Ann Thorac Surg 1998;65:S31-S34
© 1998 The Society of Thoracic Surgeons
The Bayer 022 Compassionate-Use Pediatric Study
Robert F. Coniff, MDa
a Bayer Corporation, West Haven, Connecticut, USA
Address reprint requests to Dr Christopher Mojcik, Bayer Corporation, 400 Morgan Ln, West Haven, CT 06516
Presented at Risk Assessment of Major Perioperative Issues in Pediatric Cardiac Surgery, Washington, DC, May 7, 1997.
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Abstract
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Background. As part of a compassionate-use study, a placebo-controlled study was undertaken to assess the efficacy of aprotinin in patients undergoing any procedure associated with cardiopulmonary bypass and at increased risk of perioperative bleeding. This article reviews results in 116 patients 16 years of age or less.
Methods. Patients were randomly assigned to four treatment groups: high dose, low dose, pump prime only, and placebo. Efficacy was measured by four parameters: requirement for units of donor blood, requirement for units of donor blood and blood product, thoracic drainage volumes, and rates of reoperation required primarily because of diffuse bleeding. Results were separately analyzed in all patients, patients undergoing primary procedures, patients undergoing repeat procedures, neonates and infants 1 year of age or less, and patients older than 1 year of age.
Results. There was a trend toward reduced blood and blood product requirements with aprotinin use, least evident in neonates and infants and particularly evident in patients undergoing repeat procedures. Aprotinin did not reduce drainage volumes in this pediatric population.
Conclusions. There is a trend toward benefit with aprotinin use in a pediatric population, as measured by requirement for blood and blood product, in patients who are more than 1 year of age and in patients undergoing a repeat operation rather than a primary sternotomy operation.
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Introduction
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In response to innumerable requests from physicians wanting to use aprotinin in patients at high risk for bleeding before its approval, the Food and Drug Administration asked us to establish a compassionate-use program. We subsequently set up two different protocols. One was an open-label protocol in which all patients considered to be at a life-threatening level of risk for perioperative hemorrhage received aprotinin. The other was a placebo-controlled protocol designed to evaluate the effect of aprotinin at several doses in patients of any age or sex undergoing any type of procedure associated with cardiopulmonary bypass and with a definite increased risk of perioperative bleeding. (Thus, uncomplicated primary procedures and uncomplicated valve repairs were ruled out.) This article reviews experience with the latter protocol in pediatric patients.
Ultimately, four centers participated in this trial; the pediatric data reviewed below come from two of those centers. Of 226 patients enrolled in the study, 116 were 16 years of age or less. There were 31 patients (19 male, 12 female) in a neonatal infant group comprising patients 1 year of age or less and 85 patients (44 male, 41 female) who were older than 1 year but less than 17 years of age. The study began with four treatment groups: 31 patients were enrolled to receive a high dose, or full-dose Hammersmith regimen; 33 patients were enrolled to receive a low dose, which was half the high dose; 18 patients were enrolled in a pump-prime-only group; and 34 patients were enrolled to receive placebo. As this study got underway, we were completing another dose-response study that had looked at the effectiveness of these same four regimens. When the analysis of the data from that dose-response study showed that the pump-prime-only regimen was not particularly effective, we deleted it from our ongoing study, which explains the small number of patients enrolled in that group.
Children with congenital heart anomalies frequently have to undergo repeated procedures; consequently, patients also were divided according to whether they were undergoing a primary or repeat sternotomy (Table 1). Seventy-three patients were undergoing repeat procedures and 43 patients were undergoing primary procedures; it would be expected that more patients undergoing repeat procedures would be enrolled, as they generally are considered to be at higher risk for hemorrhage.
The number of patients in this study was too small to permit formal statistical analysis of outcome data. Also, because this was a compassionate use study, and one done during a very busy period, we did not do hands-on monitoring of the trial, so the data may not be quite as clean as data from a more formal trial. Nevertheless, the descriptive results are suggestive.
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Efficacy results in all patients
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There was a tendency for patients receiving aprotinin to require fewer units of donor blood, particularly evident in the mean number of units transfused in high-dose patients compared with placebo patients (2.9 versus 4.6 units). The tendency toward lower blood requirement with aprotinin was more marked when both donor blood and blood product (platelets, cryoprecipitate, and fresh-frozen plasma) were considered. Again, the tendency was most evident in the mean number of units of blood or blood product required by high-dose patients compared with placebo patients (mean, 2.9 versus 11.3 units). A similar trend was evident in the median number of units of blood or blood product required by these two groups (3 versus 6 units) (Table 2).
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Table 2. Efficacy Results in All Patients Less Than 17 Years of Age (Variable = Units of Donor Blood or Blood Product)
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An unexpected result was that fewer patients in the high-dose and low-dose groups than in the pump-prime and placebo groups required no blood whatsoever. However, a higher proportion of patients in the pump-prime and placebo groups required 5 or more units of blood. This suggests that fewer patients in the high-dose and low-dose groups had marked bleeding. When both blood and blood product were considered, again more patients in the pump-prime and placebo groups required no units, but fewer patients in the high-dose group required 20 or more units.
There was no difference between groups in volume of thoracic drainage. This was very unexpected, because in all other trials in the United States we have done—primarily involving adult patients—significant reductions in both thoracic drainage rates and total thoracic drainage volume occurred with aprotinin use.
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Patients requiring reoperations
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Only 7 patients required reoperation for diffuse bleeding. Two of these patients were in the high-dose group, 3 were in the low-dose group, and 2 were in the placebo group, so no aprotinin effect was apparent.
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Efficacy results in primary procedures versus reoperations
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Results with respect to need for blood or blood and blood product among just those patients undergoing primary procedures were very similar to the overall results among all patients. There was a slight trend toward less total thoracic drainage in high-dose patients than in placebo patients (mean, 204 versus 293 mL; median, 121 versus 266 mL), which may have clinical significance in a pediatric population.
A greater trend toward reduction of transfusion requirements with aprotinin use was observed among patients undergoing repeat procedures. This was most evident when considering need for units of both blood and blood product and number of patients requiring 20 or more units (Table 3). Aprotinin use showed no benefit with respect to mean volumes of thoracic drainage; in fact, thoracic drainage was unexplainably higher in the high-dose and low-dose groups than in the pump-prime and placebo groups.
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Table 3. Efficacy Results in All Redo Patients Less Than 17 Years of Age (Variable = Units of Donor Blood or Blood Product)
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Efficacy results in neonates and infants
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The 31 patients in this trial who were 1 year old or less mostly underwent primary operations, and as we have seen, aprotinin efficacy seems to be greater in redo patients. Our randomization procedure allotted only 3 patients in this subgroup to receive the high-dose regimen, which also may have distorted results. Looking only at units of donor blood required, more units were required by the high-dose group than by either the low-dose or placebo groups (mean, 5.7 versus 5.0 versus 3.7 mL). There was a trend toward benefit with aprotinin use with respect to requirements for both blood and blood product, but the trend was less marked in this age group than among older patients (Table 4). No patients in the high-dose or low-dose groups required more than 20 units of blood or blood product; this compares with 12.5% of the pump-prime patients and 16.7% of the placebo patients who required this unusually large amount of blood and blood product. Thoracic drainage again was unexplainably higher in the high-dose and low-dose patients than in the placebo patients. Most patients had drainage between 0 and 500 mL.
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Efficacy results excluding neonates and infants
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Among patients from 1 year through 16 years of age, results showed a trend toward reduced requirements for donor blood (Table 5) and, even more markedly, blood and blood product (Table 6) with aprotinin use. Aprotinin use similarly appeared to reduce the percentage of patients requiring large amounts of either blood or blood and blood product (see Tables 5, 6). No effect of aprotinin use on thoracic drainage was apparent.
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Table 5. Efficacy Results in All Patients Greater Than 1 and Less Than 17 Years of Age (Variable = Units of Donor Blood)
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Table 6. Efficacy Results in All Patients Greater Than 1 and Less Than 17 Years of Age (Variable = Units of Donor Blood or Blood Products)
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Safety
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Mortality in this pediatric population was quite small. Of the nine deaths that occurred, four occurred among patients receiving aprotinin and five occurred in the placebo group, suggesting no unfavorable trend with aprotinin use (Table 7).
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Summary
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The study results suggest a trend toward benefit with aprotinin use, as measured by requirements for blood and blood product, in patients who are more than 1 year of age. This benefit seems to be particularly present in patients undergoing a repeat operation rather than a primary sternotomy operation.
The question arises as to whether the parameters we looked at in this study are the appropriate ones to consider in a pediatric population. They are the parameters we looked at in all our large, controlled, multicenter trials in adults, predominantly in patients undergoing either primary or repeat coronary artery bypass grafting. In those populations, we invariably found aprotinin highly effective in reducing blood requirements at both high and low dose, although not when used as a pump prime. Aprotinin use also was always associated with significant reductions in thoracic drainage rates and total thoracic drainage volumes. This contrasts with the absence of any beneficial aprotinin effect on thoracic drainage in this study. Thus, in designing any future trials of aprotinin use in a pediatric population, consideration might be given to choosing parameters other than those traditionally used in adult populations.
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Discussion
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DR ERIC L. CEITHAML (Jacksonville, FL): I would like to know more about how patients were selected. In your primary operation group, were patients selected on the basis of certain diagnoses? Were they selected on the basis of complexity and expected length of cardiopulmonary bypass run?
Also, did you take into account other things that we as cardiac surgeons can do to reduce bleeding? We know that modified ultrafiltration will reduce bleeding in a pediatric pump population; was the use of this procedure accounted for? Was the possible use of fibrin glue accounted for?
DR CONIFF: Keep in mind that this was a compassionate-use protocol that was initiated before the drug became commercially available. The indication for enrolling patients was largely left to the discretion of the investigators. The only criteria required were that in their judgment (1) the patient was at increased risk for bleeding, whether because of type of procedure, condition of the patient, or whatever and (2) the procedure to be done required the use of cardiopulmonary bypass.
I want to make clear that, as I mentioned, this study was not designed in the same way that we ordinarily would design a pivotal trial. Our objectives were first of all to make the drug available to physicians who wanted to use it and only then to just get a feel for its effectiveness in indications that we had not formally examined. So, for example, although we ordinarily do not allow the use of fibrin glue in our adult studies because it confounds the data, its use was not taken into account in this study. Therefore, I fully agree that the data I presented are muddy, but they are all we have.
DR KAMAL POURMOJHADAM (Seattle, WA): I do not believe it is very helpful to group patients up to 17 years of age with neonates in the same study. Patients approaching 17 years of age may be pediatric patients in a legal sense, but not in a medical sense. Take the question of dosage, which was given per square meter. When you give a dosage per square meter to a neonate, you are giving much more than you would be giving to a 17-year-old boy with a body weight of 40 or 50 kg. So the dosages are not comparable between the low-weight and high-weight patients. You also need to take into account the dilution caused by the oxygenator, which is much higher in the small patients than it is in the other patients.
I also wonder how we can explain the extremely high blood losses and requirements for blood units, which are unusual in adult patients and, in my experience, very unusual in pediatric patients. So I think there are many questions that can be raised about these data.
DR CONIFF: I agree. I also agree that many patients who are 16 years of age are close to adult size, so they may behave physiologically more like adults than true pediatric patients. A cutoff at a younger age may be desirable in future studies.
DR CELIA C. D’ERRICO (Ann Arbor, MI): In establishing the safety of aprotinin in this population, it is very important to know whether the infant patients included patients in whom thrombosis might be particularly disadvantageous, or even catastrophic. For example, this would be the case in patients who had arterial switches or Norwood procedures, where shunt thrombosis might be devastating. Such patients constitute a very different group from patients undergoing ventricular septal defect closure or tetralogy repair. Do you have any information regarding the distribution of diagnoses or the procedures performed?
DR CONIFF: We do not have that information; patients were looked at as a total population. But I can tell you that the incidence of thrombotic events in the entire group was extremely low.
DR WULF DIETRICH (Munich, Germany): Do you know if there were patients with arterial switches and Norwood procedures included in the study?
DR CONIFF: There certainly were. Although there were some patients in the study undergoing fairly straightforward septal defect repair procedures, most patients underwent more complicated operations for very complex situations.
I want to mention that I looked very carefully at the incidence of a complete listing of side effects, and I found that there seemed to be fewer events than I was used to seeing in our large coronary artery bypass studies done in adult patients. Certainly there were very, very few thrombotic events.
DR WILLIAM J. GREELEY (Philadelphia, PA): To summarize some reactions to your data, the small treatment effects that were found indicate that in future studies larger numbers of patients are required to achieve appropriate power for analysis. Inclusion criteria have to be standardized, as well as adjusted for diagnoses and perhaps other risk factors for bleeding. And the great variation in drug metabolism between neonates and much older patients needs to be taken into consideration, perhaps by looking at total body water or other such factors.
This article has been cited by other articles:
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D. M. Arnold, D. A. Fergusson, A. K.C. Chan, R. J. Cook, G. A. Fraser, W. Lim, M. A. Blajchman, and D. J. Cook
Avoiding transfusions in children undergoing cardiac surgery: a meta-analysis of randomized trials of aprotinin.
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March 1, 2006;
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[Abstract]
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L. A. Gramlich and S. D. Barnes
Aprotinin Use in Pediatric Cardiac Surgery
Seminars in Cardiothoracic and Vascular Anesthesia,
March 1, 2001;
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117 - 121.
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Abstract
Introduction
