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Ann Thorac Surg 1998;65:S52-S55
© 1998 The Society of Thoracic Surgeons

Pharmacoeconomics Analysis in a Pediatric Population

^a Department of Pediatric Anesthesiology, Mott Children’s Hospital, University of Michigan Medical Center, Ann Arbor, Michigan, USA

Address reprint requests to Dr D’Errico, Pediatric Anesthesiology, Mott Children’s Hospital, University of Michigan Medical Center, 1500 E Medical Center Dr, Rm F-3900, Ann Arbor, MI 48109-0211

Presented at Risk Assessment of Major Perioperative Issues in Pediatric Cardiac Surgery, Washington, DC, May 7, 1997.

	Abstract

Top Abstract Introduction Methodologic concerns The Pediatric Reoperative Open... Conclusion Discussion References

 
Background. Pharmacoeconomics is becoming increasingly important in the health-care environment, but pharmacoeconomic studies are fraught with problems. Pharmacoeconomics can be applied to analysis of the benefits of pharmacologic hemostasis.

Methods. This article reviews the available methods of pharmacoeconomic analysis and their inherent methodologic concerns. It reviews pharmacoeconomic studies of pharmacologic hemostasis, with particular focus on the Pediatric Reoperative Open Heart Surgery Study. In this study, patients were randomized to receive either high-dose aprotinin, low-dose aprotinin, or placebo. Results were analyzed from the viewpoint of cost-benefit, cost-effectiveness calculated with use of a roll-back decision tree, and cost-effective ratios.

Results. Cost-benefit analysis showed low-dose aprotinin to have a greater cost-benefit than high-dose aprotinin, cost-effectiveness analysis and analysis of cost-effective ratios showed high-dose aprotinin to be more cost-effective than low-dose aprotinin, and all analyses showed aprotinin to be preferable to placebo.

Conclusions. Aprotinin in pediatric repeat open heart operations not only has a cost-benefit but is cost-effective as well.

	Introduction

Top Abstract Introduction Methodologic concerns The Pediatric Reoperative Open... Conclusion Discussion References

 
Pharmacoeconomics may be considered to involve the study of how to generate the most benefit, enhance patient survival and quality of life, and effect the lowest overall cost. Or it may be considered to involve evaluation of a drug’s clinical, economic, and humanistic attributes, and their effect on health-resource utilization and cost. It is useful to establish the parameters of the field and some of the concepts and terminology used in pharmacoeconomic studies before engaging specifically the question of aprotinin cost-effectiveness for the pediatric patient.

Three types of pharmacoeconomic studies are quoted in the literature. A primary study focuses specifically on financial issues; these probably are the best studies available. A secondary study is a study done secondarily to a study of a drug’s efficacy and safety. Because this type of study is at least to some extent protocol-driven, consideration must be given to the fact that the study data may not hold up in other clinical settings. A third type of study involves extrapolations from data present in the literature, combining the data from various studies and doing statistical analysis of the cost factors involved.

Five methods of analysis are available. Cost-minimization analysis involves comparing two drugs that work identically and have identical outcomes, basically looking only at the cost of delivery of these drugs. Cost-benefit analysis looks at both the cost and benefit of a drug’s use and attempts to assign a dollar value to each. For example, if one incurs the cost of giving aprotinin and thereby saves on the cost of blood, how do these two costs compare? Cost-effectiveness analysis begins to look at more subjective factors. In this type of analysis, cost and benefit are measured in terms of a specific objective. For example, was the patient’s hospital stay shortened?

Cost-utility analysis gets much more confusing, because it involves evaluation of benefit in terms of quality of life. It is very difficult to assign dollar values to the utilities that comprise quality of life. What is the worth of a year of life? What is the worth of a year of life if the patient is chronically hospitalized? Survival assumes particularly momentous value in a pediatric population compared with an adult population, because saving a child’s life means that child can look forward to many more years of life.

Cost-of-illness analysis is an emerging approach that identifies and considers both the direct and indirect cost of a disease.

	Methodologic concerns

Top Abstract Introduction Methodologic concerns The Pediatric Reoperative Open... Conclusion Discussion References

 
Pharmacoeconomic studies are fraught with problems. Since their first appearance in the literature in 1979, available studies have used differing terminology and often have approached their data from differing perspectives. As noted above, when the data are from protocol-driven studies, they may not reflect real-life outcomes and costs. There are difficulties in generalizing the results of one institution in respect to another, as institutions may differ in patient populations, practice techniques, experience in the management of particular types of conditions, and drug-acquisition costs. Small sample sizes pose problems, with sample size often limited by institutional and physician pressures to end the randomization procedure, stop placebo use, and treat all patients.

Many cost considerations are almost impossible to quantify. Attempts to calculate direct, indirect, and intangible costs and consequences can become quite complex. For example, a child’s hospitalization may cause one parent to miss work for a week, whereas another parent may be on vacation that week. Another example: You may give 5 units of a given type of blood, unaware that your hospital will soon be receiving patients with injuries from an automobile accident and no more of that type of blood is on hand, so your decision has just affected the cost of those trauma cases. Again, a patient may be delayed in the operating room, thereby causing some other operating room to incur the cost of overtime nurses for 20 minutes. Costs associated with long-term outcomes are particularly hard to come by. They require follow-up over years and consideration of such factors as required patient return visits and laboratory tests and patient quality of life.

The characteristics of an ideal pharmacoeconomics study would be very similar to those of an ideal clinical study. It would be a head-to-head study that either is placebo-controlled or directly compares one product with another relevant product, encompasses long-term evaluation, uses measurements that are disease-specific, uses generic quality-of-life scales and a good utility scale, and considers true costs.

Two reports highlight some of the issues involved in the cost-benefit study of specifically pharmacologic hemostasis. In 1994, Hardy and Bélisle [1] noted that although -aminocaproic acid and tranexamic acid are less expensive than aprotinin, studies were needed to compare their efficacy, and that without head-to-head long-term studies it will be difficult to say that one drug is better than another from any standpoint, whether cost or some other factor. In 1996, Harmon [2] noted that 27% of adult patients received blood that was unnecessary during cardiac operations, but concluded that bleeding is costly and adds increased risk to operation. The report noted that the cost of operative hemorrhage includes the cost of blood products and the cost of increased closure and operating room time, and that the cost of postoperative hemorrhage includes the cost of reexploration when it is required. I believe still other, hidden costs need to be considered, such as the cost of transfusion-related or drug-related complications, the effects on blood bank supplies, and the impact on patient lives.

	The Pediatric Reoperative Open Heart Surgery Study

Top Abstract Introduction Methodologic concerns The Pediatric Reoperative Open... Conclusion Discussion References

 
This study was partly a continuation of D92922, with our continuing to enroll patients after our participation in the initial study in an effort to increase the sample size to significant numbers. It was a randomized, placebo-controlled, double-blind trial involving 61 children with a median age of 3.7 years. There were three demographically similar study groups. One group received high-dose aprotinin: 240 mg/m² (1.7 x 10⁶ KIU/m² intravenously) and in the extracorporeal circuit prime, followed by an intravenous infusion of 56 mg · m^-2 · h^-1 (4 x 10⁵ KIU · m^-2 · h^-1). A second group received low-dose aprotinin: 120 mg/m² (8.6 x 10⁵ KIU/m²) followed by 28 mg · m^-2 · h^-1 (2 x 10⁵ KIU · m^-2 · h^-1). The third group received placebo. Our results showed that the patients receiving aprotinin had fewer exposures to banked-blood components in the first 24 postoperative hours, decreased time in the operating room, no adverse change in blood urea nitrogen and creatinine levels, and no difference in overall complication rate compared with patients receiving placebo.

To evaluate the cost-benefit of aprotinin, we looked at four factors: cost of the drug, cost of operating room time from the time of separation from bypass to chest closure, cost of blood products, and cost of hospital stay beyond 14 days (Table 1). Our analysis confirmed the finding of most pharmacoeconomic studies in adults, namely, that most of incurred costs occur in the first 24 hours. Approximately a $1,000 difference in operating room time cost was noted between patients receiving aprotinin and those receiving placebo; this represents a difference of 15 minutes in operating room time. There was almost a $2,000 difference in the cost of blood products, related to the distinct difference in the number of units transfused to patients who received aprotinin and those who did not.

View larger version (16K): [in this window] [in a new window]   Fig 1. Decision analysis tree for the use of aprotinin in repeat pediatric cardiac operations with regard to the probability of an exposure to banked blood products in the first 24 hours after bypass. The utilities relate to the known benefit to receiving no exposures to banked blood. The branches represent the probability of each treatment group receiving an exposure to banked blood. This analysis shows high-dose aprotinin (AHD) to be more cost effective in relation to the risk of receiving banked blood products. (ALD = low-dose aprotinin; P = placebo.)

	Conclusion

Top Abstract Introduction Methodologic concerns The Pediatric Reoperative Open... Conclusion Discussion References

 
Pharmacoeconomics is imperative to determine cost in relationship to patient outcomes. The adoption of standardized methods to enhance the practice, interpretation, relevance, and credibility of pharmacoeconomics will benefit medicine and medical-care utilization. Pharmacoeconomic data increasingly will be required to support formulary additions or deletions.

In our pharmacoeconomics study of aprotinin use in pediatric reoperative open heart surgical procedures, cost-benefit analysis showed low-dose aprotinin to have a greater cost-benefit than high-dose aprotinin, cost-effectiveness analysis and analysis of cost-effective ratios showed high-dose aprotinin to be more cost-effective than low-dose aprotinin, and all analyses showed aprotinin to be preferable to placebo. We conclude that aprotinin in pediatric repeat open heart operations not only has a cost-benefit but is cost-effective as well. Further dose-response studies are needed.

	Discussion

Top Abstract Introduction Methodologic concerns The Pediatric Reoperative Open... Conclusion Discussion References

 
QUESTION FROM THE AUDIENCE: We know that the inflammatory response in open heart operations extends into the postoperative period. Is there any evidence to suggest that extending the infusion of aprotinin into the first 24 hours, during which time inflammation continues to increase, would be beneficial in terms of length of stay and length of mechanical ventilation?

DR D’ERRICO: We do not have any data on that, because we stopped all our infusions in the operating room. But I do think that how long the patient is intubated and how long the patient stays in the intensive care unit are inflammation issues that aprotinin may be affecting. In fact, I believe that the most important use of aprotinin will turn out to be antiinflammatory, even though all the early focus has been on its hemostatic action. So I do think that there is a need to study the effects of continuing the infusion of aprotinin in the intensive care unit, perhaps even until the patient is extubated.

QUESTION FROM THE AUDIENCE: I found your concluding comment about the need for further dosing studies to be very important. One of our problems is that in pediatric and even adult surgery, we actually are giving different doses to patients of different sizes. I think that perhaps some of the adverse effects we encounter relate to variability in plasma concentration.

We have published data showing that the half-life of aprotinin is about 5 hours. So if a patient’s plasma level is 100 KIU/mL (0.014 mg/mL) when you stop infusion at the end of the operation, it is 40 KIU/mL (0.006 mg/mL) 5 hours later, which is the level that pretty much paralyzes fibrinolysis. We also have reported that with full-dose aprotinin you hit a plasma level of 250 KIU/mL (0.034 mg/mL) and with half-dose a level of 125 KIU/mL (0.017 mg/mL) with an impressive standard deviation. So at half-dose, you still have some antiinflammatory effect in some individuals, assuming that 250 KIU/mL (0.017 mg/mL) inhibits contact activation. But there are other things that are being inhibited as well.

My question is, what clinical outcome parameters or molecular markers can we use to develop a dosing strategy?

DR D’ERRICO: That is an important issue. I think your hospital hierarchy will want to see a focus on time to extubation and length of stay in the intensive care unit, because most of your cost is incurred during that time. Time to extubation and chest tube removal also is going to be a quality issue for patients, because we all know that patients who have chest tubes are in much more pain than other patients.

We really do not know how much aprotinin we have given to our patients because we do not know the dilution factor. For example, we do not know who used 500 mL and who used 1,000 mL for the pump prime. Actually, we loaded the pump with the same amount that we loaded the patient with, regardless of volume of the pump prime, so that even our pump prime started with different levels of aprotinin.

So I agree that there is a need to study concentration levels in relation to clinical outcomes. In this day and age, it is not enough to relate concentration to some laboratory marker; people want to see some change in clinical outcome. In Boston and at Children’s Hospital in Philadelphia, some work has been done looking at the long-term effects of bypass in children. I think that some of the most important studies to be conducted will look at the effects of bypass on such factors as intelligence and personality change. And if aprotinin has an antiinflammatory effect in the brain and consequently saves brain cells, it may turn out that it has an important role with respect to such factors.

QUESTION FROM THE AUDIENCE: Hospitals really do try to push for use of less expensive drugs whenever they can be as effective as more expensive ones. In your comparison groups, did you compare aprotinin with some less expensive drug, such as aminocaproic acid?

DR D’ERRICO: We did not. Aminocaproic acid is much less expensive, and I think that is a study that definitely needs to be done. But it must be done on a long-term basis and it must look at all the parameters of effectiveness, including chest-tube drainage, blood loss, and perhaps end-organ damage as well. It is necessary to get hospitals to look at the global picture of what happens in the long run, rather than just at the cost of a drug.

QUESTION FROM THE AUDIENCE: Are there any redo patients to whom you do not give aprotinin because you are not as concerned about bleeding?

DR D’ERRICO: I cannot think of any.

QUESTION FROM THE AUDIENCE: You operate on many patients who have had aprotinin before. Have you seen any adverse reactions from repeated use of aprotinin in the same patients?

DR D’ERRICO: Actually, we have had very few complications. We have had a couple of anaphylactic reactions, without long-term sequelae. We follow the consensus opinion in our practice and try to schedule operations at least 6 months apart, and we pretreat many of our repeat patients.

QUESTION FROM THE AUDIENCE: Are there any reasons for giving the initial or bolus dose earlier, and even preoperatively? By the time we start to open the chest, some hemodynamic instability may have occurred and the inflammatory process is probably underway.

DR D’ERRICO: In our study, we loaded our patients immediately upon placing the arterial line and running a heparin dose-response curve. So they were receiving aprotinin before we proceeded to preparing them for the operation. But I think your point is well taken. We really did not have the option of administering aprotinin any earlier. Because of financial considerations, most of our patients walk in about an hour before the operation. By the time we can put lines in them, they are on their way to the operating room.

DR PHILIPPE POUARD (Paris, France): We also load patients immediately after placement of the arterial line. We take 20 minutes for the loading dose. We have had one anaphylactic reaction with circulatory arrest, which required that we go on bypass very, very quickly. This was in a young girl, and she is well now. But ever since this occurred, we give a test dose very slowly, and we stop as soon as any dysrhythmia appears in the electrocardiogram or there is any decrease in arterial pressure or change in the heart rate.

DR WULF DIETRICH (Munich, Germany): I disagree on the issue of timing. Measurements we have done showed no significant increase of the hemostatic parameters in the prebypass time. So in our understanding, it is not necessary to give aprotinin before bypass. We start aprotinin administration very late, or we start it if the surgeon is ready to go on the pump immediately. This is a very important safety issue related to this drug, because the pump may be life-saving in these patients. We believe that delaying the first dose of aprotinin is safer for the patient.

DR ROSS M. UNGERLEIDER (Durham, NC): If it turns out that there is a substantial contribution from an inflammatory standpoint, then maybe giving it earlier will be better.

DR WILLIAM J GREELEY (Philadelphia, PA): I would like to offer some comments that may provide additional perspective. It is important that we understand the methodology reviewed in this presentation. We are increasingly going to be exposed to data like this.

But from a pharmacoeconomics viewpoint, the pharmacy charges involved in an average congenital heart case amount to only 2% to 4% of the average total cost of a congenital heart operation. It makes sense to focus effort on cost reduction on the remaining 98% rather than the 2% represented by drug costs. Half of that other 98% is incurred in patient processing: in the operating room, in the intensive care unit, and on the ward. It is patient-related throughout. The outcome that must be focused on is moving the patient through the system.

A major cost component is length of stay in the intensive care unit. But unfortunately, we still tend to think in terms of 24-hour blocks of time when it comes to intensive care unit stay. A patient may be extubated earlier, or taken off monitoring earlier, and still will be kept in the intensive care unit for 24 hours. We need to shift to a mind-set that distinguishes between patients at high risk and patients at low risk. Low-risk patients can be kept in the intensive care unit for 3 hours and then out they go. And then you flex your nursing staff around that revised process. Medicine is 70% labor, and it is a drug’s effect on the labor pool that determines its greatest impact on costs.

	References

Top Abstract Introduction Methodologic concerns The Pediatric Reoperative Open... Conclusion Discussion References

 

1. Hardy J.F., Bélisle S. Natural and synthetic antifibrinolytics in adult cardiac surgery: efficacy, effectiveness and efficiency. Can J Anesth 1994;41:1104-1112.[Medline]
2. Harmon D.E. Cost/benefit analysis of pharmacologic hemostasis. Ann Thorac Surg 1996;61:S21-S25.
3. D’Errico C.C., Shayevitz J.R., Martindale S.J., 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]

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