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Ann Thorac Surg 1998;65:667-673
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

High-Dose -Aminocaproic Acid Versus Aprotinin: Antifibrinolytic Efficacy in First-Time Coronary Operations

Department of Anaesthesiology, Johannes Gutenberg University, Mainz, Germany
Department of Cardiothoracic & Vascular Surgery, Johannes Gutenberg University, Mainz, Germany
Institute for Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University, Mainz, Germany

Accepted for publication September 3, 1997.

Dr Eberle, Department of Anesthesiology, Johannes Gutenberg University Medical School, Langenbeckstr 1, D-55131 Mainz, Germany (e-mail: beberle@anaesthesie.klinik.uni-mainz.de).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background. The antifibrinolytic efficacy of a high-dose regimen of -aminocaproic acid (-ACA) was compared with aprotinin in first-time coronary operations.

Methods. In a prospective, double-blinded, randomized study, 20 patients received high-dose -ACA (10 g both as a loading and cardiopulmonary bypass priming dose, 2.5 g/h until 4 hours after protamine), and another 20 patients received aprotinin (2 x 10⁶ KIU [280 mg] for loading and priming, 0.5 x 10⁶ KIU/h [70 mg/h]). Ten untreated patients served as controls.

Results. Both agents reduced postoperative levels of thrombin/antithrombin III complexes, D-dimers, fibrin degradation products, free plasma hemoglobin (-ACA versus aprotinin, p = not significant; p < 0.05 versus controls), and amount of retransfused autologous blood (p < 0.001). -ACA increased, aprotinin suppressed antiplasmin–plasmin complex generation (-ACA versus controls, p < 0.02; -ACA versus AP, p < 0.0001). For 4 hours after discontinuation, more chest drainage occurred with -ACA than aprotinin (137 ± 90 mL versus 62 ± 29 mL; means ± standard deviation; p < 0.02). Cumulative 12-hour drainage was similar for aprotinin (391 ± 220 mL) and -ACA (582 ± 274 mL), but higher without inhibitor (1,091 ± 541 mL; p < 0.001 versus drugs). Postoperatively, aprotinin was associated with the lowest autologous retransfusion incidence and highest hematocrits (p < 0.01 versus -ACA). Homologous transfusion exposures did not differ.

Conclusions. In first-time coronary operations, higher postoperative hematocrit and less shed blood retransfusion constitute only subtle advantages of aprotinin over high-dose -ACA.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
The nonbiological surfaces of extracorporeal circuits induce a host of humoral and cellular inflammatory responses. Blood components prone to activation by artificial surface contact include coagulation and fibrinolysis, the kallikrein-kinin and complement system, platelets, and leukocytes. After cardiopulmonary bypass (CPB) and heparin reversal, a typical clinical syndrome of microvascular bleeding ensues due to impaired platelet function and hyperfibrinolysis.

Prophylactic inhibition of fibrinolysis using the biological serine protease inhibitor aprotinin (AP) [1] or the synthetic lysine analogs -aminocaproic (-ACA) and tranexamic acid is now common clinical practice. The efficacy of these agents in reducing perioperative blood loss in adults has been described in numerous studies; reductions in thoracic drainage volume and transfusion exposure range from 30% to more than 50% [2][3].

Various dosage regimens of antifibrinolytics for cardiopulmonary bypass procedures have been suggested and compared [2][3][4][5]. -ACA has been found in adults to be either as effective as [6] or inferior to AP [4][5]. Meanwhile, a protocol using a higher dose of -ACA (ie, 30 g total) than in these studies has been used successfully without untoward sequelae [7][8].

Our present study carried the hypothesis that a high-dose -ACA regimen might prove equivalent or superior to conventional, but more expensive, AP prophylaxis in first-time coronary bypass graft procedures. We compared effects of both regimens on intermediate outcomes, such as profiles of coagulation, fibrinolysis, postoperative blood loss, and autologous retransfusion, and on homologous red cell replacement as a final outcome variable.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Patients
With approval from the state’s ethics committee (December 1, 1994) and written informed consent of the patients, we performed a prospective, controlled, randomized double-blinded study comparing two groups of patients (20 each) undergoing elective first-time aortocoronary bypass grafting. A third group of 10 patients was included as a control; these patients fulfilled all inclusion and exclusion criteria of the randomized groups, but had not received antifibrinolytics.

Exclusion criteria were age younger than 18 or older than 75 years; previous history of thoracic operation, deep vein thrombosis, or exposure to AP; pregnancy or concomitant steroid treatment; preexisting hemorrhagic diathesis, or thrombolytic therapy within less than 48 hours; known allergy to -ACA or AP; left ventricular ejection fraction less than 0.3; hematocrit level less than 35%; platelet count less than 100/nL; creatinine level of 1.5 mg/dL or greater; emergent, redo, or combined cardiac/noncardiac operation; and rethoracotomy because of surgical hemorrhage.

Anesthesia and Operation
Patients received standard premedication doses of oral flunitrazepam in the evening before and on the morning of operation. Intravenous doses of cimetidine (5 mg/kg) and dimetinden (0.1 mg/kg) for blockade of H₁ and H₂ receptors were administered immediately before induction of anesthesia. Patients were anesthetized with intravenous doses of midazolam (0.1 mg/kg), fentanyl (10 mg/kg), etomidate (0.1 mg/kg), and pancuronium (0.15 mg/kg). Repetitive doses were given for maintenance as needed.

Coronary revascularization by left internal mammary artery or multiple saphenous vein grafts was performed on moderately hypothermic CPB (32°C measured by urinary catheter thermistor). Cardiopulmonary bypass provided a systemic flow of 2.4 L/m² body surface area at mean arterial pressures between 50 and 90 mm Hg. Components of the CPB system included a centrifugal pump (Biomedicus, Minneapolis, MN), a nonheparin-coated circuit and a hollow fiber membrane oxygenator (Sorin Biomedica Monolyt, Milan, Italy). The system was prefilled with 2,250 mL of an asanguineous priming solution. Anticoagulation for CPB was started with intravenous heparin (400 U/kg), and continued by intermittent repetition so as to keep kaolin-activated clotting time more than 480 seconds (Medtronic Hemotec, Düsseldorf, Germany). Distal anastomoses of the internal mammary artery and saphenous vein grafts were established during cardioplegic cardiac arrest, using cold crystalloid cardioplegic solution (St. Thomas). After CPB, heparin anticoagulation was reversed by intravenous protamin (initial dose 3 mg/kg), until the activated clotting time had normalized.

Continuous hemofiltration (Rapido BLS; Baxter, Munich, Germany) and autotransfusion of washed autologous red blood cells (Haemonetics, Munich, Germany) were used routinely in combination with CPB. During the initial 6 hours after skin closure, blood draining from chest tubes was collected with a 30-µm filter into the cardiotomy reservoir, to be reinfused if at least 250 mL had collected and blood replacement was required. Threshold for its postoperative reinfusion or for homologous red blood cell transfusion was set at a hematocrit level of less than 27% accompanied by signs or symptoms of hypovolemia.

Drug Administration Protocol
Starting before skin incision, one group of patients (-ACA, n = 20) received -ACA (50 mg/mL), the other (AP, n = 20) AP (10,000 KIU/mL [1.4 mg/mL]) into a central venous line. A test dose of 1 mL of the respective agent was followed after 10 minutes by a loading dose of 200 mL of solution given over 30 minutes. Thereafter, the agents were infused continuously at a rate of 50 mL/h until the start of CPB; 200 mL of agent were added to the CPB prime, and 50 mL/h were infused from CPB weaning until 4 hours after heparin reversal. This resulted in an AP regimen of 2.0 x 10⁶ KIU [280 mg] for loading and CPB priming, each followed by infusion of 0.5 x 10⁶ KIU/h [70 mg/h]; and in an -ACA regimen of 10 g both as loading and priming dose, with 2.5 g/h as infusion. This -ACA dosage was selected on the basis of the high-dose -ACA regimen published by Daily [7] and Vander Salm [8] and their colleagues.

A third group of patients (control, n = 10) did not receive any pharmacologic antifibrinolysis. The solutions were prepared by our hospital pharmacy from AP (Trasylol; Bayer, Leverkusen, Germany) and -ACA (Amicar; Kabi, Switzerland) to result in identical dosage volumes and appearance, and were administered in a double-blinded fashion.

Measurements
The following parameters were determined before induction, 5 minutes after onset of CPB, immediately after weaning from CPB (but before protamine administration), and 1, 2, 4, 8, 12, and 24 hours after skin closure: hematocrit (%): free plasma hemoglobin (mg/L) by nephelometry; platelet count (L/µL); activated partial thromboplastin time (seconds), thrombin time (seconds), prothrombin time (%), fibrinogen (mg/dL), and antithrombin III (%) by standard laboratory analyses; thrombin/antithrombin III complex (TAT [µg/L]), plasmin-antiplasmin complex (µg/L), fibrinogen-fibrin split products (mg/L), and D-dimers (µg/L) by enzyme-linked immunosorbent assays.

At the respective postoperative time points, cumulative volume loss into all drainage containers including the cardiotomy reservoir was recorded, as well as incidence and amount of retransfused drainage volume and of homologous packed red cell transfusions within the first 24 postoperative hours.

Statistical Analysis
Continuous data with approximately normal distribution were analyzed by analysis of variance (factorial and for repeated measurements), with post-hoc comparisons between groups by Scheffé’s test; otherwise, nonparametric testing was performed. Nominal data were evaluated using contingency table analysis. The significance level was set at a p value of less than 0.05 (two-tailed).

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
There were no intergroup statistical differences in age, weight, severity of coronary artery disease, indicators of cardiac function, CPB duration, aortic cross-clamp time, technical aspects of the revascularization procedure, or incidence of perioperative myocardial infarction. Groups were comparable in their baseline cardiovascular, coagulation, or fibrinolytic status. Patients’ morphometric and physiologic characteristics, as well as operative variables are shown in Table 1.

View larger version (33K): [in this window] [in a new window]   Thrombin-antithrombin complex levels increase until termination of cardiopulmonary bypass (CPB) in all patients. Thereafter, the thrombin-antithrombin complex remains elevated for 12 postoperative hours in untreated patients, more than in patients receiving aprotinin or -aminocaproic acid (-ACA) (*p < 0.05 versus aprotinin or -aminocaproic acid). Box plot shows medians, interquartile ranges (boxes), and 10th/90th percentiles (whiskers).

View larger version (31K): [in this window] [in a new window]   Perioperative profiles of fibrinogen-fibrin split products (A) and, specifically, D-dimers (B). Both aprotinin and -aminocaproic acid (-ACA) effectively suppress their appearance. Untreated patients show highly elevated levels of fibrinolytic products (*p < 0.0001 versus active drugs). Data are means ± standard errors.

View larger version (25K): [in this window] [in a new window]   Perioperative profile of antiplasmin-plasmin complex levels. Patients treated with -aminocaproic acid (-ACA) show a significant increase of about 12 hours (*p < 0.02 versus control). Aprotinin is most effective in suppressing antiplasmin-plasmin complex generation (**p < 0.0001 versus -aminocaproic acid). Data are means ± standard errors.

Chest Tube Drainage and Replacement of Autologous and Homologous Blood
Cumulative 12-hour pericardial and pleural drainage was highest in untreated patients (1,091 ± 541 mL; p < 0.001 versus active drugs). During a 4-hour period after antifibrinolytic drug administration, AP reduced chest drainage transiently more than -ACA (62 ± 29 mL versus 137 ± 90 mL; p < 0.02; Fig 4). This effect was not large or sustained enough to result in significantly lower cumulative 12- or 24-hour drainage (AP, 391 ± 220 mL; -ACA, 582 ± 274 mL; not significant between AP and -ACA). Lost red blood cell mass, calculated from drainage volume and its hematocrit, at 8 hours postoperatively was found to be lowest after AP (AP, 69 ± 12 mL; -ACA, 105 ± 13 mL; control, 161 ± 28 mL; p < 0.01).

View larger version (22K): [in this window] [in a new window]   Four-hourly (bars) and cumulative (lines) postoperative thoracic drainage in first-time coronary artery bypass patients treated with either aprotinin, -aminocaproic acid (-ACA), or untreated controls. Both antifibrinolytics are highly effective (**p < 0.001 versus control). For 4 hours after completion of drug infusion, aprotinin reduces drainage transiently more than -aminocaproic acid (*p < 0.02 versus -aminocaproic acid or control). Cumulative 24-hour analysis is not sensitive enough to recognize this difference. Graph shows means ± standard errors.

Complications
The incidence of perioperative new Q-wave myocardial infarctions in the three groups was 1 of 20 (AP), 1 of 20 (-ACA), and 0 of 10 (untreated patients; not significant). Allergic reactions to the test drugs or postoperative thrombotic complications were not observed.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

 
The main findings of this study are as follows: -ACA, even in high dosage, remained marginally inferior to AP in suppressing fibrinolytic activation and postoperative bleeding. From a clinical perspective, both regimens were equivalent in reducing the volume of chest drainage after primary coronary artery bypass grafting. Postoperative retransfusion of shed blood reduced homologous transfusion exposure as effectively as both pharmacologic agents, but increased considerably the systemic load of products of coagulation and fibrinolysis.

With regard to drainage loss and homologous transfusions, our findings are quite consistent with results of three other prospective randomized trials comparing lower doses of -ACA with AP [4][5][6]. After intraoperative administration of approximately 18 g of -ACA or conventional high-dose AP for a variety of cardiac surgical procedures, Trinh-duc and colleagues [6] reported no difference in cumulative blood loss or homologous transfusion between agents. Their data, however, showed a trend to lower losses with AP at any point in time. In this study, heterogeneity of procedures and cumulative instead of interval analysis may have obscured subtle differences. In fact, despite using higher doses of -ACA, we still observed transiently lower blood loss in a 4-hour interval after the end of the AP infusion, in combination with higher postoperative hematocrits. Another trial also reported a small advantage of 2 x 10⁶ KIU [280 mg] AP (followed by 5 x 10⁵ KIU/h [70 mg/h]) over 80 mg/kg -ACA (followed by 30 mg · kg^-1 · h^-1) in terms of mediastinal drainage and transfusion incidence [5]. Comparing a total dose of 10 g of -ACA followed by 2 g/h with conventional high-dose AP in elective open heart procedures, Penta de Peppo and co-workers [4] found both drugs effective in lowering postoperative blood loss. Again, a small edge in favor of AP was evident, but without reduction of transfusion exposure. Synopsis of these and our observations indicates that increasing -ACA dosage beyond a total of approximately 15 to 20 g per adult patient will not add to its clinical benefit. Very likely, those dose adjustments of -ACA will not compensate for any advantages invoked by the large inhibitory spectrum of AP, including plasmin and kallikrein inhibition, preservation of platelet function, and ₂-antiplasmin.

Homologous transfusion incidence in our AP and -ACA groups was within the range reported in a recent review article. In our nonrandomized untreated group, the incidence was lower than in untreated controls of other researchers [3]. Although the use of an open, nonrandomized control group is a limitation of our study design, data of our control group appear to be biased, if anything, more in favor of autologous blood conservation than of homologous blood use. Hence, low transfusion exposure appears to depend more on nonpharmacologic autologous blood conservation (eg, consequent reinfusion and strict transfusion protocols) than on the selection of any particular antifibrinolytic agent. As a consequence, transfusion reduction by pharmacologic antifibrinolysis was of very limited effectiveness in our setting of first-time coronary operation. This observation is in agreement with those of other researchers [3][4][9].

In our study, postoperative blood loss was only transiently reduced more by AP than by -ACA. An additional indirect indicator of larger intraoperative blood loss and autologous turnover in our untreated group are elevated plasma levels of free hemoglobin. They are attributable to increased suctioning and more retransfusion during and after operation. Apparently, both antifibrinolytics reduce trauma to blood components by improving perioperative hemostasis.

Other than in the end points of blood loss and transfusion, our three groups showed several unequivocal differences in biochemical profiles. Our results confirm the inhibitory effect of AP on the contact phase of coagulation; this has been described before in vitro and in vivo [10][11]. According to our data, AP prolongs the activated partial thromboplastin time for about 4 hours. Prolongation of celite activated clotting time and kephalin-activated coagulation time by AP has been described and discussed in depth [6][12][13]. Aprotinin’s antithrombin properties are a potential advantage over -ACA and its analogs as they may balance the inhibition of postoperative fibrinolysis to some degree. On the other hand, we did not observe marked preservation of antithrombin III by AP. Antifibrinolytics have even been implicated in early postoperative graft failure, but data from controlled studies have, so far, not been able to corroborate this suspicion [14][15].

In contrast to both intervention groups, our untreated patients had elevated TAT concentrations from termination of CPB until several hours after skin closure. Thrombin formation, as evident from increased TAT, occurs with onset of CPB despite clinically adequate heparinization [11]. After termination of CPB, TAT complexes may be expected to clear rapidly from the plasma in patients with active treatment. We found that TAT levels in drainage blood at 8 hours postoperatively were always excessively high, and patients treated with shed blood reinfusion showed higher postoperative TAT appearance in their circulation than patients without reinfusion. Thus, autologous reinfusion of shed drainage blood may be an important cause of postoperative TAT elevation.

Both AP and -ACA suppressed effectively the release of markers of fibrinolysis during CPB when compared with no treatment. We measured antiplasmin-plasmin complex levels as a marker of plasmin activation; plasminogen was not analyzed in this series because enzymatic determination of plasminogen using chromogenic substrates is impaired in the presence of serine protease inhibitors like AP [16]. Aprotinin inhibits kallikrein, the activation of plasminogen, and plasmin activity itself by forming reversible enzyme inhibitor complexes. Our data show that AP reduced the generation of measurable ₂-antiplasmin-plasmin complexes very efficiently. In contrast, -ACA competitively blocks plasminogen’s high-affinity lysine-binding sites; thus, it prevents binding of plasminogen to fibrinogen and fibrin monomers and their subsequent proteolytic cleavage by plasmin [10]. Plasmin inhibition may require higher -ACA concentrations than plasminogen inhibition [17]. Of all groups in our study, -ACA treatment produced by far the highest postoperative peak of antiplasmin-plasmin complexes. We assume that our high-dose -ACA regimen was indeed effective in displacing plasminogen from the fibrin surface, thereby retarding fibrinolysis, but it failed to suppress the formation of active plasmin and its binding to natural inhibitors.

Reinfusion of activated blood did not appear to contribute significantly to postoperative antiplasmin-plasmin complex levels, as a correlation with retransfusion volumes was not observed. Lower antiplasmin-plasmin complex levels in drainage fluid of AP-treated patients may merely reflect lower plasma levels.

Thus, our data indicate that fibrinolysis is readily inhibited by both treatments, although at different levels of the cascade. Analogous to tranexamic acid, -ACA may also be a weak noncompetitive plasmin inhibitor [6][10] showing, for instance, some platelet preservation when given prophylactically [18][19]. However, the major portion of plasmin inhibition in our -ACA group was apparently still provided by endogenous ₂-antiplasmin, despite our high-dose approach. A decrease in antiplasmin activity for about 20 hours after CPB with or without prophylactic tranexamic acid, and significant antiplasmin preservation by AP have been reported by Blauhut and colleagues [19]. These investigators discussed a possible interference of AP with their chromogenic substrate assay for antiplasmin. We observed a postoperative 12-hour peak of antiplasmin-plasmin complexes, measured by enzyme-linked immunosorbent assays, with -ACA and in controls, but not in AP-treated patients. This is very much in agreement with the data of Blauhut and co-workers, and confirms enhanced consumption of endogenous plasmin inhibitor when synthetic antifibrinolytics are used. As a consequence, the direct inhibition of proteolytic plasmin activity of AP at the serine enzyme site may make it more effective in blocking plasmin in its other roles as activator of platelets, kinin, and complement pathways.

The marked postoperative increase of fibrin degradation products in our untreated patients is, of course, primarily attributable to the lack of any antifibrinolytic drug effect [8]. However, a secondary amplification by shed blood reinfusion may have occurred, as indicated by the correlation between reinfusion volume and markers of fibrinolysis. Finally, circulating fibrin degradation products themselves may interfere again with platelet aggregation and thrombin activity [10]. Thus, antifibrinolytics very likely reduce systemic presence and effects of products of intravascular coagulation and fibrinolysis through several routes (eg, by reducing their generation as well as their recirculation due to increased drainage and retransfusion). On the other hand, consequent retransfusion of autologous, although activated, blood helps to curtail homologous blood exposure. This measure appeared as effective as antifibrinolytic drug prophylaxis. Therefore, our findings support recommendations to use antifibrinolytics preferably in patients at high risk of hemorrhage, but low risk of thrombotic complications.

In conclusion, high-dose -ACA has been found to be almost equivalent, but definitely not superior to AP in inhibiting CPB-induced fibrinolytic activation and postoperative bleeding. High-dose -ACA prophylaxis does not result in less homologous transfusion when compared with AP. Aprotinin better preserves postoperative hematocrit levels, and decreases the need to reinfuse shed blood. Reduced shed blood turnover helps to attenuate the systemic load of products of coagulation, fibrinolysis, and hemolysis. Thus, in blood conservation after first-time coronary operation, a subtle advantage of AP over high-dose -ACA remains.

	References

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