least 10 minutes before the loading dose. The loading dose of 1 x 10⁶ KIU was given over a 20-minute period after the induction of anesthesia. This dose was followed by 1 x 10⁶ KIU added to the pump prime.

For the EACA (Amicar, Lederle, Puerto Rico), a test dose of 250 mg was administered through a central line at least 10 minutes before the loading dose. The loading dose of 5 g in a physiologic saline vehicle was given over a 20-minute period after the induction of anesthesia and was followed by 1.25 g/h until 4 hours after bypass. In addition 5 g was added to the pump prime before cross-clamping to ensure hemodilution did not decrease the blood concentration of EACA. This dose was established to ensure a blood level of at least 130 µg/mL, this level having been shown to inhibit in vitro fibrinolysis [12].

Perioperative measurements
At the end of the operation, the surgeons made a subjective assessment of the degree of intraoperative bleeding. The grades were minimal = 1, mild = 2, moderate = 3, and severe = 4. Chest drainage was measured at 4-hour intervals for 24 hours after bypass. A sample of the drainage fluid was taken from the drainage bottle to estimate its hemoglobin concentration so the grams of hemoglobin lost in the drainage could be estimated. Transfusion frequencies and volumes were recorded intraoperatively and up until 24 hours postoperatively.

For troponin I, neuron-specific enolase (NSE), and S-100ß measurements, blood samples were taken at induction of anesthesia, 30 minutes into bypass, and 1, 4, and 24 hours after bypass. Citrated samples for D-dimer measurements were taken at the induction of anesthesia and 1 hour after bypass. The sera and plasmas were stored in liquid nitrogen until the assays were performed. Troponin I was measured with a microparticle enzyme immunoassay (Abbott, Chicago, IL), NSE and S-100ß with an immunoradiometric assay (Sangtec Medical, Bromma, Sweden), and D-dimer antigen with an enzyme-linked immunoassay (AGEN Biochemical Ltd, Brisbane, Australia). Blood urea measurements were made before the operation and 24 hours after the procedure.

The duration of each patient’s stay in the operating room, cardiac and general intensive care wards, and the general ward was recorded. Electrocardiographic (ECG) analysis was performed 1 day preoperatively, as well as 5 days and 3 months postoperatively. In addition, continuous ECG monitoring was undertaken during the patient’s stay in intensive care. Patients were asked before their operation whether they had taken aspirin within the previous 10 days.

Statistical analysis
As not all data were normally distributed, and to minimize the distortion of extreme outliers, nonparametric analysis was used throughout. Differences between treatment groups were tested with the Mann–Whitney test, differences being significant when p was less than 0.05. Within each treatment group, changes from base line values were tested with the Wilcoxon signed ranks test. Differences in frequencies of events were tested with ² analysis. Measurements of the low-dose aprotinin and EACA groups were expressed as medians and the 25th and 75th percentiles. Data were collated onto proformas and transcribed onto the statistical package, SPSS 8.0 for Windows (SPSS Inc, Chicago, IL).

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Demographics
The distribution of demographic preoperative and intraoperative variables between the low-dose aprotinin and EACA groups were similar with regard to age, male:female ratio, body surface area, preoperative hemoglobin and platelet count, preoperative urea, previous sternotomy, minimum temperature during bypass, cross-clamp time, and operation group. When the 100-patient study population was considered as a whole, the more complex surgical group of valve operation plus either a second valve operation or associated CABG had significantly higher cumulative chest drainage volumes than the single-valve replacements at 8, 12,16, 20, and 24 hours postoperatively (p < 0.05). This finding demonstrated the need for stratification by surgical groups before randomizing to either treatment group as was done in this study.

Intraoperative bleeding
The surgeons’ grading of intraoperative bleeding showed the mean (SD) scores in the low-dose aprotinin and EACA groups were not statistically different, being 2.07 (0.74) and 2.07 (0.84), respectively.

Postoperative bleeding
The cumulative mediastinal chest drainage volumes measured at 4-hour intervals were similar in the low-dose aprotinin and EACA groups (Fig 1). The grams of hemoglobin lost in this drainage were also similar in both groups (Fig 2). This loss was independent of the patients’ body surface area.

View larger version (19K): [in this window] [in a new window]   Fig 1. Cumulative chest drainage for the first 24 hours postoperatively. No significant difference existed between the treatment groups. Results are expressed as the medians, the error bars represent the 25th and 75th percentiles. Due to measurements being to the nearest 50 mL, medians and ranges for both groups were often identical. (EACA = epsilon aminocaproic acid.)

View larger version (16K): [in this window] [in a new window]   Fig 2. Cumulative hemoglobin loss for the first 24 hours postoperatively. There was no significant difference between treatment groups. (EACA = epsilon aminocaproic acid.)

Transfusion requirements
The percentage of patients requiring blood, platelet, or fresh frozen plasma transfusion intraoperatively or postoperatively was not significantly different between the treatment groups (Fig 3). The odds ratio of the EACA-treated patients requiring transfusion of any blood product intraoperatively or postoperatively compared with patients treated with low-dose aprotinin was 0.78 with a 95% confidence interval of 0.33 to 1.83. As this interval includes one, the results indicate no significant difference in the likelihood of transfusion with low-dose aprotinin or EACA therapy.

View larger version (27K): [in this window] [in a new window]   Fig 3. Percentage of patients requiring intraoperative and postoperative transfusion in the low-dose aprotinin and epsilon aminocaproic acid (EACA) groups. There was no significant difference between treatment groups. (FFP = fresh frozen plasma.)

D-dimer levels
Compared with preoperative measurements, D-dimer levels increased only slightly in both groups by 1 hour after bypass. This increase was similar in both low-dose aprotinin and EACA groups (51 and 34 ng/mL, respectively). Reference to an historic but surgically similar group of patients receiving no antifibrinolytic therapy demonstrated threefold levels of D-dimer at this stage, when measured with the same method [13]. This finding suggests that both drugs reduced D-dimer levels.

Length of stay
Patients from low-dose aprotinin and EACA groups had similar lengths of stay in the operating room, intensive care, and general wards. The median time spent in the operating room was 180 and 183 minutes for the low-dose aprotinin and EACA groups, respectively. The median length of stay in the intensive care ward was 44.5 and 45.9 hours, respectively. Patients whose recovery in the intensive care ward was delayed were transferred to another general intensive care ward. This transfer happened with similar frequency in both treatment groups.

Safety data: renal
Urea levels were not significantly different 1 day after operation between the groups.

Safety data: cardiac
Troponin I levels were measured at each stage. The levels in the low-dose aprotinin group were significantly lower than those in the EACA group 1 and 4 hours after bypass (Fig 4). This difference had disappeared by 24 hours after bypass. However, ECG measurements did not reflect this difference. Changes in ST segment and the prevalence of arrhythmias were observed equally in each group.

View larger version (16K): [in this window] [in a new window]   Fig 4. The changes from base line levels of troponin I perioperatively. In this and subsequent figures, stage 0 = induction of anesthesia, stage 1 = 30 minutes into bypass, stage 2 = 1 hour after bypass, stage 3 = 4 hours after bypass, stage 4 = 24 hours after bypass. p values refer to the differences between the treatment groups.

View larger version (13K): [in this window] [in a new window]   Fig 5. The changes from base line levels of neuron specific enolase (NSE) during and after bypass. (EACA = epsilon aminocaproic acid.)

View larger version (14K): [in this window] [in a new window]   Fig 6. The changes from base line levels of S-100ß during and after bypass. The results for the patients with no neurologic deficit are expressed as medians, the error bars representing the 25th and 75th percentiles. The other two series are the individual data points for 2 patients, 1 of whom had perioperative hemiparesis and another who had two grand mal seizures.

	Comment

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The goal of this study was to supply information toward answering the question of whether low-dose aprotinin or EACA should be the antifibrinolytic therapy of choice for CPB operation in terms of clinical efficiency, safety, and economy. The comparison of the mechanisms of both drugs will be published at a later date.

Clinical efficiency
A recent meta-analysis of 52 studies of high-dose aprotinin, low-dose aprotinin, or EACA therapy [5] showed similar odds ratios for the reduced chance of requiring transfusion or reoperation to secure hemostasis with each therapy. This meta-analysis confirms our findings of equal efficiency in this regard with low-dose aprotinin and EACA therapy. However, most studies in the meta-analysis investigated aprotinin whereas only 9 studied the less expensive EACA therapy.

A previous double-blind, randomized, placebo-controlled study of 150 patients at our hospital demonstrated that high-dose aprotinin was slightly more effective than low-dose aprotinin (2 x 10⁶ KIU) in reducing postoperative bleeding and transfusion requirements. However, both regimes reduced urgent reoperations for hemostasis and low-dose aprotinin was still effective in reducing transfusion requirements [11]. The present study continued on from that work and showed that low-dose aprotinin and EACA were equally effective in reducing blood loss, and as far as transfusion requirements. Intraoperative bleeding was also similar. The work indicated that both therapies were equally effective against aspirin-induced bleeding. As no placebo group was considered, the degree of these reductions cannot be shown, but numerous studies leave no doubt of the effectiveness of antifibrinolytic therapy compared with no therapy. Similar low levels of D-dimer 1 hour after operation in both groups suggest that both therapies are similarly efficient at inhibiting fibrinolysis.

Safety
Aprotinin is a serine protease inhibitor originating from bovine lung. It carries a risk of a hypersensitivity reaction. The incidence of this reaction is low (having been reported to be less than 0.5%), these reactions often occurring in patients previously exposed to aprotinin [14]. There has been little evidence of hypersensitivity with EACA therapy during CPB operation [15]. A number of studies have failed to demonstrate any adverse effects of aprotinin therapy in terms of reduced graft patency [16], although the recent Image trial failed to resolve the matter [17]. There have been no investigations of any effect EACA may have on graft patency.

Troponin I is a marker of myocardial tissue damage [18] and was significantly lower in the aprotinin-treated patients in the first hours after bypass, the difference disappearing 24 hours after bypass. A placebo-controlled study had previously shown that troponin T levels are reduced with aprotinin treatment [19]. This finding was reflected in this study but the clinical findings do not support a hypothesis that aprotinin offers myocardial protection.

It has been shown that aprotinin therapy will prolong the ACT used to monitor heparin therapy when a celite activator is used in the test, thus causing an overestimation of the heparin levels [20]. When kaolin is used as the activator, this artifact is overcome [21]. Any effect of EACA on the ACT is important and remains to be investigated.

No clinical difference in adverse neurologic outcomes was observed between the low-dose aprotinin and EACA groups. The fact that 2 patients with neurologic adverse events showed higher levels of S-100ß 24 hours after bypass indicates that this marker is sensitive to damage to the nervous system.

Economic savings
A recent study [11] at this institution demonstrated that compared with no antifibrinolytic treatment, low-dose aprotinin therapy resulted in considerable savings. The cost of the dose of EACA used in this study was AUS$134 cheaper than low-dose aprotinin therapy. We showed equivalent results from both therapies in terms of transfusion requirement and lengths of stay in the operating room and intensive care. This similarity may indicate that with EACA therapy, the savings of using the cheaper drug could be added to the previously described economic benefits of low-dose aprotinin therapy.

This study indicates that EACA offers benefits similar to those of low-dose aprotinin in regard to intraoperative and postoperative blood loss, transfusion requirements, and safety outcomes, at a lower cost.

	Acknowledgments

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We thank the Prince Charles Hospital Foundation and the Prince Charles Hospital Private Practice Education and Research Trust Fund for their support of this project. We also thank the cardiac surgeons, anaesthetists, and intensive care unit staff for their advice and continual support. Thank you also to Laurie Kear, Tammy Smith, and Michelle L’Estrange for randomizing and organizing the treatments. We are grateful to Majella Hales for assisting with the final stages of this study, including gaining patients’ consent and collecting data. We appreciate the technical assistance of Glenda Bellingham and Neville Marsh in performing assays. The support and guidance of James Morton was vital to the success of this project. We are also grateful to AGEN Biochemical Ltd, Brisbane, Australia, for their generous support.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mark F. O’Brien Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ray, M. J. Articles by O’Brien, M. F. Search for Related Content PubMed PubMed Citation Articles by Ray, M. J. Articles by O’Brien, M. F. Related Collections Cardiac - pharmacology Extracorporeal circulation