Departments of 1 Anaesthesia and 2 Haematology, Southampton University Hospitals, Southampton, UK
* Corresponding author: Southampton University Hospitals, Tremona Road, Southampton SO16 6YD, UK. E-mail: ravi.gill{at}suht.swest.nhs.uk
Accepted for publication November 8, 2004.
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Abstract |
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Methods. Patients were randomized to one of three treatment groups: an aprotinin group, a tranexamic acid group, and a control group receiving normal saline. Intra-operative cell salvage was used for all patients. The primary outcomes were the number of patients exposed to allogeneic red blood cells, allogeneic coagulation products or any allogeneic transfusion (allogeneic red blood cells and/or allogeneic coagulation products).
Results. Patients were 2.5 times more likely to receive any allogeneic transfusion in the tranexamic group than in the aprotinin group (21 patients out of 60 compared with nine out of 60, respectively). The relative risk of any allogeneic transfusion comparing aprotinin with tranexamic acid was 0.43 (95% confidence interval 0.210.86; P=0.019). Patients in the control group were four times more likely to receive any allogeneic transfusion when compared with the aprotinin group (37 patients out of 60 compared with nine out of 60, respectively). The relative risk of any allogeneic transfusion comparing aprotinin with control was 0.24 (95% confidence interval 0.130.46; P<0.001).
Conclusions. When used in addition to intra-operative cell salvage, aprotinin is the most efficacious pharmacological therapy for reducing patient exposure to any allogeneic transfusion during first-time cardiac surgery.
Keywords: antifibrinolytic agent, tranexamic acid ; blood, transfusion ; equipment, cell savers ; polypeptides, aprotinin ; surgery, cardiac
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Introduction |
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In cardiac surgery, the need for any allogeneic transfusion (the transfusion of either allogeneic red blood cells and/or allogeneic coagulation products) can be modified by a range of different techniques. Intra-operatively, mechanical and pharmacological methods may maintain a patient's haematocrit, reduce the development of coagulopathy and reduce intra-operative and postoperative blood loss. These methods may therefore reduce the need for any allogeneic transfusion.
Mechanical therapies include intra-operative cell salvage (ICS) and acute peri-operative normovolaemic haemodilution. In coronary artery bypass surgery intra-operative cell salvage is the optimal mechanical method for reducing peri-operative transfusion of allogeneic red blood cells.7
The most commonly used pharmacological therapies to reduce peri-operative blood loss and the need for allogeneic transfusion in cardiac surgery are the antifibrinolytic agents aprotinin and tranexamic acid. Aprotinin is a non-specific serine protease inhibitor, and in addition to its antifibrinolytic properties it may promote platelet function.8 Tranexamic acid is a synthetically derived antifibrinolytic agent that has its effects by prevention of the interaction between plasminogen and fibrin.
There have been three meta-analyses of antifibrinolytic therapy in cardiac surgery. These, when compared with placebo, favour their use to reduce postoperative blood loss and reduce exposure to allogeneic red blood cells.911 However, there are few adequately powered studies comparing antifibrinolytic agents. Furthermore there are no adequately powered studies comparing different antifibrinolytic agents when ICS was also used.
Our hypothesis was that during first-time cardiac surgery the use of an antifibrinolytic agent in addition to ICS would lead to a reduction in patients exposed to allogeneic red blood cells and/or allogeneic coagulation products (fresh frozen plasma, platelets and cryoprecipitate) in comparison with ICS alone. We report the results of a randomized, double-blind, placebo-controlled trial comparing two antifibrinolytic therapies in patients undergoing first-time cardiac surgery who all had ICS.
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Methods |
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Written informed consent was obtained from all patients who agreed to recruitment into the trial. After consent, use of computer-generated random numbers determined patient allocation to one of the three treatment groups. The aprotinin group treatment protocol was 2 million kallikrein inhibitor units (kiu) of aprotinin i.v. in 200 ml volume at the start of surgery, an identical dose into the cardiopulmonary bypass (CPB) prime volume, and an i.v. infusion of aprotinin 500 000 kiu in 50 ml volume per hour throughout the operation. The tranexamic acid group treatment protocol was tranexamic acid 5 g i.v. in 200 ml volume using normal saline as a diluent, normal saline 200 ml into the CPB prime volume, and an i.v. infusion of normal saline 50 ml h1 throughout the operation. The control group treatment protocol was 200 ml volumes of normal saline as an i.v. bolus, and also into the CPB prime volume, and an i.v. infusion of 50 ml volume of normal saline per hour throughout the operation.
The appropriate treatment regime was identified, prepared and blinded by the pharmacy technical services department. The drug or control solutions were prepared with the only identifying marks being the patient's name, study identification number and expiry date. All study investigators, patients, surgeons, anaesthetists and persons involved in the patient's peri-operative care were blinded to treatment allocation. Sealed envelopes were available to facilitate unblinding should the need arise. It was prospectively decided to exclude patients who had been unblinded intra-operatively from the final data analysis, their treatment group allocation being randomly assigned back to another future patient by an independent observer. Final unblinding of the study occurred when the last patient had left hospital.
All patients received standard anaesthesia and peri-operative care. Prior to skin incision, patients were given a test dose of 5 ml of blinded study solution appropriate to their group allocation. Then, provided no ill effects had occurred, the full dose of 200 ml of study solution was administered and the i.v. infusion of study drug started. Intra-operative cell salvage (Compact A; Dideco, Sorin Biomedica, Italy) of shed blood was used in all patients from skin incision until closure of the sternum at the completion of surgery.
Blood samples were analysed for standard haematological variables, including haemoglobin concentration, platelet count, fibrinogen concentration, INR and activated partial thromboplastin time. A celite-activated thrombelastogram (Haemoscope®, Illinois, USA) was performed using standard and heparinase cups as appropriate. The following time points for blood analysis were used: pre-operatively; on rewarming during CPB; after the infusion of cell salvaged blood; and after any allogeneic coagulation product transfusion. Haemoglobin concentrations were recorded on postoperative day 1 and just before hospital discharge.
All patients received anticoagulation with heparin 400 IU kg1 of body weight to achieve a celite-activated clotting time (ACT) of greater than 800 s before CPB. If this ACT was not achieved, further boluses of heparin 100 IU kg1 body weight were administered.
Cardiopulmonary bypass flow was 2.4 litrel min1 m2. While on CPB the trigger for the transfusion of allogeneic red blood cells was a haemoglobin concentration of less than 70 g litre1, patients were cooled to 32°C, and mean arterial pressure was maintained between 50 and 80 mm Hg with the use of phenylephrine. After rewarming and completion of the aspects of surgery requiring CPB, patients were weaned from the CPB machine. After termination of CPB, heparin was neutralized using protamine 4 mg kg1. The blood within the CPB circuit was drained into the cell salvage device. Subsequently, this blood and salvaged shed blood was washed and centrifuged by the cell salvage device then retransfused to the patient.
Postoperatively the trigger for transfusion of allogeneic red blood cells was a haemoglobin concentration of less than 85 g litre1. If a patient bled excessively, coagulation products were administered according to a modification of a protocol described previously12 for the management of postoperative cardiac surgical bleeding (Fig. 1). The definition of excessive bleeding was >4 ml kg1 h1 in any one hour, >2 ml kg1 h1 for two consecutive hours or >5 ml kg1 in the first 4 h after surgery.
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Audit of the Southampton University Hospitals cardiothoracic database had shown that 60% of patients in the control group would be exposed to any allogeneic transfusion. Sample size calculations were based on the power to detect a relative reduction in the exposure to any allogeneic transfusion of 45% from a baseline transfusion rate of 60% (absolute reduction of 27%), with a power of 80% and an error of 5%. This gave a sample size of 60 patients for each group.
A grant from the National Blood Transfusion Service was used to reimburse the cost of a clinical research fellow, and to fund additional National Health Service, costs including the provision of the allocation and blinding of drugs by the pharmacy technical services department.
Data were entered into a database (Microsoft® Access 2000), statistical analysis was with Analyse-it for Excel® v1.71 (Analyse-it Software Ltd., Leeds, UK). Continuous data were analysed for normality with the ShapiroWilk W-test. Parametric data were analysed with analysis of variance (ANOVA) and non-parametric data were analysed with the KruskalWallis one-way ANOVA by the ranks method.13 Fisher's exact test was used to calculate relative risks of transfusion between groups and confidence intervals were calculated using Woolf's approximation.14 Two between-group comparisons were made for each primary outcome. Therefore, differences between groups were deemed significant if they achieved significance of P<0.025.15
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Results |
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Nine patients in the aprotinin group received any allogeneic transfusion compared with 21 in the tranexamic acid group and 37 in the control group (Table 2). Comparing aprotinin with control, the relative risk of receiving any allogeneic transfusion was 0.24 (95% CI 0.130.46; P<0.0001). Comparing aprotinin with tranexamic acid, the relative risk of receiving any allogeneic transfusion was 0.43 (95% CI 0.210.86; P=0.0195).
Both the aprotinin and tranexamic acid groups showed a significant reduction in mediastinal drainage 4 and at 24 h after surgery when compared with the control group (Table 3).
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Discussion |
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This trial extends our knowledge of how to reduce the need for allogeneic transfusion in cardiac surgery patients, demonstrating the significant additive benefit of combining two intra-operative techniques, one pharmacological and the other mechanical. There has not previously been an adequately powered, randomized controlled trial addressing the question of whether combining antifibrinolytic treatment with intra-operative cell salvage provides additional benefit in reducing allogeneic transfusion.
Allogeneic red cell and allogeneic coagulation product transfusions are used for different reasons during surgery. However, there are common negative implications of their use. These are the morbidity and mortality risks for the individuals transfused2 4 and the depletion of a blood supply which is proving difficult to maintain.6 In the UK the percentage of patients receiving an allogeneic transfusion during cardiac surgery varies from 15% to 80%.16 Whilst some of this variability relates to case mix and aspects of peri-operative care, using ICS and aprotinin could substantially reduce the transfusion of allogeneic red blood cells and allogeneic coagulation products in many centres.
The results of this trial are consistent with previous literature. ICS has been shown to be an effective method of conserving red blood cells intra-operatively and reducing peri-operative allogeneic red cell transfusion during cardiac surgery.7 The antifibrinolytics aprotinin and tranexamic acid have been shown to reduce blood loss and the need for red cell transfusion during cardiac surgery.911
A recent meta-analysis of trials compared aprotinin with tranexamic acid for the proportion of patients exposed to allogeneic red blood cells.11 This identified seven randomized controlled trials comparing aprotinin against tranexamic acid in cardiac surgery. Use of tranexamic acid was associated with a relative 21% increase in the risk of requiring allogeneic red blood cells, compared with aprotinin. However, the total number of participants in these trials was relatively small and the difference did not reach statistical significance (relative risk=1.21; 95% CI 0.831.76). Within this series only one, inadequately powered, trial used intra-operative cell salvage.17
The causes of bleeding in cardiac surgery are surgical damage to blood vessels and the development of coagulopathy principally related to cardiopulmonary bypass. The coagulopathy results from a combination of an acquired defect in platelet function, inappropriate fibrinolysis and a reduction in circulating coagulation factors.1820 The greater benefit derived from aprotinin in this trial may be due to a more efficacious antifibrinolytic effect or possibly its platelet protective effects.8
Adverse events were not different between the groups in this trial. Electrocardiogram and troponin I analysis did not reveal an excess of myocardial infarction in either of the treatment groups compared with control. One meta-analysis has shown a reduction in mortality compared with placebo in patients given aprotinin.9 This effect was not replicated in a more recent meta-analysis.11 In this trial, mortality and major morbidity were not different between the groups.
The correct transfusion triggers to apply in cardiac surgery remain contentious. There is no agreement about the area of optimal haematocrit on cardiopulmonary bypass.21 22 Following the publication of the TRICC, study we know the safe transfusion trigger in critically ill patients, but two recent publications show that the debate as to what is an adequate haemoglobin after cardiac surgery or for patients with acute coronary syndromes remains unanswered.23 24 The transfusion triggers that were used for this study are commonly used in cardiac centres in the UK.
This study was not designed to include a formal costbenefit analysis of the use of antifibrinolytic therapy for cardiac surgery. However, there are significant cost differences between the two antifibrinolytic agents that were studied. A brief summary of the average costs of the allogeneic red cell and coagulation products transfused, together with the additional drug costs for each of the study groups, is shown in Appendix 1.
The potential limitations of this trial lie in four areas: (i) the equivalence of the doses of aprotinin and tranexamic acid; (ii) the possibility of bias with the use of allogeneic red blood cells and coagulation products; (iii) our exclusion from data analysis of patients who were unblinded at physician request; and (iv) the breadth of applicability of the results within cardiac surgery in general.
The dose of aprotinin used in this trial is that associated with the greatest reduction in allogeneic transfusion.911 The evidence for the most effective dose of tranexamic acid does not exist.11 In this study the median dose of tranexamic acid given to patients was 61 mg kg1 (range 5181 mg kg1). The range of doses quoted in the Cochrane Review as being used in previous studies has been between 2.5 and 100 mg kg1. One study that attempted to determine the optimal dose of tranexamic acid for blood conservation in cardiac surgery found no additional benefit for total doses of tranexamic acid in excess of 22 mg kg1.25 The dose of tranexamic acid used represents that considered appropriate for optimal efficacy in cardiac surgery. The effective blinding of the trial and the use of protocols for any allogeneic transfusion controlled for potential between-group bias in the use of allogeneic red blood cells or allogeneic coagulation products. We chose to exclude patients from analysis who had been unblinded at physician request. This was in an attempt to prevent the potential for bias and the possibility of statistical error. However, if those patients are included in the analysis (on an intention-to-treat basis), the results for differences between the groups for all end-points remain the same. The results of this trial would be of limited importance if they could only be applied to a minority of cardiac surgical patients. However, since this study examined both coronary artery surgery and valve surgery patients our findings apply to the overwhelming majority of first-time adult cardiac surgery.22
Aprotinin is the most effective intra-operative pharmacological regimen to use with ICS to reduce peri-operative allogeneic transfusion. This combination of aprotinin and mechanical technology is so effective in reducing allogeneic transfusion that it should be used for almost all adult patients undergoing first-time cardiac surgery.
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Appendix |
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Acknowledgments |
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References |
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