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Ann Thorac Surg 2008;85:1662-1668. doi:10.1016/j.athoracsur.2008.01.087
© 2008 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

The Impact of Aprotinin on Blood Loss and Blood Transfusion in Off-Pump Coronary Artery Bypass Grafting

Hartmuth B. Bittner, MD, PhD*, Janine Lemke, MS, Michelle Lange, MS, Ardawan Rastan, MD, Friedrich W. Mohr, MD, PhD

Heart Center of the University of Leipzig, Cardiovascular and Thoracic Surgery, Leipzig, Germany

Accepted for publication January 11, 2008.

* Address correspondence to Dr Bittner, Heart Center Leipzig, Struempellstr 39, Leipzig, 04289, Germany (Email: heartbeatgermany{at}aol.com).

Presented at the Poster Session of the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 27–29, 2008.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Administration of the serine protease inhibitor aprotinin has been proven efficacious in cardiopulmonary bypass–supported cardiac surgery to reduce bleeding and transfusion requirements. Its role in off-pump surgery is not so well defined. The present study assessed the effect of aprotinin in off-pump coronary artery bypass grafting on perioperative blood loss and transfusion rates.

Methods: A total of 761 consecutive adult patients who underwent off-pump coronary artery bypass grafting were retrospectively reviewed. The majority (87%) received aspirin preoperatively. Heparin was intravenously administered for a kaolin-based activated clotting time of greater than 300 seconds. Aprotinin was administered as a 1 million or 2 million kallikrein inhibiting unit bolus to 391 patients after median sternotomy. The control group (n = 370) underwent surgery during the same period without receiving aprotinin. Blood loss was measured intraoperatively (cell-saving device) and postoperatively by quantifying mediastinal chest tube drainage.

Results: Aprotinin was associated with a significant reduction in postoperative blood loss (p < 0.001) and less excessive postoperative hemorrhage (p < 0.001) compared with the control group. Transfusion rates and amount of blood products administered were also reduced by aprotinin (p < 0.01 for both). Significantly more patients in the aprotinin group were free of any blood product transfusion (54.7%) compared with the control group (41.4%; p < 0.01). The safety profile was comparable between aprotinin and control patients.

Conclusions: Aprotinin proved efficacious and safe in the reduction of postoperative bleeding and transfusion requirements in patients undergoing off-pump coronary artery bypass grafting.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
The antifibrinolytic serine protease inhibitor aprotinin has demonstrated consistent efficacy in reducing perioperative blood loss and transfusion requirements in cardiac surgery with cardiopulmonary bypass [1–6]. Hemostasis was also improved in patients with antiplatelet therapy (aspirin or clopidogrel) continued to within less than 5 days before on-pump coronary artery bypass grafting (CABG) [7–9]. The role of aprotinin in off-pump coronary artery bypass grafting (OPCABG) is not so well defined. This type of surgery has resulted in reduced perioperative bleeding and blood transfusion requirements when compared with on-pump procedures [10–12], but allogeneic transfusions are still frequently needed [13, 14]. Three small studies demonstrated beneficial hemostatic effects after aprotinin treatment in patients undergoing OPCABG with a significant reduction in postoperative blood loss compared with placebo [15–17]. Transfusion requirements were also lower in aprotinin-treated patients, but no statistical significance was reached. Similar results were seen in a small nonrandomized, retrospective comparative study [18].

The aim of this retrospective study was to further evaluate the benefit of aprotinin in OPCABG on perioperative blood loss and transfusion requirements in a markedly larger patient population. Given the recent safety concerns about the use of aprotinin [19], we also assessed the occurrence of postoperative complications.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
This retrospective study reviewed prospectively collected data from the cardiac surgery registry of 761 consecutive adult patients undergoing OPCABG surgery at our heart center. Data of patients receiving intraoperative aprotinin (Trasylol; Bayer Vital, Leverkusen, Germany) were compared with data of patients without aprotinin administration (control group). All 391 aprotinin and 370 control patients had surgery between January 2004 and December 2005. No other antifibrinolytic agents were administered. The study was approved by the heart center's ethics committee; the need for patient consent was waived.

Patient characteristics, administration of anticoagulant and antiplatelet medication, and hematologic variables were all recorded preoperatively. All patients received benzodiazepines as premedication. Surgical and anesthetic techniques were constant for all patients. Anesthesia was induced with midazolam and sufentanil, and maintained with propofol infusion. Muscle relaxation was performed using pancuronium bromide. Standard monitoring methods included electrocardiography, radial or femoral artery catheter, central venous catheter, peripheral venous catheter, urinary catheter, and rectal temperature probe. Off-pump procedures were performed by 4 surgeons with similar experience in this type of surgery using suction-type stabilizer techniques in combination with a carbon dioxide blower and normal saline mister. All patients underwent median sternotomy. Anticoagulation was performed with intravenous sodium heparin (mean, 15,749 IU for aprotinin versus 15,291 IU for control patients; p = 0.256) and monitored measuring the activated clotting time using kaolin cartridges (Medtronic Europe, Tolochenaz, Switzerland). The target activated clotting time was greater than 300 seconds. After completion of the anastomoses, heparinization was reversed with protamine sulfate (mean, 13,933 IU for aprotinin versus 13,324 IU for control patients; p = 0.208) targeting the preoperatively measured activated clotting time. Duration of surgery and number of bypasses were similar between the groups (Table 1). The decision to administer aprotinin was at the discretion of the surgeon and anesthetist performing the procedure. Owing to a small risk of anaphylactic reactions [20], aprotinin was only administered following heparinization after sternotomy and exposure of the base of the heart, allowing for immediate cardiopulmonary bypass connection if necessary. This precaution is always taken at our heart center, even if patients had no previous exposure to the drug as was the case in this study. The standard aprotinin protocol for on-pump procedures was modified for off-pump requirements and comprised an aprotinin test dose of 10,000 kallikrein inhibiting units and a 1 million or 2 million kallikrein inhibiting unit bolus dose. Blood loss was measured by quantifying blood using a cell-saving device intraoperatively and by mediastinal chest tube drainage postoperatively after transfer to the intensive care unit (ICU). Excessive hemorrhage was defined as a blood loss of more than 300 mL/h or more than 1,000 mL/12 h, both within the first 24 hours after arrival in the ICU. In addition, blood samples were taken immediately after arrival in the ICU and on the first and second postoperative day to assess hematologic variables. Packed red blood cells, fresh-frozen plasma, and platelet infusions were used perioperatively at the discretion of the anesthetist and surgeon to treat increased blood loss. Indicators for transfusion requirement were a hematocrit level of less than 25%, patients older than 75 years of age, hemodynamic instability, and the occurrence of tachycardia. The use of blood products was documented during surgery, in the 24 hours after arrival in the ICU, and from 24 hours until discharge. Serum creatinine was measured preoperatively, and 24, 48, and 72 hours postoperatively. All complications were documented throughout hospitalization.


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  		Table 1 Baseline Characteristics and Intraoperative Data a
 
Statistical analyses were performed using SPSS 12.0 software (SPSS Inc, Chicago, IL). Comparison of treatment groups was carried out using Student's t test, Mann-Whitney U test, or {chi}2 analysis. Kruskal-Wallis tests and {chi}2 analysis were used to assess differences among surgeons. Differences were considered significant for probability values less than 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Aprotinin was administered to 391 patients during surgery. Their preoperative data compared well with the data recorded for the control group (n = 370; Table 1), including similar New York Heart Association (NYHA) scores. According to the EuroSCORE, most patients belonged to the medium-risk group, although there was a tendency for higher risk in the aprotinin group both for the additive and the more accurate logistic score. The majority of the patients (87.0%; aprotinin 86.6% versus control 87.4%) received aspirin preoperatively, and some were administered clopidogrel (18.5%; aprotinin 19.0% versus control 17.9%). Neither aspirin nor clopidogrel were discontinued before surgery. For both groups, median ICU time and median hospital time was 21 hours and 10 days, respectively.

Figure 1 shows the impact of aprotinin on mediastinal bleeding. Whereas blood loss was similar between the groups during surgery (mean, 244.7 ± 326.9 mL; median, 200 mL; interquartile range, 0 to 400 mL for aprotinin versus mean, 240 ± 393.3 mL; median, 100 mL; interquartile range, 0 to 300 mL for control patients; p = 0.14), there was a significant reduction in the aprotinin group at 24 hours (mean, 730.5 ± 406.3 mL versus mean, 967.3 ± 495.9 mL; p < 0.001) and 48 hours (mean, 893.5 ± 525.1 mL versus mean, 1147 ± 635.3 mL; p < 0.001) after arrival in the ICU. This amounts to a reduction in postoperative bleeding of 24.5% after 24 hours and 22.2% after 48 hours owing to aprotinin. Excessive postoperative bleeding occurred in both groups but was significantly higher in the control population (p < 0.001; Fig 2). Without aprotinin administration, the incidence of excessive hemorrhage was 2.25 times higher, but reexploration rates were not significantly different. Of the 16 patients requiring reexploration for excessive postoperative thoracic bleeding, 7 had received aprotinin (1.8% of 391 patients) and 9 were control patients (2.4% of 370 patients; p = 0.54). The number of patients experiencing gastrointestinal bleeding (4 aprotinin versus 5 control) and cerebral bleeding (1 aprotinin versus 2 control) was similar between the groups. Postoperative erythrocyte count, hematocrit, and hemoglobin levels were all improved by aprotinin with significant differences from the control group (Table 2).


Figure 1
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  		Fig 1. Impact of aprotinin ({blacklozenge}) on intraoperative and postoperative (24 hours and 48 hours) blood loss compared with control patients ({ballotbox}).

 

Figure 2
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  		Fig 2. Incidence of excessive postoperative bleeding (mediastinal chest tube drainage).

 

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  		Table 2 Postoperative Hematologic Variables a
 
There were minor differences among the 4 surgeons with regard to preference for aprotinin administration. One surgeon used aprotinin in only 24.9% of the cases compared with 60.4%, 61.7%, and 72.4% for the other 3 surgeons. Excessive hemorrhage rates were significantly higher for this surgeon. There were no significant differences among the surgeons in the rethoracotomy rate (p = 0.79).

Transfusion requirements did not differ between the groups during surgery but were significantly reduced in the first 24 hours after surgery for aprotinin patients. There were significant differences between the groups in the number of patients requiring blood products (p < 0.01; Fig 3). Overall, 54.7% of aprotinin patients did not need any allogeneic blood transfusion perioperatively compared with 41.4% of control patients (p < 0.01). Tables 3 and 4 Go summarize blood product requirements (packed red blood cells, fresh-frozen plasma, or platelets) during and after surgery. The main blood product used was packed red blood cells. The number of patients receiving packed red blood cells and platelets perioperatively was similar between the groups; there was, however, a nearly significant difference for patients receiving fresh-frozen plasma (p = 0.09; Table 4). The amount of packed red blood cells and fresh-frozen plasma blood units required perioperatively was, however, significantly reduced in aprotinin patients owing to significant reductions in the first 24 hours after surgery (Table 3). Use of platelets was rare and did not differ between the groups.


Figure 3
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  		Fig 3. Effect of aprotinin (black bars) on administration of blood products during and after off-pump coronary artery bypass grafting compared with control patients (white bars).

 

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  		Table 3 Blood Product Requirements During and After Surgery a
 

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  		Table 4 Blood Product Requirements of All Transfused Patients a
 
Postoperative renal complications were comparable between the groups (Table 5). Eighteen patients in the aprotinin group and 15 patients in the control group required dialysis after surgery. There were only slight increases in mean serum creatinine concentrations after surgery compared with preoperative levels, with similar concentrations being observed in both groups (Fig 4). Stroke, myocardial infarction, low output syndrome, symptomatic transitory psychotic syndrome, and mortality all occurred with similar frequency in aprotinin and control patients (Table 5).


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  		Table 5 Postoperative Complications a
 

Figure 4
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  		Fig 4. Mean serum creatinine concentrations in patients receiving aprotinin during off-pump coronary artery bypass grafting (gray bars) versus control patients (white bars).

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
The clinical benefit of aprotinin in on-pump cardiac surgery (reduction in perioperative blood loss, transfusion requirements, and the risk of reoperation owing to excessive bleeding) is well documented [4–6, 21, 22]. So far, only four studies with a small sample size have been undertaken to investigate the impact of aprotinin in OPCABG [15–18]. These studies reported significantly reduced postoperative blood loss when aprotinin was used, but found no significant effects on transfusion rates. Rethoracotomy rates were low in both aprotinin and control groups.

This retrospective comparative study investigated the impact of aprotinin in OPCABG in a larger patient population (n = 761). In contrast to the aforementioned studies, aprotinin was administered as a 1 or 2 million kallikrein inhibiting unit bolus dose and only after median sternotomy and exposure of the heart for fast cardiopulmonary bypass connection should an anaphylactic reaction occur. This regimen also differs from the US Food and Drug Administration–approved regimen and was related to the preferences and experiences of the anesthetists and surgeons involved, the adjusted body weight, the expected length of surgery, and the lack of literature data on aprotinin use in off-pump cardiac surgery.

Aprotinin significantly reduced bleeding in the first 24 hours after surgery by 24.5% compared with the control group. It might have long-lasting properties because the rate of bleeding within the second postoperative day (24 hours to 48 hours) after OPCABG was still significantly lower in the aprotinin-treated patients. A benefit of reduced bleeding was an improvement in postoperative hematologic variables such as erythrocyte count, hematocrit, and hemoglobin. Aprotinin also lowered the incidence of excessive blood loss by 2.25 times. However, reexploration rates for bleeding were not significantly different between the two groups. The recent meta-analysis by Brown and associates [23] of randomized, controlled aprotinin studies including adult on-pump CABG, isolated valve, or combined CABG and valve surgery up to July 2006 found that in this type of surgery only high-dose aprotinin, but not low-dose aprotinin, significantly reduced the rate of reexploration compared with placebo. The markedly lower aprotinin dose used during off-pump surgery in the present study compared with the on-pump dose regimen might therefore account for the similar reexploration rates in aprotinin and control patients.

The need for blood transfusions was also decreased: both the number of transfused patients and the transfused blood volume were significantly reduced. Overall, 54.7% of aprotinin patients did not need any allogeneic blood transfusion perioperatively, thus avoiding a transfusion-related increased risk of postoperative cardiac complications, serious infections, prolonged ICU stay, overall morbidity, or death [24]. Similar important observations were made by Engelberger and colleagues [15]; however, the target activated clotting time was markedly lower, and heparin reversal was not performed.

The strength of this study lies in the large number of patients investigated. There were no significant differences in patient characteristics, risk scores, management, operative time, arterial revascularization, surgical revascularization techniques, number of distal anastomoses, baseline and end-of-surgery activated clotting time values, and temperature. Low temperature in particular could be a factor for bleeding after OPCABG surgery. All OPCABG patients were managed with identical temperature-conserving methods (hot line, warming blanket, Bear Hugger). Main limitations are the retrospective nature of the study and the absence of randomization, which might have biased patient selection.

The administration of up to 2 million kallikrein inhibiting units of aprotinin did not result in a higher rate of postoperative complications during hospitalization. Mean serum creatinine concentrations during the initial 72 hours after surgery increased only slightly and to a similar extent compared with the control group. An increased incidence of renal failure, myocardial infarction, or stroke, which was associated with aprotinin administration in cardiopulmonary bypass–supported CABG reported by Mangano and coworkers [19], was not observed. The data analysis of the present study suggests that the aprotinin-associated complications observed in the study referenced above did not occur solely owing to the administration of aprotinin. It might be related to the combined use of cardiopulmonary bypass and aprotinin, differences in preoperative renal function of the patients, and the timing and dose of the perioperative aprotinin administration. In the present study, aprotinin was administered after the bolus administration of heparin and the exposure of the base of the heart and after pericardiotomy.

Cardiopulmonary bypass has been shown to result in complex inflammatory responses, which are intimately linked to the coagulation cascade and fibrinolysis. It induces complement activation, endotoxin release, leukocyte activation, the expression of adhesion molecules, and the release of many inflammatory mediators including oxygen-free radicals, arachidonic acid metabolites, cytokines, platelet-activating factor, nitric oxide, and endothelins [25]. Comparison of the overall pattern of coagulation activation in on-pump and off-pump CABG showed significantly lower activation after OPCABG during surgical intervention and in the very early postoperative hours [26, 27]. During the following 30 postoperative days, however, a prothrombotic pattern comparable to the one after on-pump CABG had developed [26]. Postoperative prothrombotic activation has been linked to surgical trauma common to both procedures [26]. Aprotinin might have a beneficial influence on postoperative prothrombotic activation after OPCABG; Poston and colleagues [17] reported that the postoperative level of prothrombin fragment 1.2 was significantly reduced in patients treated with aprotinin compared with the placebo group.

In summary, aprotinin proved efficacious and safe in the reduction of postoperative bleeding and transfusion requirements in OPCABG. There were no differences in major adverse cardiac events and mortality in this large number of patients treated perioperatively with aprotinin compared with control patients.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CRH. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass J Thorac Cardiovasc Surg 1990;99:788-797.[Abstract]
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