HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ray, M. J. Articles by O’Brien, M. F. Search for Related Content PubMed PubMed Citation Articles by Ray, M. J. Articles by O’Brien, M. F.

Ann Thorac Surg 1999;68:940-945
© 1999 The Society of Thoracic Surgeons

---

Original Articles: Cardiovascular

Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass

^a Departments of Haematology, The Prince Charles Hospital, Brisbane, Victoria, Australia
^b Cardiac Surgery, The Prince Charles Hospital, Brisbane, Deakin University, Victoria, Australia
^c the School of Public Health, Queensland University of Technology, Brisbane, Australia

Address reprint requests to Dr Ray, Haemostasis Research Laboratory, The Prince Charles Hospital, Brisbane, 4032, Australia;
e-mail: mjray{at}bit.net.au

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Aprotinin therapy is now widely used during cardiac surgery. This study examined the clinical and economic effectiveness of high-dose or low-dose aprotinin in comparison to placebo.

Methods. In a double blind, randomized study, three groups of 50 patients received high-dose aprotinin costing AUS$614 per patient (AUS$ = Australian dollars), low-dose aprotinin costing AUS$220 per patient or placebo. Resource use influenced by aprotinin therapy was measured.

Results. Both doses were effective in reducing chest drainage and postoperative transfusion requirements, high-dose being more effective than low-dose. Both doses reduced the rate of reoperations for hemostasis. A base case of statistically significant differences associated with the high-dose and low-dose aprotinin showed cost savings of AUS$77 and AUS$348 per patient, respectively. If the demonstrated less significant reductions in operating room and ward stay are included, these savings become AUS$463 and AUS$715, respectively. Alternately, if cross-matches are replaced by group-and-hold and cell savers are not used, the savings per patient would be AUS$196 and AUS$467, respectively.

Conclusions. While high-dose aprotinin is clinically more effective than low-dose aprotinin, low-dose therapy demonstrates greater cost savings.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The administration of aprotinin during cardiopulmonary bypass (CPB) surgery has been shown to reduce intraoperative and postoperative bleeding [1, 2]. Aprotinin has been shown not to alter the degree of clot formation during bypass but to inhibit plasmin digestion of clots [3]. The amount of blood lost during and after surgery is only an intermediate outcome, the relevant health outcomes being the associated reduction in transfusion requirements, morbidity, and mortality. The transfusion sparing benefit of high-dose aprotinin [4] has been shown to have a negative cost-benefit [5], but is more cost-effective than antifibrinolytic therapy with the cheaper -aminocaproic acid [6].

Excessive diffuse postoperative bleeding culminates in reoperation (reopens) in approximately 3% of patients [1], this frequency being significantly reduced with high-dose and low-dose aprotinin therapy [1, 7, 8].

Limited health care resources necessitate providers delivering quality surgical care in a cost-effective mode. Aprotinin is expensive, so using the smallest effective dose would increase efficiency.

The purpose of this study is to explore the relative clinical and economic efficiency of high-dose and low-dose aprotinin compared to no treatment in the context of a clinical study. The two questions addressed are: (a) is it more efficient to use high versus low-dose aprotinin? and (b) is it efficient to use aprotinin?

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
After providing informed consent, 150 consecutive patients undergoing aortic valve, and/or mitral valve replacement surgery were studied. This surgery type was selected to provide a homogeneous group that generally requires more transfusion. Exclusion criteria were previous aprotinin therapy, less than 18 years old, abnormal preoperative coagulation profile for reasons other than anticoagulant therapy, or refusal to receive blood transfusions. The demographics of the three groups were similar in regard to age, sex, operation type, valve type, preoperative platelet function, cross-clamp time, minimum temperature during bypass, and body surface area.

Aprotinin or placebo administration
To test for anaphylaxis, treatment was preceded by administration of 10,000 kallikrein inhibitor units (KIU) (4 mg) of aprotinin (preservative-free Trasylol, Bayer AG, Leverkusen, Germany). In this double-blind study, patients were randomized to one of the following groups:

1. High-dose aprotinin (Hammersmith regimen). This consisted of 2 x 10⁶ KIU (280 mg) infused over 20 minutes after the induction of anesthesia followed by 0.5 x 10⁶ KIU per hour (70 mg/h) until the patient left the operating room. In addition, 2 x 10⁶ KIU was added to the pump prime.
   
2. Low-dose aprotinin consisted of 1 x 10⁶ KIU (140 mg) of aprotinin infused for 20 minutes after the induction of anesthesia and followed by 1 x 10⁶ KIU added to the pump prime.
   
3. The placebo group received a volume of saline equivalent to the volume administered in the low-dose aprotinin group.
   

Perioperative measurements
At the end of operation, the surgeons were asked to assess the degree of intraoperative bleeding. For each patient, the cumulative volume of mediastinal chest drainage was measured every 4 hours for the first 24 hours postoperatively. The hemoglobin content of this drainage was estimated so that drainage volumes could be expressed as grams of hemoglobin. Intraoperative and postoperative transfusions were also recorded. The duration of each patient’s stay in the operating room, the intensive care ward, and the general ward was recorded.

Resource use data
The parameters that determined the potential costs and cost savings associated with the use of aprotinin were preoperative crossmatching, dose of aprotinin, cell saver utilization, operating room time, reopen rate, volumes of blood products transfused intraoperatively and postoperatively, and lengths of stay in intensive care and general ward.

In valuing resource use, the health services costs that were common in the three arms were ignored, and only the cost differences associated with aprotinin therapy as compared to the placebo arm were evaluated.

To establish the cost of reopens, a chart audit was performed for 32 consecutive reopen patients having valve replacement surgery without aprotinin therapy prior to this study.

All costs are reported in Australian dollars (AUS$).

Statistical analysis
When the data analyzed was not normally distributed, non-parametric analysis was used. The null hypothesis that two samples come from the same population was tested with the Mann-Whitney U test, and for three samples, the Kruskal-Wallis one way analysis of variance. Differences in transfusion rates between groups were tested with ² analysis. Differences were considered statistically significant when p was < 0.05. The SPSS version 6.1 statistical program was used.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Intraoperative outcomes and costs
Cost of aprotinin
The cost of aprotinin was AUS$110 per 100-mL vial (1x10⁶KIU) or AUS$64 per 50 mL vial (0.5x10⁶KIU). This translates to a per patient cost of AUS$ 614 for high-dose aprotinin and AUS$220 for low-dose aprotinin.

Blood loss
The surgeons assessed the intraoperative bleeding as minimal = 1, mild = 2, moderate = 3, and severe = 4. On this basis, the mean (standard deviation) scores for high-dose, low-dose, and placebo groups, respectively were 2.1 (0.7), 2.1 (0.9) and 2.3 (0.9). These values are not statistically different, indicating aprotinin therapy was not observed to cause a significant reduction in intraoperative bleeding.

Transfusion requirements
The reduction in frequency of intraoperative transfusion with high-dose and low-dose aprotinin compared to placebo (Fig 1 ) did not reach statistical significance.

View larger version (29K): [in this window] [in a new window]   Fig 1. Frequency of intraoperative and postoperative blood product transfusion in the high-dose aprotinin, low-dose aprotinin and placebo groups.

Thus the mean intraoperative transfusion costs per patient for high-dose aprotinin, low-dose aprotinin, and placebo were AUS$16, AUS$52, and AUS$66 respectively. The risks and costs associated with transmission of blood-borne disease have not been considered.

Hypersensitivity reactions
Anaphylactic reactions to aprotinin have been reported [12]. These often occurred after repeat administration of aprotinin [13], although frequencies are low [14, 15]. The protocol for this study excluded patients with prior exposure to aprotinin. With the additional safeguard of the test dose, the risk of hypersensitivity reactions was therefore assumed to be zero and no attempt was made to estimate the expected cost of hypersensitivity reactions.

Cell saver use
The frequency of cell saver use was similar in each of the three groups. Within each treatment group the use of the cell saver demonstrated no significant reduction in the frequency of intraoperative or postoperative transfusion or postoperative hemoglobin loss (Table 1). This finding may have been influenced by the fact that the cell saver use was not randomized.

Postoperative outcomes and costs
Blood loss
The cumulative hemoglobin loss through mediastinal drainage of both high-dose and low-dose aprotinin groups was significantly less than that of the placebo group at each 4-hourly interval (p < 0.0001) (Fig 2). The hemoglobin loss of the high-dose group was significantly less than that of the low-dose group at the 8, 16, 20, and 24 hour intervals (p < 0.05). During the critical first 4 hours postoperatively, high-dose and low-dose aprotinin therapy reduced the hemoglobin loss in comparison to the placebo group by 77% and 68%, respectively.

View larger version (19K): [in this window] [in a new window]   Fig 2. Median cumulative hemoglobin loss from mediastinal drainage for high-dose aprotinin , low-dose aprotinin and placebo • patients. The error bars represent the 25th and 75th percentiles. * p < 0.05.

Reopens
Of the 150 patients studied, 5 were reopens. All these patients were from the placebo group. This was a significant reduction in the rate of reopens in the aprotinin treated groups compared to the placebo group (p = 0.004, Fisher exact).

Reopens are associated with substantial additional costs due to the additional surgery and the nursing and room costs associated with the increased length of stay in intensive care and general wards. Consequently, reduction in the reopen rate achieved with aprotinin is very important in offsetting the costs of treatment. Hospital records showed that compared with a standard care episode for a valve replacement, the extra costs for the 5 reopen patients ranged from AUS$2,120 to AUS$12,860 with a median of AUS$4,880.The cost of reopens (calculated by multiplying the risk of reoperation by the median additional cost incurred by patients who underwent reoperation) in this study is therefore AUS$488 per patient.

Time in the postoperative and general wards
High-dose and low-dose aprotinin treated patients had median general ward stay times that were 22 and 21 hours less, respectively, than placebo patients. This difference failed to reach statistical significance. For ward stay analysis, the data for the 5 patients having urgent reopens was excluded because their increased ward stay has already been tallied as above.

Cost minimization analysis
Economic evaluations of health care programs are defined as the comparative analysis of alternative courses of action in regard to both costs and consequences. Where the differences between alternatives are shown to be nonexistent or unimportant, the efficiency evaluation is essentially a search for the least cost alternative—that is, a cost minimization analysis. Technically, it is this type of analysis which best fits the present context because there were no differences in important health outcomes such as mortality rates or the incidence of cerebrovascular accidents among the aprotinin and placebo groups.

This study showed only two statistically significant sources of cost savings to offset the cost of aprotinin therapy: (1) cost differences associated with the volume of blood products transfused, and (2) the number of reopens. This base-case scenario showed that, assuming the cost of blood products is a de facto cost to the hospital, low-dose aprotinin resulted in considerably more cost savings than did high-dose aprotinin (Table 2).

Scenario 1
What if differences demonstrated in the study, that failed to achieve statistical significance, were included? The reduction of approximately 25 minutes in operating room time with aprotinin therapy could, with appropriate management changes, yield savings in variable (mainly labor) costs of AUS$192. A reduction in length of stay in the general ward of 9 or 8 hours for high-dose and low-dose aprotinin respectively may save AUS$194 or AUS$175 in room related costs. These effects on the results reported in Table 2 are dealt with as simple "line item" adjustments and show considerably greater cost savings, not reversing the conclusion that low-dose aprotinin is optimal for cost minimization (Table 3).

Secondly, the reduced transfusion requirements associated with high-dose, and to a lesser extent low-dose aprotinin therapy means that a group, antibody screen, and holding of the serum sample for a rapid cross-match (if necessary) may be able to replace the routine preoperative full cross-match. According to the Medical Benefits Schedule (MBS) (a charge that the federal government sets for reimbursement purposes) the charge per patient for a group is AUS$36.75 and a cross match is AUS$99.75 respectively. Following this approach, the use of aprotinin therapy may be associated with cost savings of AUS$63 per patient that may be used to offset the cost of the drug. The effect of scenario 2 on the base-case scenario confirms that the treatment is cost saving, with low-dose aprotinin still being optimal therapy (Table 3).

Scenario 3
The goal of sensitivity analysis is to identify the variables that are critical in that their values are most likely to change the results. So, lastly, it was asked "what if the assumptions made from the results of this study regarding the costs and frequency of reopens lacked external validity?"

In this study, the cost saving due to the reduced rates of reopens in the low-dose and high-dose aprotinin patient groups were based on a median extra cost of the five reopens of AUS$4880. The audit of the charts of 32 reopen patients showed the median extra cost was AUS$5,550. This indicates that the estimated cost saving associated with the prevention of reopens based on the study data is conservative.

To illustrate the effect of the magnitude of reductions in the frequency of reopens on the cost calculus, reductions of 1.0% to 3.0% were considered. When only the cost saving accrued through decreased blood transfusion were considered, and scenarios 1 and 2 were ignored, it required a reduction in reopen rate of 3.0% before there were cost savings with low-dose aprotinin, high-dose aprotinin not affording any cost benefit (Table 3).

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
This study has demonstrated a dose-related efficiency of aprotinin in reducing postoperative bleeding and transfusion requirements. The hemoglobin loss postoperatively was markedly reduced with low-dose aprotinin and significantly more reduced with high-dose aprotinin. A similar trend was observed with the postoperative transfusion of blood, platelets, and fresh frozen plasma. Most importantly, there was a significant reduction in the reopen rate with both treatments.

When considering the economic consequences of aprotinin therapy, it is important to concentrate on final health outcomes rather than intermediate clinical end-points. The base-case scenario suggested by the study showed low-dose aprotinin had the greatest cost saving per patient. There were similar cost savings through reduction in urgent reopens in both groups, greater savings in transfusion costs in the high-dose group, but a considerably greater cost in the high-dose group for the drug itself.

This evaluation has been based on the cost structure within this particular hospital, so care must be taken when applying the findings to other institutions within or outside Australia. Because the magnitude of the advantage of low-dose over high-dose aprotinin is the result of offsetting savings in transfusion costs and the cost of aprotinin in the two groups, the conclusions are dependent on the relationship between these costs. A US study comparing high-dose and half-dose aprotinin similarly concluded that the half-dose aprotinin provided the significant cost benefit [17].

It is difficult to preoperatively predict which patients are going to bleed excessively, so this prophylactic therapy suffers a real cost disadvantage when given to patients who will benefit little. If aprotinin could be administered postoperatively to only those patients showing early signs of bleeding, there is potential for greater cost savings. Further study to define the efficacy of such treatment is currently in progress at this institution.

Whereas high-dose aprotinin is more efficient than low-dose aprotinin at reducing bleeding and transfusion requirements, from the economic perspective, low-dose aprotinin is the preferred treatment.

	Acknowledgments

 
We would like to thank The Prince Charles Hospital Foundation for funding this study. We would also like to express our appreciation for the cooperation and assistance given by the surgeons, anesthetists and nursing staff. We especially thank Laurie Kear who randomized the patients and allocated the drugs. We are grateful to Bayer (Australia) for supplying the aprotinin. We would like to acknowledge the suggestions give by Dr Geoff Hawson and the statistical advice given by Associate Professor Geoff McLachlan.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

1. Lemmer J.H., Dilling E.W., Morton J.R., et al. Aprotinin for primary coronary artery bypass grafting. Ann Thorac Surg 1996;62:1659-1668.[Abstract/Free Full Text]
2. Ray M.J., Marsh N.A., Perrin E.J., Just S.J.E., O’Brien M.F., Hawson G.A.T. Preoperative platelet dysfunction increases the benefit of aprotinin in cardiopulmonary bypass. Ann Thorac Surg 1997;63:57-63.[Abstract/Free Full Text]
3. Ray M.J., Marsh N.A. Aprotinin reduces bleeding after cardiopulmonary bypass by direct inhibition of plasmin. Thromb Haemost 1997;78:1021-1026.[Medline]
4. Lemmer J.H., Jr, Stanford W., Bonney S.L., et al. Aprotinin for coronary bypass operations. J Thorac Cardiovasc Surg 1994;107:543-551.[Abstract/Free Full Text]
5. Harmon D.E. Cost/benefit analysis of pharmacological hemostasis. Ann Thorac Surg 1996;61:S21-S25.
6. Van Norman G., Lu J., Spiess B., Soltow L., Gillies B. Aprotinin versus aminocaproic acid in moderate-to-high-risk cardiac surgery. Anesth Analg 1995;80:SCA19.
7. Schonberger J.P., Everts P.A., Ercan H., et al. Low-dose aprotinin in internal mammary artery bypass operations contributes to important blood savings. Ann Thorac Surg 1992;54:1172-1176.[Abstract]
8. Concha M., Munoz I. Experience with low-dose aprotinin. In: Pifarré R., ed. Blood conservation with aprotinin. Philadelphia: Hanley & Belfus, 1995:293-312.
9. Lathi K.G., Hariawala M., Fotouhi F., Symes J.F. Economics of aprotinin in cardiac surgery. Anesth Analg 1995;80:SCA119.
10. Guest J.F., Munro V., Cookson R.F. The annual cost of blood transfusions in the United Kingdom. Clin Lab Haem 1998;20:111-118.[Medline]
11. Lubarsky D., Hahn C., Bennet D., et al. The hospital cost (fiscal year 1991/1992) of a simple perioperative allogenic red blood cell transfusion during elective surgery at Duke University. Anesth Analg 1994;79:629-637.[Abstract/Free Full Text]
12. Diefenbach C., Abel M., Limpers B., et al. Fatal anaphylactic shock after aprotinin re-exposure in cardiac surgery. Anesth Analg 1995;80:830-831.[Medline]
13. Dietrich W., Barankay A., Hahnel C., Richter J. High dose aprotinin in cardiac surgery. J Cardiothorac Vasc Anesth 1992;6:324-327.[Medline]
14. Bidstrup B., Harrison J., Royston D., Taylor K., Treasure T. Aprotinin therapy in cardiac operations. Ann Thorac Surg 1993;55:971-976.[Abstract]
15. Goldstein D.J., Oz M.C., Smith C.R., et al. Safety of repeat aprotinin administration for LVAD recipients undergoing cardiac transplantation. Ann Thorac Surg 1996;61:692-695.[Abstract/Free Full Text]
16. D’Errico C.C., Shayevitz J.R., Martindale S., Mosca R.S., Bove E.L. The efficacy and cost of aprotinin in children undergoing reoperative open heart surgery. Anesth Analg 1996;83:1193-1199.[Abstract]
17. Lazzara R.R., Kidwell F.E., Kraemer M.F., Wood J.A., Starr A. Reduction in costs, blood products, and operating time in patients undergoing open heart surgery. Arch Surg 1997;132:858-860.[Abstract]

This article has been cited by other articles:

				J. R. Brown, N. J.O. Birkmeyer, and G. T. O'Connor Meta-Analysis Comparing the Effectiveness and Adverse Outcomes of Antifibrinolytic Agents in Cardiac Surgery Circulation, June 5, 2007; 115(22): 2801 - 2813. [Abstract] [Full Text] [PDF]

				D. Fergusson, K. C. Glass, B. Hutton, and S. Shapiro Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clinical Trials, June 1, 2005; 2(3): 218 - 232. [Abstract] [PDF]

				B. S. Donahue Factor V Leiden and Perioperative Risk Anesth. Analg., June 1, 2004; 98(6): 1623 - 1634. [Abstract] [Full Text] [PDF]

				P. K. Smith, S. K. Datta, L. H. Muhlbaier, G. Samsa, A. Nadel, and J. Lipscomb Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials Ann. Thorac. Surg., February 1, 2004; 77(2): 635 - 642. [Abstract] [Full Text] [PDF]

				L. Englberger, B. Kipfer, P. A. Berdat, U. E. Nydegger, and T. P. Carrel Aprotinin in coronary operation with cardiopulmonary bypass: does "low-dose" aprotinin inhibit the inflammatory response? Ann. Thorac. Surg., June 1, 2002; 73(6): 1897 - 1904. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ray, M. J. Articles by O’Brien, M. F. Search for Related Content PubMed PubMed Citation Articles by Ray, M. J. Articles by O’Brien, M. F.