Eur J Cardiothorac Surg 1998;14:360-366
© 1998 Elsevier Science NL
Aprotinin counterbalances an increased risk of peri-operative haemorrhage in CABG patients pre-treated with Aspirin1
M. Kleina,
P.R. Keithb,
H.-P. Daubena,
H.D. Schultea,
H. Beckmannc,
G. Mayerc,
O. Elertb,
E. Gamsa
a Heinrich-Heine-University Duesseldorf, Department of Thoracic- and Cardiovascular Surgery, Moorenstrasse 5, D-40225 Duesseldorf, Germany
b University of Wuerzburg, Dept. of Cardiothoracic Surgery, Josef-Schneider-Strasse 6, D-97080 Wuerzburg, Germany
c Bayer Vital GmbH, Bayerwerk, D-51368 Leverkusen, Germany
Received 1 October 1997;
received in revised form 18 May 1998;
accepted 22 June 1998.
Corresponding author. Tel.: +49 211 8117384; fax: +49 211 8117384; e-mail: kleinmi@uni-duesseldorf.de
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Abstract
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Objective: As Aspirin (ASA) has proven efficacy in preventing patients with CAD from complications related to cardiovascular diseases, most patients scheduled for CABG are treated with ASA therapy. Consequently, impaired haemostasis is a problem in the management of CABG patients. Clinical studies have shown that Aprotinin can reduce bleeding and the use of blood products by 50% in patients both with and without pre-operative ASA therapy. Concerning the combined effect of peri-operative low-dose ASA therapy and intra-operative high-dose Aprotinin therapy, the gathering of additional and prospective data seemed to be necessary. Methods: We conducted a double-blind two-centre randomised three-arm study in patients with elective primary CABG surgery. Three groups have been tested, comprising 119 patients in total (group A: ASA+Aprotinin, group B: placebo+Aprotinin, group C: placebo+placebo) to investigate a possible reduction of bleeding in Aprotinin treated patients. For all patients, thromboxane levels were used to identify ASA or placebo treatment. Results: The post-operative blood loss is significantly reduced by 21% after Trasylol® administration (B vs. C; P=0.009). The unexpected result of this study has been that the pre-treatment with ASA led to a further reduction of 18% (A vs. C; P<0.0001). The difference between the two Aprotinin groups (A and B) is significant (P=0. 01) in favour of ASA pre-treatment. Myocardial infarction (MI) had been diagnosed at levels of 1.8% in total (2/113), 2.6% (1/38) in group B and 3.2% (1/31) in group C. An additional blinded evaluation of ECG, enzyme levels and clinical status revealed `definite, probable and possible' MIs of 5% in group A, compared to 16% in group B and 13% in group C, thus providing no evidence for a higher risk of infarction by Aprotinin treatment. When comparing the ASA group to non-ASA pre-treatment, a strong trend towards a reduction in MI rate becomes obvious, from 15% to 5% in favour of the ASA pre-treatment (P=0.08). Concerning other peri-operative complications, no statistical difference between the groups could be detected. Conclusions: A reduction in post-operative blood loss in primary elective CABG surgery with intra-operative Aprotinin treatment could be confirmed. A low-dose ASA treatment combined with a high-dose aprotinin administration during surgery not only neutralised a potentially higher risk of bleeding, but did in fact reduce the post-operative blood loss. The protective effect of ASA on peri-operative MI has been evident through a reduction of MI rate in ASA treated patients.
Key Words: Aspirin therapy • Aprotinin therapy • Cardiac surgery • Blood loss • Myocardial infarction
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Introduction
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The treatment of coronary artery disease (CAD) today includes mostly a therapy with ASA in addition to anti-anginous medication
[1]
[2]
[3]
[4]. The anti-aggregatory effect of ASA, the irreversible acetylation of cyclooxygenase, leads to an impaired haemostasis, a fact that creates a practical problem in most patients who are scheduled for CABG surgery and are being pre-treated with ASA
[5]
[6]
[7]
[8]. As a consequence, ASA therapy in elective cases is mostly being discontinued 5–10 days prior to surgery in order to reduce the risk of an increased peri-operative blood loss.
Aprotinin, on the other hand, is known to decrease the peri-operative bleeding risk and there have been hints of the same efficiency in patients pre-treated with ASA.
The main interest of this prospective, randomised, double-blind, three-arm, two-centre study has been the peri-operative blood loss of CAD patients undergoing an elective CABG surgery. The verum patients were treated with a low-dose ASA therapy pre-operatively and received a high dose of Aprotinin intra-operatively. The effectiveness of ASA therapy has been monitored through the determination of thromboxane B2 levels drawn just before surgery. The myocardial infarction rate has been determined both by the routine clinical diagnostics of the centre and by an independent cardiologist reviewing the anonymous data on ECG and enzyme levels.
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Material and methods
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The study had been approved by the local Ethics Committees and has been carried out according to Good Clinical Practice (GCP) requirements. After having given written consent, the patients were randomised into three treatment groups: group A ASA/Aprotinin, group B placebo/Aprotinin, group C placebo/placebo. After enrolment the patients underwent a minimum 10-day run-in period on ASA (100 mg/day) or placebo until surgery. The Aprotinin was been applied according to the Hammersmith scheme: 10 min after a test dose, a loading dose of 2x106 KIU was given, followed by continuous infusion of 0.5x106 KIU/h until chest closure or for 6 h maximum. Two 2x106 KIU had been added to the pump prime volume.
Male and female patients scheduled for primary elective CABG surgery, aged over 18 years, requiring two or more grafts and pre-treated with ASA were enrolled in the study unless they met one or more of the following exclusion criteria:
- episodes of unstable angina in the previous 6 weeks;
- cerebrovascular event in the previous 3 months;
- previous sternotomy;
- known or suspected previous exposure to Aprotinin;
- any known coagulopathy;
- history of any bleeding diathesis;
- history of gastroduodenal ulcer or upper gastrointestinal bleeding;
- need for intravenous heparin prior to surgery;
- status requiring homologous donor blood in the priming volume;
- suspicion of intake of non-steroidal anti-inflammatory drugs during run-in period;
- acute myocardial infarction in the previous 6 weeks;
- need for combined surgery (e.g. CABG and valve surgery);
- endocarditis;
- positive testing for HBV, HCV, HIV infections;
- participation in other studies;
- known or suspected allergy to Aprotinin;
- anticoagulant medication 2 weeks prior to surgery;
- malignancies;
- serum creatinine in excess of 2.0 mg/dl (177 µmol/l);
- pre-donation of autologous blood prior to hospitalisation;
Compliance with ASA therapy had been checked at admission. The thromboxane B2 levels were determined by an enzyme immuno essay (Biotrake, Amersham). All patients underwent a standardized procedure in anaesthesia and surgery. The peri-operative heparin management was been controlled either by heparin titration (Hepcon HPT >2.5) or by (Kaolin-) activated clotting time (>400 s). The heparin antagonization was been performed with a protamin regimen in a ratio of 1:1.3.
Transfusion criteria were set at a hematocrit of less than 18% during, and less than 21% after, surgery. The drainage volumes were documented at intervals of 6 h up to 24 h post-operatively and then at drainage removal. Transfusion requirements, adverse events, lab sheets and other clinical data have been documented in the case report file (CRF).
Routine physical examinations and ECGs were recorded on days 1, 3, 5 and 12 (or discharge) as well as complete lab sheets which were additionally taken at time of arrival in ICU, and enzyme levels in 6 h intervals up to 24 h. The incidence of peri-operative MI was in the centres by the following definitions: no MI, definite MI (new Q-wave post-operatively), probable MI (ECG signs of ischemia plus relevant enzyme increase) and possible MI (without increased enzyme levels). The validity was checked by a blinded evaluation through a non-related cardiologist. The cut-off level for thromboxane B2 was set at 20 ng/ml. Additional exclusion criteria after run-in period were: death within 6 h post-operatively and re-thoracotomy due to surgical bleeding.
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Statistics
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Demographic and anamnestic data were analyzed descriptively. The treatment groups were being tested for comparability. An analysis of variance was been performed in order to assess the target variable blood loss between the groups A and C. For comparison of the main target variable and the transfusion requirements between the groups A and B, a hierarchical procedure was been performed using full 
levels for both tests. For the valid for efficacy (VFE) analyses the patients were assigned according to the randomization and high or low thromboxane B2 levels. Four patients of group C (placebo/placebo) with inhibited thromboxane B2 levels were evaluated separately as group X as they formed a fourth arm of the study which had been omitted before for ethical reasons. Fisher's exact test was used for the comparison of MI rates.
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Results
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Of the 119 patients who had been enrolled in the study, six dropped out for various reasons, so 113 were left for ITT analysis. Three of those were invalid, in four the thromboxane levels were missing, leaving 106 patients for VFE analysis. Demographic and clinical data are summarized in Table 1Table 2. There were no statistical differences between the groups.
The blood loss was significantly reduced in the placebo/Aprotinin group B compared to the control group C placebo/placebo as shown in Table 3Table 4. The reduction is even more pronounced when comparing group A to group C with a P-value<0.001. A blood-loss reduction of 21% is reached in the group ASA/Aprotinin in comparison with the group B placebo/Aprotinin, P=0.01.
These results were validated in an additional multivariance analysis. No transfusions had been required in 73% of group A, in 89% of group B and in 79% of group C. In group A 2.4 units per patient had to be transfused, 3.0 units were transfused in group B and 2.67 units in group C. No platelet concentrates or cryoprecipitate had to be used (Table 4).
Neither treatment nor centre effects could be observed in terms of surgery, bypass or cross-clamping time i.e. all groups were statistically comparable. Concerning the total hospital or ICU stay, no differences could be detected. There were no differences in the NYHA classification at the time of discharge. The incidence of peri-operative MI amounted to 2.6% (1/38) in group B vs. 3.2% (1/31) in group C, no infarctions had been diagnosed in group A. In contrast to these clinical results, a different situation resulted from the independent cardiological evaluation using Chaitman's definition of MI
[35]. Definite MIs were diagnosed in 5% of groups B and C. Additionally, probable and possible infarctions were found with a frequency of 5% to 8% over all groups (Table 5). For efficacy of platelet inhibition shown by thromboxane levels, Fisher's test showed a trend for MI reduction in patients with low levels (P=0.12).
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Table 5. Synopsis of the patients with MI according to central evaluation, heart enzymes, NYHA class and relevant operation data
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The occurring adverse events did not differ in terms of frequency and type from those commonly observed in cardiac surgery. There was no difference between the treatment groups.
Two deaths occurred. In both cases no relation to study medication could be detected. The post-operative laboratory data revealed no unusual occurrences. Of special interest in the context of study medication are the courses of haemoglobin and creatinine. The haemoglobin values were comparable between the treatment groups at baseline and post-operative determination times. Concerning the course of creatinine, no difference between the groups could be found (Table 6). A post-operative renal function disorder could not be observed at any time.
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Discussion
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Aspirin is efficient in the prevention of complications related to cardiovascular disease. Unstable angina, subendocardial myocardial infarctions and recent myocardial infarctions in particular, are reduced by ASA therapy
[1]
[2]
[3]
[4]
[30]
[31]
[32]. It also has been shown to improve early graft patency rates
[8]
[33] when administered pre-operatively and continued into the post-operative period. Peri-operative continuation of either low-dose or high-dose ASA treatment provides for a similar post-operative graft patency of 93% resp. 92%
[8]
[15]
[19]. However, patients receiving ASA may also have an increased blood loss when undergoing cardiac surgery
[5]
[7]
[8]. ASA is a inhibitor of thromboxane formation leading to platelet dysfunction with decreased capillary vasoconstriction and impaired platelet aggregation
[17]
[18]. The potential risk for more bleeding persists for 5 to 10 days after ASA ingestion
[6]
[7]. An increased bleeding tendency is generally expected to be associated with pre-operatively ingested high doses of ASA
[5]
[15]. In pre-operative low-dose ASA therapy several authors observed an increased blood loss
[7], whereas others did not
[20]. One explanation for these contradictory results might be that long-term low-dose ASA treatment has a cumulative effect on plasma concentration of ASA. This might result in a plasma concentration similar to that which occurs after much higher doses of ASA, as suggested by Weksler
[21]. Consequently, possible variation in the time of exposure to ASA might explain these varying results of blood loss
[7]
[13]
[20]. Nevertheless, there is a potential risk of increased intra- and post-operative blood loss for patients on ASA undergoing elective revascularisation procedures. To reduce the risk of an extended peri-operative bleeding, several investigators have recommended to discontinuing ASA treatment at least 5–10 days before an elective procedure
[5]
[7]
[8]
[15]. This policy, however, is not feasible at all for emergency cases and unstable patients may be placed at risk concerning cardiovascular events before surgery. In many cases, CABG was performed with an Aspirin- associated morbidity accepted. A possible pharmacological intervention to reduce the risk associated with ASA exposure could be combined intra-operative therapy with Aprotinin. The efficacy of Aprotinin for improving haemostasis in CABG procedures has been proved in various clinical trials
[9]
[10]
[11]
[12]. Whereas most of these early studies excluded the previous use of Aspirin, today it is known that Aprotinin shows a similar positive effect in ASA pre-treated patients.
[13]
[14]
[16]
[34].
This study was planned to prove the preserving effect of Trasylol® in a high-dose regimen on blood loss and transfusion requirements in patients with a continued low-dose ASA treatment undergoing aorto-coronary bypass graft surgery. It was designed with a 10-day run-in phase to provide groups with either 95% of platelet inhibition or a full platelet function at time of surgery. As a quality control, and to eliminate any influence of ASA-containing drugs, thromboxane B2 levels were determined by a validated ELISA prior to surgery. All analyses were done with regard to these levels.
The study consisted of three arms: group A (ASA/Aprotinin); group B (placebo/Aprotinin); group C (placebo/placebo). The fourth arm (ASA/placebo) was deliberately omitted for ethical reasons. By chance, this group has been re-established on the basis of the thromboxane selection method, though with only the small number of n=4 (group X).
All groups were comparable in sample size, demographics, relevant concomitant diseases and risk factors, status of coronary heart disease, NYHA class, left ventricular function and surgical procedure except for the implantation of arterial grafts (IMA) which were remarkably less prepared in the ASA/Aprotinin group. The fact that one centre prepared the IMA to 78.7% and the other to 28.9% serves as an explanation. This remained without statistical effect when this fact was tested as a co-variable to the first efficacy variable.
As expected for Trasylol® trials in open heart surgery, the post-operative blood loss is significantly reduced by 21% after Trasylol® administration (B vs. C; P=0.009). The unexpected result of this study is that the pre-treatment with ASA led to a further reduction of 18% (A vs. C; P<0.0001). The difference between the two Aprotinin groups, A and B, is also significant (P=0.01) in favour of the ASA pre-treatment. According to the statistical procedures this finding remains stable in spite of considerable centre effects and significantly fewer arterial grafts – involving a higher bleeding risk – in the ASA/Aprotinin group. Currently, there is neither an explanation nor a hypothesis explaining the aspect of the Aprotinin interaction with the endothelial cells and/or with the platelets.
The mean blood loss in group X (ASA/placebo) did not differ from group C (placebo/placebo). Many factors like small group number, centre effects, different kind of response to ASA may have caused this result which stands in contrast to the conclusions of other trials.
This study has been too small-sized to verify a superiority of ASA/Aprotinin in terms of transfusion requirements. Considerable centre effects could be observed. The need for donor blood was falsified in group B (placebo/aprotinin) by one patient who required considerable amounts of donor blood for a series of post-operative complications. The haemoglobin values were comparable between the treatment groups at baseline and at all post-operative determination times. Thus, donor blood transfusions were sufficiently carried out in all groups without giving the advantage or disadvantage to one form of drug therapy.
Type and frequency of adverse events were more likely to depend upon the surgical procedure and the condition of the patient condition than on the treatment. No serious adverse events and no deaths were judged to be related to the study drug.
Myocardial infarctions had been diagnosed in a total of 1.8% (2/113) with no infarction in group A, 2.6% (1/38) in group B and 3.2% (1/31) in group C. As part of the study design, a central blinded analysis of all ECG and enzyme levels additionally was done according to the definition by Chaitman
[36]. This led to the detection of a higher rate of peri-operative myocardial infarctions (PMI). PMI remains a major and frequent complication following CABG. There are wide variations in the reported incidences of PMI because an accurate detection is difficult post-operatively and also because different criteria of diagnosis are used in the literature. The incidence of PMI in patients undergoing CABG varies markedly from 5% to 23%
[36]. Besides the fact that different diagnostic criteria are used, an accurate diagnosis of PMI is difficult to establish post-operatively because false positive and false negative results have been noted with all diagnostic techniques
[36]. Obviously, this analysis included smaller and smallest infarctions also. However, definite MIs were not seen in group A, but in 5% of group B as well as in group C. Probable MI – non-transmural ECG signs – had been diagnosed in 5% of group A, in 11% of group B and in 7% of group C. The central blinded evaluation revealed `definite and probable' MIs in 5% of group A versus 16% and 13% of groups B and C, respectively, providing no evidence for an enhanced infarction rate by Aprotinin treatment. Summarizing the ASA groups A and X and comparing them to the non-ASA groups B and C, a trend towards reduction in the MI rate and ischemic events becomes obvious, from 15% to 5% in favour of the ASA pre-treatment (P=0.08). The assumption of a beneficial effect of ASA in preventing peri-operative myocardial infarction becomes evident in this trial. While Murkin et al.
[16] reported no higher prevalence of myocardial infarction, this is in contrast to a report of Cosgrove et al.
[28] which, while similarly demonstrating significant reductions in blood loss and transfusion requirements, noted an apparent dose-related trend for increased Q-wave myocardial infarction in Aprotinin-treated patients. It was thought that the increase of ACT in the aprotinin-treated patients may have led to under-anticoagulation. Although it has been suggested that heparin dosage could be reduced in the presence of Aprotinin
[22], this theory is erroneous
[24]
[25]. The increase in ACT
[29] seen in the presence of Aprotinin is largely artificial because of an in vitro interaction between the celite activator, heparin and Aprotinin
[23]
[26]. As such, it is not recommended that the heparin dosage is reduced below the usual 350–500 IU/kg body weight, and the ACT should be maintained above 750 s during CBP in Aprotinin-treated patients
[24]
[27]. Concerning other peri-operative complications, like cerebrovascular events or pulmonary effects, there was no difference between the compared groups and the total number of such events was too small for any statistical analysis. Relevant post-operative changes of laboratory parameters to the baseline were recorded, all of them belonging to those commonly observed in CABG surgery and unrelated to the study drug.
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Conclusions
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The study has confirmed the reduction in post-operative blood loss in primary elective CABG surgery when Aprotinin is applied during operation. By ASA pre-treatment until surgery, and Aprotinin administration during surgery, not only a potentially higher bleeding risk was avoided but a substantial further reduction in post-operative blood loss was achieved. These effects could not be verified in terms of transfusion requirements because of a too small sample size, remarkable centre effects and advanced surgical techniques. The protective effect of ASA on peri-operative myocardial infarction has gained evidence by both clinical and central blinded evaluation.Appendix A. Conference discussion
Dr U. Althaus (Bern, Switzerland): I think this presentation has shown a rather surprising result. Looking at the post-operative blood loss, I guess that the majority of surgeons in the audience would have expected that patients from group B who had Aprotinin without previous Aspirin treatment showed a reduced blood loss compared to group A who had Aprotinin with previous Aspirin treatment. How do you explain this unexpected finding?
Dr Klein: When we saw the results at first in the statistics, which were done outside of the centres, we did not expect an additional reduction of blood loss in the group treated with Aprotinin plus Aspirin. It, however, had not been the aim of the study aim to point out the differences between the two groups (Aprotinin without Aspirin and Aprotinin with Aspirin). However, we cannot offer an explanation at this time.
Dr R. Dion (Brussels, Belgium): In our institution, the cardiologists use Aspirin in very unstable patients, in addition to intravenous heparin and nitrates. If the patients stabilize, we always try to discard Aspirin for 4 days before operating on them. After having listened to your presentation, I believe that we should not take the risk anymore of stopping the Aspirin in a highly unstable patient and delaying the operation for 4 days, rather we should keep the Aspirin and use Aprotinin during the procedure. Would you agree with that attitude?
Dr Klein: We conceived the study on the grounds of having more and more patients with an unstable cardiac situation which often results in infarctions pre-operatively, whereas our standard pre-operative regimen includes a discontinued Aspirin treatment 5–10 days prior to surgery. The results of this study demonstrate, as an answer to your question, that, under this Aprotinin regimen, it is possible to continue the Aspirin therapy without risk of uncontrollable blood loss. Surprisingly, the blood loss of these patients lay well below the average.
Dr A. Arbulu (Detroit, MI, USA): We had a similar study several years ago, but we have a third group besides the Aprotinin. All our patients get Aspirin when they come to coronary surgery. The third group received aminocaproic acid, Amicar. We found that the results in the aminocaproic acid and the Aprotinin were exactly the same. The significant difference was that the aminocaproic acid was significantly cheaper.
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Footnotes
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Presented at the 11th Annual Meeting of the European Association for Cardio-thoracic Surgery, Copenhagen, Denmark, September 28 – October 1, 1997. 
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L. J. Dacey, J. J. Munoz, E. R. Johnson, B. J. Leavitt, C. T. Maloney, J. R. Morton, E. M. Olmstead, J. D. Birkmeyer, and G. T. O'Connor
Effect of preoperative aspirin use on mortality in coronary artery bypass grafting patients
Ann. Thorac. Surg.,
December 1, 2000;
70(6):
1986 - 1990.
[Abstract]
[Full Text]
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Abstract
Introduction
