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Anesth Analg 2008; 107:1469-1478
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318182252b
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CARDIOVASCULAR ANESTHESIOLOGY

Tranexamic Acid and Aprotinin in Primary Cardiac Operations: An Analysis of 220 Cardiac Surgical Patients Treated with Tranexamic Acid or Aprotinin

Wulf Dietrich, MD, PhD*, Michael Spannagl, MD{dagger}, Johannes Boehm, MD{ddagger}, Katharina Hauner, MD{ddagger}, Siegmund Braun, MD§, Tibor Schuster, MS||, and Raimund Busley, MD

From the *Institute for Research in Cardiac Anesthesia; {dagger}Department of Hemostasiology, Ludwig Maximilian University, Munich; Departments of {ddagger}Cardiac Surgery and §Clinical Chemistry, German Heart Center Munich; ||Department of Medical Statistics and Epidemiology, Klinikum Rechts der Isar; and ¶Department of Anesthesiology, Behandlungszentrum Vogtareuth, Vogtareuth, Germany.

Address correspondence and reprint requests to Wulf Dietrich, MD, PhD, Institute for Research in Cardiac Anesthesia, 80639 Munich, Winthirstr. 4, 80639 Munich, Germany. Address e-mail to wulf.dietrich{at}t-online.de.

Abstract

BACKGROUND: Antifibrinolytics are widely used in cardiac surgery to reduce bleeding. Allogeneic blood transfusion, even in primary cardiac operations with low blood loss, is still high. In the present study we evaluated the impact of tranexamic acid compared to aprotinin on the transfusion incidence in cardiac surgical patients with low risk of bleeding.

METHODS: This prospective, randomized, double-blind study included 220 patients undergoing primary coronary artery revascularization (coronary artery bypass grafting [CABG]) or aortic valve replacement (AVR). Randomized in blocks of 20, patients received either tranexamic acid (approximately 6 g) or full-dose aprotinin (approximately 5–6 x 106 Kallikrein Inhibiting Units). Transfusion was guided by a strict transfusion algorithm. Molecular markers of hemostasis were determined to assess differences in the mode of action of the two drugs. Primary end-points were the incidence of allogeneic red cell transfusion and 24-h postoperative blood loss. Data were analyzed according to the intention-to-treat principle and compared using the {chi}2 and Mann-Whitney U-test.

RESULTS: Two-hundred-twenty patients were enrolled (CABG: 134, AVR: 86). In the aprotinin Group 47% of patients received allogeneic blood during the hospital stay as compared to 61% in the tranexamic acid group (P = 0.036). Aprotinin conferred a 23% reduction in allogeneic transfusion risk (RR 0.77, 95% CI 0.53–0.88). Overall, no significant difference in postoperative bleeding was observed, although 24-h blood loss was reduced in aprotinin-treated CABG patients (500, 350–750 mL vs 650, 475–875 mL (median, 25th–75th percentile); P = 0.039). Despite the lower transfusion rate, the hemoglobin concentration on the first postoperative day was higher in the aprotinin group (11.3, 9.9–12.1 vs 10.6, 9.9–11.6 mg/dL; P = 0.023). The fibrinolytic activity at the end of operation determined by D-Dimer was comparable in both groups. (0.15, 0.11–0.17 mg/L [aprotinin] versus 0.18, 0.12–0.24 mg/L [tranexamic acid]). The activated partial thromboplastin time was prolonged up to 4 h postoperatively in the aprotinin group, while the heparin requirement was reduced: 19% of the patients in the aprotinin group and 45% in the tranexamic acid group received at least one additional bolus heparin during cardiopulmonary bypass (P < 0.001). Troponin T levels postoperatively and on postoperative day 1 were significantly higher in the tranexamic acid group (P = 0.017). No differences in renal, cardiac, or mortality outcomes were observed.

CONCLUSION: Considering the rate of transfusion of red blood cells, tranexamic acid was slightly inferior in patients undergoing CABG, but there was no difference in patients receiving AVR. Tranexamic acid seems to be less effective in operations with increased bleeding such as CABG. Clinical benefit depends on specific patient and institution characteristics (ClinicalTrials.gov NCT00396760).

Perioperative bleeding remains a problem in cardiac surgery.1 The risk of transfusion of allogeneic blood products on short-2 and long-term3 outcome is well documented. Even in first time cardiac surgery, the transfusion requirement is alarmingly high.4,5 Thus, a multimodal approach to reduce allogeneic blood transfusion is warranted.1 The nonspecific proteinase inhibitor aprotinin and the specific plasmin inhibitor tranexamic acid both reduce intra- and postoperative bleeding tendency in cardiac surgical patients and, thus, allogeneic blood requirement.6

Tranexamic acid, a small molecule (molecular weight 157 dalton), which interacts with the lysine binding site of plasminogen and of its conversion product plasmin, specifically inhibits access of plasmin to fibrin and has no other direct impact on hemostasis. In contrast, the nonspecific serine-protease inhibitor aprotinin directly inhibits plasmin in lower concentrations, whereas higher concentrations attenuate the intrinsic contact phase activation of hemostasis resulting in a mild anticoagulatory effect.7

The blood-saving effect of aprotinin is confirmed in many clinical trials. A recent review cited more than 70 trials investigating and confirming the efficacy of aprotinin.1 In contrast, studies on tranexamic acid are much less numerous than studies of aprotinin; only 35 were included in the above-mentioned review and only limited information about dosage and safety aspects is available.8 Few head-to-head comparisons of the two drugs are reported.9–14 Fourteen comparisons between the two drugs in cardiac surgery are reported in a systematic review, however, the study size was often small (between 32 and 1040 patients), the study quality low (only 3 studies (157 patients) with concealed treatment allocation - Cochrane quality A), and the dosages of tranexamic acid varied widely.6 In none of these studies was renal or cardiac safety an end-point.

Though aprotinin seems to be more effective in reducing blood requirements6,15 and re-exploration for bleeding,1 it is much more expensive than tranexamic acid. Additionally, recent concerns about the safety of aprotinin, especially renal outcomes, have arisen.16–18 Results and interpretation of these data are inconsistent19,20 and discussion of this issue continues.21,22 In October 2007 patient enrollment in a large study comparing different antifibrinoloytics was stopped (http://www.fda.gov/cder/drug/earlycomm/aprotinin.htm), because a trend to higher mortality in the aprotinin group was noted and Food and Drug Administration and, later, the European authority, requested marketing suspension. These concerns involved provisional withdrawal of aprotinin being marketed.

The present controlled, prospective, double-blind study investigated the blood-saving effect of both drugs in a well-defined patient population. Only patients with a relatively low risk of excessive blood loss, undergoing first-time coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) were included. Our hypothesis was that tranexamic acid is as effective as aprotinin in this patient population in reducing the incidence of allogeneic blood requirement. Additionally, molecular markers of coagulation were determined to assess differences in the mode of action of the two drugs.

METHODS

This nonindustrial sponsored study was supported by the Department of Anesthesiology of the German Heart Center, Munich. After approval by the local Ethics Committee of the medical faculty of the Technical University Munich, written informed consent was obtained from all participating patients. Patients >18 yr were included if the scheduled operation was either primary CABG due to coronary artery disease or AVR due to aortic stenosis, aortic insufficiency or combined valve lesion. Exclusion criteria were previous cardiac operation, known previous exposure to aprotinin, emergency operation, coumarin treatment ≤5 days of operation (aspirin or thienopyridine therapy was not an exclusion criteria), or refusal of allogeneic blood transfusion.

Patients were randomized by a computer-generated list in blocks of 20 patients to receive aprotinin or tranexamic acid and stratified 3:2 for CABG and AVR. Study and placebo medication was managed by the hospital pharmacy. For each patient, a paper bag labeled with the randomization number was prepared containing 6 identical 100 mL white bottles with saline or aprotinin (1 x 106 kallikrein inhibiting units [KIU]/bottle) and one brown 80 mL bottle containing saline or 8 g tranexamic acid. Patients were treated with both preparations during the operation: 1 mL test dose then 200 mL (2 x 106 KIU aprotinin or saline) IV over 10 min (white bottles), followed by continuous IV infusion of 50 mL (5 x 105 KIU aprotinin or saline)/h for the duration of surgery; an additional 200 mL (2 x 106 KIU aprotinin or saline) was added to the cardiopulmonary bypass (CPB) circuit priming fluid. The first drug bolus and placebo were given after sternotomy when the surgeon was ready to cannulate the aorta quickly in case of a hypersensitivity reaction.23 Simultaneously, patients received a bolus of 20 mL (2 g tranexamic acid or saline) medication (brown bottle) followed by continuous infusion of 10 mL/h (1 g tranexamic acid/h or saline); an additional bolus of 20 mL (2 g tranexamic acid or saline) was added to the CPB circuit priming fluid.

Anesthesia was performed with sufentanil and midazolam supplemented with inhaled sevoflurane; neuromuscular blockade was achieved by either pancuronium bromide or rocuronium. CPB was performed in standard technique using a membrane oxygenator, an open cardiotomy reservoir, and uncoated tubing systems. Venous cannulation was done with a double-stage cannula. The oxygenator was primed with 1500 mL crystalloid solution, the flow rate set to 2.4 L/m2, and the patients were moderately cooled to 32°C. Either cold crystalloid or blood cardioplegia was used. Intraoperative blood salvage by cardiotomy suction and retransfusion of shed blood during CPB was used in all patients.

Porcine unfractionated heparin was administered IV 375 U/kg before CPB and 10,000 U in the priming solution. Anticoagulation was measured simultaneously with celite and kaolin activated clotting time (ACT) every 30 min (target ACT, 480 s; Hemochron 800, Intern Technidyne Corp, Edison, NY). If the celite ACT was <480 s an additional bolus of 125 U/kg heparin was added. After cessation of CPB, heparin was antagonized by protamine chloride 1:1 per the initial heparin dose.

Allogeneic red blood cells (RBC) were transfused, if the hematocrit was <18% during CPB, <21%–24% postoperatively, or if physiologic signs (tachycardia >100/min with adequate volume load and pain care and/or tachypnoe with >25 breaths per minute and/or a decrease of central venous oxygen saturation below 65%) of the patient indicated a need to improve oxygen supply. Indication for fresh frozen plasma was a 100% prolonged activated partial thromboplastin time (aPTT) and for platelet transfusion a platelet count <80,000 mm2, both in the presence of increased bleeding.

Blood samples were drawn before induction of anesthesia, at the end of operation, after chest closure, 4 h postoperatively, and the morning of the first, third, and fifth postoperative day. Citrated blood was centrifuged (3000G, 10 min) and the plasma immediately frozen (–80°C) in aliquots. D-Dimer levels were assessed on a Dade Behring Blood Coagulation System analyzer using the D-Dimer PLUS reagent (Dade Behring, Germany), a latex-enhanced turbidimetric test for quantitative determination of cross-linked D-Dimer (reference, 0.06–0.25 mg/L). Thrombin activation, determined by formation of prothrombin fragment 1 + 2 (F1+2), was measured using a microtiter plate-based sandwich immunoassay (reference, 69–229 pmol/L; Enzygnost monoclonal, DadeBehring, Germany). Cardiac Troponin T was measured by enzyme immunoassay based on electrochemiluminescence using the Elecsys 2010 analyzer (lower detection limit, 0.01 ng/mL; recommended diagnostic threshold, 0.03 ng/mL for acute coronary syndromes; Roche Diagnostics, Switzerland). All measurements were performed immediately after thawing the plasma.

The impact of aprotinin and tranexamic acid on fibrinolysis and coagulation in whole blood was studied with rotational thromboelastometry24 at the end of operation using a computerized, multi-channel rotational thromboelastometry instrument (Pentapharm, Munich, Germany). The aPTT was determined with Pathromtin SL reagent (Dade Behring, Germany) on the blood coagulation system analyzer (reference,25–37 s). This reagent contains silicon dioxide particles as the surface activator and plant phospholipids (but not celite).

Postoperatively, patients' lungs were ventilated in the intensive care unit until warming to 37°C, oxygenation and hemodynamics were sufficient, and blood loss was <100 mL/h. Indication for repeat surgical hemostasis was driven by clinical judgment and blood loss >200 mL/h in two consecutive hours. To evaluate 1 yr outcome, patients or their families were contacted by phone 1 yr after the operation and interviewed for their physical status.

Mortality was defined as all deaths occurring during the hospitalization and within 30 days of the procedure. Renal insufficiency was stated as first-time dependency on renal dialysis postoperatively, or an increase of postoperative creatinine > = 2 mg/dL, or a difference > = 0.7 mg/dL between the pre- and maximal postoperative plasma creatinine concentration. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease study formula per National Kidney Foundation guidelines.25 Preoperative risk was assessed by the Cleveland Clinic Risk Score26 and the Euro Score.27

Statistical Analysis
Sample size was calculated based on an estimated 24-h postoperative drainage loss of 600 mL ± 350 mL (mean ± sd) in both groups. A difference of 250 mL among groups and subgroups was perceived as clinically relevant. A sample size of 40 patients per group would provide 80% power to detect this difference at an {alpha} level of 0.025 with two-sided test of significance. Since stratification of patients with CABG and AVR was defined prospectively, it was decided that 200 patients would be sufficient, considering an accrual ratio of 3:2 for CABG and AVR patients. Assuming a drop-out rate of 10%, the total sample size estimate was 220 patients. Subgroups were only analyzed for primary end-points, considering an adjusted {alpha} error level of 2.5%. The study was not powered to detect small differences in renal outcome, mortality, nonfatal myocardial infarction or stroke.

The primary study end-points were incidence of patients with allogeneic RBC transfusion and 24-h postoperative drainage blood loss. Secondary end-points were biomarkers of plasmin-induced fibrin degradation and prothrombin cleavage as measured by D-Dimer and F1+2 concentration at the end of operation, and heparin requirement during CPB.

Continuous data were presented as mean ± sd or as median with 25th–75th percentiles. Categorical variables were reported as percentages. All analyses were based on the intention-to-treat population, although a per-protocol analysis (PP) was also performed. For continuous variables, differences between treatment groups were assessed by two sample Student's t-test or Mann-Whitney U-test for nonnormal distributed variables. {chi}2 test or Fisher's exact test, if appropriate, were used to compare categorical variables. Statistical significance was attributed to P values <0.025 for primary end-point measurements and <0.05 for secondary end-point variables. Bonferroni adjustment of {alpha} error level was used for multiple comparisons.

The authors had full access to the data and take responsibility for its integrity. T.S. was responsible for the accuracy of data analysis.

RESULTS

Two-hundred-twenty patients, 110 per group, operated on between December 2004 and June 2005 were enrolled. Demographic and procedural data as well as distribution of patients were comparable (Tables 1 and 2, Fig. 1). All patients underwent first-time cardiac surgery. Protocol deviations occurred in 15 patients, with 12 requiring operative procedures beyond CABG or AVR, one using robotic assistance, one suspected allergic reaction resulting in discontinuation of drug infusion, and one open aprotinin use for a second CPB.


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  		Table 1. Demographic and Procedural Data (Mean ± sd or n [%])

 

Figure 15
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  		Figure 1. Consolidated Standards of Reporting Trials (CONSORT) Diagram of Patient Enrollment. The diagram shows the number of patients screened and finally included in the analysis. All analyses were based on the intention-to-treat population (ITT), however, a per-protocol analysis (PP) of those patients, in whom only the index operations were performed, was also done. Patients with deviations from the study protocol are depicted in the figure.

 


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  		Table 2. Blood loss and Transfusion Data (Median [25th–75th Percentile])

 

Patients in the aprotinin and tranexamic acid groups received a median (25th–75th percentile) of 5.2 (5.0–5.5) x 106 KIU aprotinin or 6.5 (6.0–7.0) g tranexamic acid, respectively. The 24-h postoperative blood loss (median, 25th–75th percentile) was comparable, but reduced in the aprotinin CABG subgroup (500, 350–750 mL vs 650, 475–875 mL; P = 0.039) (Table 2). The incidence of allogeneic blood transfusion was lower in the aprotinin group (47% vs 61%; P = 0.036) (Table 2, Fig. 2). With exclusion of patients having protocol deviations, PP analysis still showed reduced incidence of allogeneic RBC transfusion in aprotinin-treated patients (42% vs 56%; P = 0.026). Patients in the aprotinin group received a mean of 1.3 ± 1.8 U allogeneic RBC during their hospital stay compared to 1.7 ± 1.8 U in the tranexamic acid group (P = 0.077). Four patients in the tranexamic acid group received platelet transfusions during their hospital stay compared with none in the aprotinin group (P = 0.044). Ten patients in each group were transfused with fresh frozen plasma during their hospital stay. The time interval between end of CPB and chest closure was shorter in aprotinin-treated patients relative to those treated with tranexamic acid (55, 45–61 vs 60, 50–70 min; P = 0.023).


Figure 25
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  		Figure 2. Incidence of allogeneic red blood cell transfusion and 24 h drainage loss.

 

Total heparin consumption was significantly lower in the aprotinin group (31,125 ± 7,125 vs 34,625 ± 9875 U; P = 0.002). In the aprotinin group, 19% of patients received an additional bolus of heparin compared to 45% of patients receiving tranexamic acid (P < 0.001) (Fig. 3). Parameters of prothrombin cleavage (F1+2) and subsequent plasmin-dependent fibrin degradation (D-Dimer) were comparable at the end of operation and 4 h postoperatively (Table 3). The relative increase in percent to the basic value was also not statistically different. ROTEM® results did not differ between the groups (data not shown). Troponin T was increased 4 h postoperatively in patients treated with tranexamic acid relative to those treated with aprotinin (0.80 ± 2.46 ng/mL vs 0.23 ± 0.31 ng/mL; P = 0.020). The percentage of patients requiring inotropic support of >3 ìg/kg dopamine was 39% in the aprotinin group compared to 61% in the tranexamic acid group (P = 0.016) (Table 4).


Figure 35
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  		Figure 3. Course of activated clotting time (ACT) and percentage of repeated heparin boluses. The left panel shows the ACT, (A) celite activated; (B) kaolin activated. The right panel (C) gives the percentage of patients with a repeat bolus of heparin to maintain celite ACT >480 s.

 

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  		Table 3. Molecular Marker of Plasmatic Coagulation (Median [25th–75th Percentile])

 

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  		Table 4. Procedural Data (Mean ± sd or Percent)

 

Rethoracotomy for bleeding was performed in five patients (tranexamic acid, 3; aprotinin, 2). Three patients (1.4%) died in hospital or within 30 days after operation (aprotinin, 2; tranexamic acid, 1). Of these three patients two, both in the aprotinin group, did not undergo an index operation but had additional interventions. One had a patent foramen ovale, which was closed after changing the two-stage venous cannula to bicaval cannulation; this patient died of ischemic stroke day 5 postoperatively. The other had a preoperatively unrecognized tricuspid insufficiency repaired 1 wk after the primary AVR and died postoperative day 42 of multiorgan failure. The tranexamic acid-treated patient (CABG) died of sudden cardiac death on postoperative day 14 after discharge. Within 1 yr of surgery, six additional patients (three per group) died. No patient developed renal failure or renal insufficiency requiring dialysis after the primary operation.

DISCUSSION

Excessive bleeding and increased transfusion requirement may lead to adverse outcome in cardiac surgery.1 A high transfusion rate was demonstrated even in low-risk cardiac patients.5 Aprotinin and tranexamic acid have been used successfully to reduce bleeding and allogeneic blood transfusion after cardiac surgery.6 We selected a patient population supposed to be at relatively low risk of getting allogeneic transfusions since even this group of patients may benefit from reduction in bleeding tendency due to treatment with antifibrinolytics. Additionally, this is a homogeneous, well comparable patient group. In the present study, aprotinin was slightly more effective than tranexamic acid in reducing the incidence of allogeneic blood transfusion (47% vs 61%; P = 0.036). This difference resulted from effects in the CABG subpopulation, as no differences were observed in the AVR subgroup.

The literature is sparse on direct comparisons of aprotinin and tranexamic acid. Only nine1 or 176 head-to-head comparisons were identified in recent reviews with conflicting results. Our results are in accordance with a study comparing cardiac surgical patients treated with aprotinin or tranexamic acid and showing no significant difference in chest tube drainage (460 vs 510 mL) but a reduction of allogeneic blood transfusion (15% vs 35%).10 In contrast, retrospective analysis comparing aprotinin and tranexamic acid in very high risk patients did not identify differences in the incidence of allogeneic blood transfusion.17 Conversely, a systematic review found a 23% reduction in transfusion requirement in aprotinin-treated patients, but this difference was not significant.6 For tranexamic acid, there are no conclusive long-term outcome data. The statement that tranexamic acid is a "safe alternative" to aprotinin18 is not supported by published data. Based upon systematic reviews, these drugs differ in that only aprotinin has been shown to reduce the risk for re-exploration to control hemorrhage.6,15 Recent guidelines for blood conservation in cardiac surgery1 gave a class I recommendation with an evidence level A for aprotinin and tranexamic acid. Sound recommendations for one drug or the other on the basis of the available direct comparisons, however, are not yet justified.

AVR is far less traumatic than CABG surgery. All CABG patients in the present study had at least one thoracic artery harvested and additional veins collected from the legs. The large wound surface area is thought to be responsible for higher blood loss in CABG surgery relative to AVR. Therefore, the effect of aprotinin was more apparent in CABG patients than in AVR patients. Our study showed no influence of preoperative thienopyridine use, possibly because of the small number of patients with this pretreatment. Interestingly, despite no overall differences in chest tube drainage 24 h postoperatively with only small effects in the CABG subpopulation, differences in transfusion requirement were observed. Hemoglobin postoperative day one was significantly higher in the aprotinin-treated patients, despite having a lower transfusion rate. This phenomenon was possibly due to differences in hemoglobin content of drainage blood, i.e., aprotinin patients lose less hemoglobin compared to other patients.

For dosing, the "full-dose" aprotinin regimen was used.28 Tranexamic acid dosing is not as well defined, with dosages between 1 g and >10 g or 10–100 mg/kg described.29,30 Our dosing of tranexamic acid (approximately 6 g per patient; 80 mg/kg) was adapted from a large study comparing aprotinin and tranexamic acid10 and is comparable to that in the continuing Canadian BART trial (http://www.controlled-trials.com/ISRCTN15166455). This dosage is much higher compared to other described dosing regimens.31 Dose-escalating studies to find the most effective dosage for tranexamic acid are warranted.

Both drugs suppressed fibrinolytic activation. The D-Dimer concentration at the end of operation was comparable in both groups and within normal ranges. Prothrombin fragment F1+2 as a parameter of thrombin generation was increased in both groups without intergroup differences. This finding contrasts with previous results, which showed a reduction in thrombin generation32 and were interpreted as anticoagulatory activity of the nonspecific serine protease inhibitor aprotinin.7 Overall, we did not see any severe disturbance of plasmatic coagulation at the end of operation.

The present study has two additional noteworthy implications. First, the number of patients receiving a second bolus of heparin for intraoperative anticoagulation was significantly reduced in aprotinin-treated patients, whereas all hemostatic variables were comparable, indicating less heparin requirement with the same quality of anticoagulation. The use of celite ACT to guide heparinization is important. However, we earlier demonstrated the different influence of aprotinin on celite and kaolin-activated ACT33 and the present study confirms these results, since, despite the use of celite ACT and reduced heparin requirement, the procoagulatory markers of hemostasis were not different between the groups. The prolongation of aPTT in the aprotinin group points in the same direction. Recently, the older discussion about the heparin-sparing effect of aprotinin34 was revitalized.35 In a rat model, aprotinin and tranexamic acid inhibited fibrinolysis but only aprotinin decreased clot formation and thrombus weight, while this was even increased with tranexamic acid.36 These results and ours indicate that in addition to an antifibrinolytic effect, aprotinin also has anticoagulant properties.7

Second, patients treated with aprotinin were less likely to receive inotropic support intraoperatively. Additionally, troponin T plasma concentrations, 4 h postoperatively and on the first postoperative morning, were significantly lower in patients treated with aprotinin, possibly indicating reduced myocardial reperfusion injury. Older studies demonstrated this effect for aprotinin37 and a recent investigation showed that aprotinin limits reperfusion injury,38 an effect attributable to suppression of proinflammatory genes. Nevertheless, our study was not designed and powered to detect potential benefits from these antiinflammatory and anticoagulatory properties of aprotinin.

A concern with aprotinin treatment is the possibility of renal impairment. A recent meta-analysis16 found, in contrast to published results,18,39 that aprotinin did not significantly increase the risk of myocardial infarction, stroke, mortality, or renal failure requiring hemodialysis. However, aprotinin use was associated with an increase in renal dysfunction defined as a creatinine increase >0.5 mg postoperatively (12.9% vs 8.4%).40 This controversial discussion continues.19–21 The problem identifying potential side effects of aprotinin is based on the retrospective nature of all large studies and the fact that the aprotinin population may be at higher risk compared to the control patients.41,42 The present study, which included patients with normal preoperative renal function, could not substantiate concerns about renal function. The highest postoperative plasma creatinine concentration was within normal range in all patients, with the exception of one patient. This patient had a preoperative undiagnosed tricuspid insufficiency, necessitating a second operation without aprotinin 1 wk after the primary operation. The patient had multiorgan failure and died subsequently day 42 postoperatively. Overall, short-term outcome was not affected by treatment in the present study. In-hospital mortality was comparable, although two of three patient deaths in the aprotinin group were not PP patients since additional unscheduled operations were performed. One-year mortality was not different between the groups.

Recently, the marketing of aprotinin was suspended because a trend towards increased mortality was noted in a large Canadian study investigating different antifibrinolytics in cardiac surgery (www.fda.gov/cder/drug/early_comm/aprotinin.htm). Since the future of aprotinin is not clear, further studies on alternative antifibrinolytics, such as tranexamic acid, are strongly needed.

Our study is subject to several limitations. First, a control group without pharmacological intervention was not included. Even though efficacy of both drugs is solidly proven and no more studies are necessary to confirm these results,43 head-to-head comparisons are needed to find the proper application and dosage of each drug. Second, the number of patients in the subgroup with AVR is marginal. Chest tube drainage was lower than estimated in our power analysis, but results for AVR did unequivocally not differ and a type II error can probably be excluded. Third, hemoglobin content in drainage blood was not measured. Thus, our explanation for the differences in transfusion outcome remains speculative. Fourth, in this low-risk population some may assert that drug intervention to reduce bleeding tendency is not indicated. However, despite a strict transfusion protocol and relatively small amounts of postoperative blood loss, the total transfusion incidence in this study was high. This likely is not an exception from general practice1,4,5 and efforts to reduce transfusion rates in all cardiac procedures are required.44 The recent absolute statement,45 that there is definitely no role for either aprotinin or other hemostatic drugs in noncomplex coronary-artery bypass surgery, should be questioned in light of these results.

In conclusion, the present study demonstrated superiority of aprotinin in comparison to tranexamic acid in terms of incidence of allogeneic transfusion requirement. However, no relevant differences in short-term and 1 yr outcome were observed between the groups. The clinical relevance of our finding may be marginal. In less traumatic operations, tranexamic acid is an adequate substitute for aprotinin, yet, for more complex procedures, nonspecific protease inhibition may be favorable. Because of the risks of bleeding and subsequent transfusion requirements, pharmacological intervention to reduce bleeding is warranted even in patients with an expected low risk of bleeding. However, further studies are warranted to evaluate the safety and efficacy of the lysine analogs for the prevention of bleeding in cardiac surgical patients.

ACKNOWLEDGMENTS

We thank Mrs. Seggebrock for assistance in data collection and review of patients' records and Mrs. Kramer for technical assistance in collecting and analyzing blood samples. Drug preparation and randomization was performed by courtesy of the pharmacist Mrs. Graf.

Footnotes

Accepted for publication April 2, 2008.

Supported by Medical Faculty of the Technical University and the German Heart Center Munich.

Clinical Trial Registration: ClinicalTrials.gov NCT00396760 (http://www.clinicaltrials.gov).

The authors W. D. and R. B. formerly held positions at the German Heart Center Munich.

W. D. received speaker honoraria from Bayer Corp. and was a paid consultant at the FDA advisory committee meetings in September 2006 and September 2007 in Washington DC. R. B. was a member of an advisory board for aprotinin.

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