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Ann Thorac Surg 1997;64:1686-1693
© 1997 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Effect of Recombinant Human Erythropoietin on Transfusion Risk in Coronary Bypass Patients

Cardiac Anesthesia Group, Massachusetts General Hospital, Boston, Massachusetts; Division of Cardiac Surgery, Cedar-Sinai Medical Center, Los Angeles, California; Department of Medicine, Maine Medical Center, South Portland, Maine; Department of Surgery, Baylor College of Medicine and Veterans Administration Medical Center, Houston, Texas; Division of Hematology, Robert Wood Johnson Medical School, New Brunswick, New Jersey; Department of Surgery, Ritter Heart Institute at the Toledo Hospital, Toledo, Ohio; Center for Aging, University of Alabama Medical Center, Birmingham, Alabama; Blood Transfusion Services, University of Massachusetts Medical Center, Worcester, Massachusetts; Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; and The Robert Wood Johnson Pharmaceutical Research Institute, Raritan, New Jersey

Accepted for publication May 28, 1997.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Patients having a cardiac operation frequently require allogeneic blood transfusions despite surgical blood-conservation techniques. Recombinant human erythropoietin (Epoetin alfa) may augment this conservation by stimulating erythropoiesis. The safety and efficacy of perioperative use of Epoetin alfa to reduce the need of allogeneic transfusion was studied.

Methods. A multicenter double-blind, placebo-controlled, parallel-group study involved 182 patients having coronary artery bypass grafting and randomized to receive Epoetin alfa (300 or 150 IU/kg) or placebo subcutaneously for 5 days before, on the day of, and for 2 days after operation.

Results. Perioperative Epoetin alfa resulted in greater increases in baseline to preoperative hemoglobin levels and hematocrit (300 IU/kg) and in presurgery to postsurgical day 1 reticulocyte counts versus placebo (p 0.05). However, there was no significant difference in transfusion requirements. Incidences of adverse events were similar in all study groups.

Conclusions. Lower incidences of allogeneic blood exposure were observed in both Epoetin alfa–treated groups; however, the differences between all treatment groups were not significant. This was probably due to the relatively short 5-day preoperative course of Epoetin alfa therapy. There were no significant differences between the three groups relative to safety. Epoetin alfa was well tolerated in this population.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Modern blood-conservation techniques, including preoperative autologous blood donation, have resulted in marked reductions in the number of units of allogeneic blood transfused into patients undergoing cardiac surgical procedures [1, 2]. This accomplishment has important implications for reducing surgical morbidity caused by the risks of allogeneic blood transfusion [3]. However, participation rates in cardiac surgery preoperative autologous blood donation programs have declined for logistic reasons, costs, and increasing patient complexity [4]. Despite technical advances, many patients still require 2 to 3 units of blood before hospital discharge, often as a result of low (ie, <25%) hematocrit (HCT) secondary to surgical blood loss [5, 6]. Transfusion-related complications such as immunosuppression, increased rates of postoperative infection, infectious disease transmission, graft-versus-host disease, longer hospitalizations, and febrile reactions continue to occur in patients undergoing cardiac surgical procedures and in other clinical settings [3, 7].

For editorial comment, see page 1579.

Recombinant human erythropoietin (Epoetin alfa) stimulates red blood cell (RBC) production in the bone marrow and increases the hemoglobin (Hb) level, HCT, and reticulocyte count in experimental animals and humans. Epoetin alfa induces reticulocytosis within 4 days after the initiation of therapy in normal human volunteers, provided adequate iron stores are available to support increased Hb synthesis [8]. Recent studies have also demonstrated that Epoetin alfa can increase the HCT in patients with depressed erythropoiesis [9–11], can augment collection of preoperative autologous blood donation [12], and can reduce allogeneic blood exposure without such preoperative donation [13, 14].

When cardiac operations are performed on an elective basis, adequate time exists for preoperative administration of Epoetin alfa. Perioperative administration of this substance can therefore be expected to increase Hb levels, thereby alleviating anemia secondary to surgical blood loss and reducing or eliminating allogeneic RBC transfusion [15, 16]. This report describes the safety and efficacy of perioperative Epoetin alfa in reducing the need of allogeneic blood transfusion in patients undergoing coronary artery bypass grafting (CABG).

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
One hundred eighty-two patients scheduled for major elective CABG were enrolled at nine study sites in the United States between November 1988 and December 1990. Patients 18 years old or older scheduled for initial or repeat CABG were eligible. Female patients were required to have been postmenopausal for 1 year or more, to be surgically sterile, or to have had a negative pregnancy test and to have been using a reliable method of birth control. Patients were excluded from the study for the following reasons: HCT greater than 45%; clinically significant laboratory abnormalities or diseases or dysfunction of the nervous, pulmonary, endocrine, gastrointestinal, or genitourinary systems; a history of primary hematologic disease, seizures, or uncontrolled hypertension (diastolic blood pressure 100 mm Hg); congestive heart failure (New York Heart Association class III or IV); clinically significant ongoing blood loss; drug or alcohol abuse within the past 2 years; peripheral vascular disease; medical conditions or therapies known to interfere with erythropoiesis; scheduled valve replacement; or lactation. Patients were also ineligible if they had received a blood transfusion or androgen therapy or had participated in an experimental study within the previous month. Attempts were made to exclude patients with iron deficiency (eg, serum ferritin level < 20 ng/mL, total iron-binding capacity > 360 µg/dL, and serum iron to total iron-binding capacity ratio < 16%). All patients provided written informed consent.

Study Design
The study was a multicenter, double-blind, randomized, parallel-group study. Participating investigators and centers were monitored throughout the duration of the study to ensure accurate, reliable, and verifiable data. The study was approved by the investigational review board of each institution taking part in the trial. Patients were registered centrally, stratified by center, and randomized before scheduled operation to receive either Epoetin alfa or placebo on the basis of a computer-generated randomization code. Patients who dropped out of the study were not replaced.

Treatment
Epoetin alfa, provided by the Robert Wood Johnson Pharmaceutical Research Institute, was administered by subcutaneous injection according to the treatment regimen to which patients were assigned. Patients received either 300 or 150 IU/kg of Epoetin alfa or the equivalent volume of placebo for 5 consecutive days before operation, on the day of CABG, and for 2 days after operation. A total of eight doses was to be administered. Identity of study medication was blinded, but the volume administered was not blinded to the investigators. Epoetin alfa was formulated to contain 10,000 IU/mL in diluent containing 2.5 mg/mL of human serum albumin and was supplied in vials containing approximately 1.1 mL of solution. Investigators were provided labeled study medication and dosing supplies for each patient. Study medications were administered by study personnel or visiting nurses. In addition, patients received oral iron supplements, 325 mg, three times a day as soon as possible preoperatively and continuing throughout the treatment period. The investigators used a policy not to transfuse patients with an HCT value greater than 24% after CABG unless clinically indicated.

Clinical Evaluations
Baseline history, physical examination, and laboratory screening including hematology (complete blood count with white blood cell differential, reticulocyte count, HCT, Hb, and platelet count), serum chemistry, urinalysis, erythropoietin (EPO) antibody titers, endogenous EPO levels, and iron store variables (ferritin and serum iron) were performed within 7 days of administration of the first dose of study medication. A baseline body weight was obtained to calculate the daily total volume of study medication. Vital signs (sitting systolic and diastolic blood pressure, pulse rate, respiratory rate, and oral temperature) and adverse events were monitored before each dose of study medication. Preoperative laboratory evaluations (within 24 hours of the scheduled operation) consisted of hematology, serum chemistry, and urinalysis. Hematology was repeated daily after CABG until discharge. Serum chemistry, urinalysis, complete physical examination, and measurement of iron store variables were also performed 1 day before discharge.

The number of units of allogeneic blood (ie, whole blood and packed RBCs) transfused was recorded daily starting on the day of operation. The patient's energy level was measured daily beginning on postoperative day 3 until 1 day before discharge. The energy-assessment tool consisted of a 100-mm unmarked visual analogue scale on which the patients were asked to indicate, with a line, a rating of their energy level on the day of assessment.

Follow-up after discharge included patient contacts by a visiting nurse 2 to 3 and 3 to 4 weeks after CABG for complete blood count, reticulocyte count, and serum EPO levels. The final patient contact was made 1 month after hospital discharge for a serum EPO antibody titer and EPO level. Adverse events were classified according to the NOVA dictionary of adverse event terms based on the International Classification of Diseases [17] and COSTART adverse event terminology [18].

Erythropoietin Antibody Titers and Serum Levels
Measurements of serum EPO antibody titers were performed using an enzyme-linked immunosorbent assay for detection of EPO in human serum [19]. The protocol included screening for the presence of EPO antibodies, confirmation of any suspected positive samples, and titration of EPO antibodies in confirmed positive samples. Serum EPO concentrations were determined with a modified competitive-binding radioimmunoassay. The assay had a normal range of 2.5 to 32 mU/mL and did not discriminate between endogenous and recombinant-derived EPO [19].

Statistical Analysis
The primary efficacy variable was the proportion of patients given a transfusion. The number of allogeneic units of RBCs transfused and the changes in Hb, HCT, and reticulocyte count from baseline to preoperative, preoperative to postoperative day 1, and postoperative day 1 to discharge were analyzed as secondary efficacy variables.

The Cochran-Mantel-Haenszel rank test (eg, stratified by investigator) was used to test for differences between treatments in the primary efficacy variable. The number of RBC units transfused and the changes in Hb, HCT, and reticulocyte count were analyzed using a two-way analysis of variance with treatment and investigator as factors; the investigator-by-treatment factor was dropped if it was not significant. For these analyses, including investigator as a stratifying variable, the investigators with fewer than 9 patients were combined into one group. A linear model analysis with treatment and investigator as factors was performed to examine mean changes in hematologic response over various time intervals.

Efficacy analyses were based on evaluable patients, ie, patients who had their scheduled operation and received at least seven doses of study medication. Because only those patients who actually underwent CABG were at risk for blood transfusions, an intent-to-treat analysis was conducted to confirm the results based on evaluable patients. The between-group differences in demographics, baseline characteristics, and patient disposition were assessed using all patients. Safety summaries were based on all patients.

All statistical tests were performed at the 0.05 level of significance, except tests of the investigator-by-treatment interaction, which were performed at the 0.10 level. Pairwise tests were performed only if there was an overall significant difference between treatment groups. No further adjustments for multiple comparisons were made.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
The study enrolled 182 patients (63 = 300 IU/kg Epoetin alfa, 63 = 150 IU/kg Epoetin alfa, and 56 = placebo). Of those, 171 (94.0%; 59 = 300 IU/kg Epoetin alfa, 60 = 150 IU/kg Epoetin alfa, and 52 = placebo) were evaluable for efficacy. Demographic and baseline characteristics of the participants are presented in Table 1. The mean age of the overall study group was 62 years, 89% of the participants were male, and 94% were scheduled for a primary CABG procedure. The majority of patients (90.7%) were not iron deficient at the time of baseline measurements and appeared to be hematologically normal (mean HCT, 41.4%). There were no significant differences between the three treatment groups in regard to any of the demographic or baseline variables (p > 0.05).

There were no significant differences reported by investigators between treatment groups in regard to the mean estimated blood loss per patient (300 IU/kg Epoetin alfa = 694 mL, 150 IU/kg Epoetin alfa = 732 mL, and placebo = 805 mL) or the proportion of patients who received intraoperative or postoperative blood salvage products (300 IU/kg Epoetin alfa = 95%, 150 IU/kg Epoetin alfa = 93%, and placebo = 92%).

Transfusion Data
Transfusion data for the cohort of patients evaluable for efficacy are summarized in Table 2. A lower proportion of patients treated with Epoetin alfa (300 IU/kg = 32.2%, and 150 IU/kg = 28.3%) than patients given a placebo (48.1%) were exposed to allogeneic blood transfusions (Fig 1), but the difference was not significant (p = 0.068). There were no significant differences between treatment groups in the mean number of allogeneic units transfused per patient (300 IU/kg Epoetin alfa = 1.37 ± 2.78 units, 150 IU/kg Epoetin alfa = 1.72 ± 3.64 units, and placebo = 1.33 ± 2.01 units; p > 0.05). No significant investigator effects were noted for the mean units of blood transfused per patient (p > 0.05), and no treatment-by-investigator interaction (p > 0.10) was detected.

View larger version (46K): [in this window] [in a new window]   Fig 1. . Percentage of patients receiving transfusion (p = 0.068).

Hematologic Variables
In general, the Hb level and HCT responses during the study paralleled each other, with little change from baseline to before the operation, followed by an initial decrease, and then a subsequent steady rise postoperatively to the time of discharge (Table 3; Figs 2, 3). The postoperative mean Hb and HCT levels were higher in the Epoetin alfa groups than in the placebo group. The reticulocyte counts increased in the Epoetin alfa groups before CABG and continued to increase until 2 days or 7 days after operation in the 150 IU/kg and 300 IU/kg groups, respectively; the reticulocyte count in the placebo group increased only after operation (Fig 4).

View larger version (28K): [in this window] [in a new window]   Fig 2. . Mean changes in hemoglobin levels over time.

View larger version (27K): [in this window] [in a new window]   Fig 3. . Mean changes in hematocrit over time.

View larger version (28K): [in this window] [in a new window]   Fig 4. . Mean changes in reticulocyte counts over time.

There was a significant (p 0.05) within-treatment group decrease in Hb and HCT from the preoperative to postoperative day 1 measurements, which was similar between groups (p > 0.05). However, reticulocyte counts rose in both Epoetin alfa–treated groups (300 IU/kg = 0.73% and 150 IU/kg = 0.69%), whereas the count decreased over this same period in the placebo group (-0.17%); the reticulocyte count changes in both Epoetin alfa treatment groups differed significantly from the charge in the placebo-treated group (p 0.05).

During the remainder of the study, postoperative day 1 to discharge, the positive changes in Hb and HCT were somewhat larger among Epoetin alfa–treated than placebo–treated patients, although there were no significant differences between treatment groups (p > 0.05). There were significant (p 0.05) within-group changes in reticulocyte count for all three treatment groups, with the change in the 150 IU/kg Epoetin alfa treatment group (1.37%) differing significantly from both the 300 IU/kg Epoetin alfa (2.84%) and the placebo treatment (2.72%) groups.

Energy Assessment
There were no differences between the three groups in response to the visual analogue energy assessment. Daily improvements were seen in all treatment groups after operation to the day of discharge (300 IU/kg Epoetin alfa = 32.7 ± 21.4 to 64.3 ± 18.1, 150 IU/kg Epoetin alfa = 33.3 ± 22.0 to 63.8 ± 22.3, and placebo = 33.7 ± 24.7 to 66.1 ± 18.3). These data suggest that patients recovered functional capacity at equal rates in each treatment group.

Erythropoietin Levels and Antibody Titers
Baseline and preoperative endogenous EPO levels were within the preestablished normal range (7.0 to 31 mU/mL); the preoperative mean EPO level was 32.8 ± 23.4 mU/mL. As shown in Figure 5, there was a small increase in the EPO levels between the baseline and the preoperative samples in the placebo group (n = 18). The postoperative daily endogenous EPO levels measured in the placebo group increased significantly compared with the preoperative values, reached a peak by postoperative day 3 (184.8 ± 227.7 mU/mL), and then declined (final EPO measurement at 3 to 4 weeks, 54.6 ± 24.8 mU/mL). Therefore, the ability to increase serum EPO levels in response to acute anemia is retained in CABG patients. However, the reticulocyte count in placebo-treated patients did not increase higher than baseline until postoperative day 3, a finding indicating that accelerated replacement of RBCs was delayed for a few days postoperatively in this treatment group.

View larger version (41K): [in this window] [in a new window]   Fig 5. . Effect of cardiopulmonary bypass on endogenous erythropoietin (EPO) production in placebo group demonstrates a significant and sustained elevation of EPO levels after operation with a maximum level at 3 days. Data are shown as the mean ± the standard deviation.

Time to Discharge
All treatment groups had similar postoperative lengths of stay. There were no significant differences in the mean time to discharge after CABG (300 IU/kg Epoetin alfa = 13.3 ± 28.7 days, 150 IU/kg Epoetin alfa = 12.1 ± 10.2 days, and placebo = 10.9 ± 6.2 days; p > 0.05).

Iron Stores
There were significant (p 0.05) within-group changes from baseline to the last measurement for serum iron (300 IU/kg Epoetin alfa = 76.9 to 52.5 µg/dL, 150 IU/kg Epoetin alfa = 86.1 to 42.9 µg/dL, and placebo = 80.9 to 37.2 µg/dL), ferritin (300 IU/kg Epoetin alfa = 218.49 to 359.49 ng/mL, 150 IU/kg Epoetin alfa = 209.38 to 382.96 ng/mL, and placebo = 170.68 to 341.95 ng/mL), and total iron-binding capacity (300 IU/kg Epoetin alfa = 309.73 to 236.82 µg/dL, 150 IU/kg Epoetin alfa = 319.91 to 245.66 µg/dL, and placebo = 319.12 to 239.02 µg/dL). There were no between-group differences.

Adverse Events
Adverse events were reported by 62 (98.4%) of the 63 300 IU/kg Epoetin alfa–treated patients, all 63 (100%) of the 150 IU/kg Epoetin alfa–treated patients, and 55 (98.2%) of the 56 placebo-treated patients during the study. Comparison of either Epoetin alfa treatment group (or both groups combined) with the placebo treatment group revealed no significant differences in the proportion of patients reporting any adverse experience. Adverse events reported by at least 20% of the patients in any treatment group are summarized in Table 4.

Three of the other 6 patients who sustained serious or unexpected adverse experiences (3 = 300 IU/kg Epoetin alfa, 2 = 150 IU/kg Epoetin alfa, and 1 = placebo) were discontinued from therapy prematurely. Cerebral vascular accidents occurred in 3 patients (1 in each treatment group). A total of 45 patients (18 [28.6%] = 300 IU/kg Epoetin alfa, 11 [17.5%] = 150 IU/kg Epoetin alfa, and 16 [28.6%] = placebo) were identified as having experienced thrombotic or vascular events during the study. In 3, 6, and 5 patients, the event occurred before operation in the 300 IU/kg, 150 IU/kg, and placebo groups, respectively; 15, 5, and 11 patients, respectively, had a thrombotic event after CABG. The incidence of thrombotic events was not significantly different between groups (overall, before operation, or after operation).

Seven patients (3 = 300 IU/kg Epoetin alfa and 4 = 150 IU/kg Epoetin alfa) died during the study or within 2 months of discontinuation of double-blind therapy, and two patients in the 300 IU/kg treatment group died more than 3 months after operation (3.5 and 7 months). No death was characterized by the investigators as being related to the study medication. Of the seven deaths during the study, two in the 150 IU/kg Epoetin alfa group were related to intercurrent infectious episodes, ie, sepsis and cytomegalovirus. The remaining five deaths were considered to be possibly drug related for the purpose of determining the incidence of mortality (5 [4.0%] of 126 Epoetin alfa–treated patients). This incidence is similar to that for CABG in the published literature [20]. It should also be noted that four of these five deaths were related to thrombotic or vascular events, and one death was related to acute renal failure. There was no significant difference in the incidence of deaths in the combined Epoetin alfa treatment groups compared with the placebo group (p = 0.06).

There were no significant differences between treatment groups in any of the clinical laboratory data. No between-group changes in systolic or diastolic blood pressure over the course of the study were reported. Both the systolic and diastolic blood pressures declined perioperatively, possibly from postsurgical hypovolemia and low HCT. The decline in systolic pressure was less pronounced than that in diastolic pressure.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of perioperative Epoetin alfa in reducing operative and postoperative transfusion requirements in patients undergoing elective CABG. Treatment with Epoetin alfa, 300 or 150 IU/kg given subcutaneously daily for 8 days, beginning 5 days before the scheduled operation, did not significantly reduce either the proportion of patients requiring a transfusion or the mean number of units of blood transfused per patient compared with placebo treatment. Among the patients evaluable for efficacy, a lower proportion of Epoetin alfa–treated patients (300 IU/kg = 32.2% and 150 IU/kg = 28.3%) than placebo-treated patients (48.1%) required allogeneic blood transfusions, although the difference was not significant (p = 0.068).

The changes in hematologic variables over different periods of the study were expected. The preoperative to postoperative day 1 decline in Hb and HCT was similar between treatment groups (p > 0.05). However, Epoetin alfa–treated patients experienced a rise in reticulocyte counts over this period, whereas placebo-treated patients experienced a decline (p 0.05). During the remainder of the study (postoperative day 1 to discharge), both groups of Epoetin alfa–treated patients experienced rises in Hb and HCT that, although yielding no overall significant difference between groups, were somewhat greater than those observed for placebo-treated patients.

There are several possible reasons this study failed to detect a significant benefit associated with Epoetin alfa therapy. One reason was the relatively short preoperative course of this therapy, which produced only a minor erythropoietic response. The Epoetin alfa regimen selected for investigation was intended to stimulate erythropoiesis but at the same time avoid an excessive rate of rise of Hb and HCT. This strategy was based on a theoretic concern that rapidly rising Hb and HCT would compromise coronary blood flow. However, the practice of rapidly increasing HCT before operation to a value of 50% or greater with Epoetin alfa was subsequently shown to be safe in patients undergoing cardiac surgical procedures [15]. The dose–response relationship between Epoetin alfa treatment and hematologic response [16] suggests that future studies should also evaluate the safety and efficacy of alternative Epoetin alfa treatment regimens [21]. Recently, Goldberg and colleagues [14] reported the safety and efficacy of a weekly Epoetin alfa regimen comprising 600 IU/kg once weekly for 3 weeks before the operation and on the day of operation.

Increasing the cumulative exposure to Epoetin alfa can be accomplished by administration of higher doses, a longer treatment period, or a combination of both. However, preoperative treatment regimens for CABG patients must be carefully designed. In the United States, a growing number of individuals are expeditiously moved from catheterization to operation. This practice may reduce the number of patients with sufficient preoperative time for Epoetin alfa treatment. Parenteral administration of iron enhances the response to Epoetin alfa [12] and may offset the effects of a reduced preoperative interval. Another option is to evaluate whether extending the duration of postoperative Epoetin alfa therapy and iron supplementation would have an impact on the need of postoperative transfusion.

Another reason Epoetin alfa failed to demonstrate a significant benefit may relate to the relatively high proportion of men enrolled in this investigation. The study population had a male to female ratio of 8:1, which exceeds that previously reported for CABG operations in epidemiologic studies [19]. Men undergoing CABG have been shown to be less likely than women to require transfusions [5]. Our study included too few patients to have adequate power to detect a significant sex-related benefit for Epoetin alfa; however, a retrospective analysis of our data suggests a lower need of transfusion among men and a greater potential benefit of Epoetin alfa in women. Transfusions were administered to 100% of the 8 women who received the placebo versus 39% of the placebo-treated men. Among the Epoetin alfa–treated patients, allogeneic transfusions were administered to 55% of the women versus 28% of the men.

The difference between men and women in transfusion requirement and Epoetin alfa response may reflect sex-related differences in baseline Hb levels. Therefore, future studies are indicated to examine the impact of surrogate markers that identify patients undergoing CABG who are at risk of needing allogeneic blood transfusions and the effect of Epoetin alfa administration in those individuals. Recently, de Andrade and co-workers [13] reported that pretreatment Hb level is an important predictor of transfusion risk and that patients who benefited most from perioperative Epoetin alfa had a pretreatment Hb level greater than 10 but less than or equal to 13 g/dL. In addition, Sowade and associates [21] reported that Epoetin beta was most beneficial in patients with a perioperative blood loss of higher than 750 mL, in those with a baseline HCT lower than 42%, and in those 60 years of age or older.

Previous open-label studies [15, 16] of perioperative Epoetin alfa use in cardiac surgical patients have not demonstrated that therapy increases the risk of complications. In the present study, there were no significant differences in the incidence of adverse events between the two Epoetin alfa–treated groups and the placebo-treated group. The overall incidences of death and myocardial infarction were consistent with those noted in other large series [19, 22]. Examination of the causes and the time of death among the Epoetin alfa–treated patients decreases some of the concern that Epoetin alfa treatment results in excessive mortality. Two of the deaths occurred 3 months or more after CABG and can be excluded from the perioperative mortality rate calculation. Further, the investigators determined that none of the other patient deaths were caused by Epoetin alfa and that the absence of deaths in the placebo-treated patients was unexpected and may be an anomaly. Still, the overall perioperative mortality rate among patients receiving active therapy was 4.0% (5/126 patients), which is comparable with that reported by Hannan and colleagues [22]. Further investigation to confirm the safety of Epoetin alfa is necessary before its use can be recommended in CABG patients as standard care.

In conclusion, a lower incidence of exposure to allogeneic blood transfusions was observed in both Epoetin alfa–treated groups than in the placebo-treated group, but the differences between treatment groups were not significant. The reduction in allogeneic transfusions was observed despite a relatively minor hematologic response to Epoetin alfa therapy, the latter possibly the result of the short preoperative exposure (5 days) to Epoetin alfa. The treatment regimen and the route of administration were well tolerated in this patient population with no increase in adverse experiences compared with placebo treatment.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This research study (H87-083) was supported in part by grants from The R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ, and Rowland Foundation, Cambridge, MA. We thank Dr Alan Zaslavsky for his help with the statistical analysis, Dr and Mrs Edwin Land for their kindness and moral support throughout the conduct of this study, and Drs M. C. Badonnel and D. Elfath for their skillful assistance. Finally, we recognize the late Dr Donald C. Finlayson for his valuable assistance and insight.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr D'Ambra, Department of Anesthesiology, Massachusetts General Hospital, Fruit St, Boston, MA 02114-2696.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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