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Ann Thorac Surg 1997;64:1579-1580
© 1997 The Society of Thoracic Surgeons
Departments of Medicine, Pathology, and Surgery, Washington University School of Medicine, St. Louis, Missouri
Nearly 7 years ago, several investigators described the use of recombinant human erythropoietin (EPO) therapy in patients undergoing cardiothoracic operations [1–3], making this new method of blood conservation a promising advance toward the goal of minimizing allogeneic blood exposure for patients in this setting [4]. Indeed, EPO therapy has subsequently been approved for use in the perioperative setting for patients undergoing autologous blood donation in Japan, the European Union, and Canada, and for use as adjuvant therapy (without autologous blood) in anemic (hematocrit 
39%) patients undergoing major surgical procedures in Canada [5]. In the United States, however, approval for EPO therapy in the surgical setting is limited to use as adjuvant therapy in anemic patients who undergo noncardiac, nonvascular surgical procedures. In this issue of The Annals of Thoracic Surgery, D'Ambra and colleagues [6] report the results of a multicenter United States study of adjuvant EPO therapy in patients undergoing coronary artery bypass grafting. Using an 8-day regimen of EPO (300 U/kg or 150 U/kg subcutaneously) beginning 5 days before the operation, D'Ambra and colleagues conclude that although the EPO-treated patients demonstrated reticulocyte responses and increased levels of hematocrit when compared with placebo-treated patients, the difference in percentage of patients exposed to allogeneic blood in the placebo group (48%) compared with EPO patients (32% and 28% at 300 U/kg and 150 U/kg, respectively) was not statistically significant (p = 0.068) using a statistical test that stratifies the data by investigator. Testing the difference between the combined EPO groups and the placebo patients using Fisher's exact test gives a statistically significant p = 0.037 (Table 1
). The EPO 150 U/kg cohort shows a benefit with EPO therapy even when patients who discontinued the study because of adverse events are taken into account.
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This study provides an opportunity to learn more about the proper use of EPO therapy in the surgical setting. The first lesson is that the time frame for an optimal response to preoperative EPO therapy is longer than 5 days. Clinical trials of adjuvant EPO therapy in orthopedic surgery demonstrated that 14-day regimens (300 U/kg per day) beginning 9 days before the operation are effective at reducing allogeneic blood transfusions [7, 8]. A recent study suggests that the best way to use EPO may be in larger (600 U/kg) weekly doses, beginning 1 month before the operation [9]. However, preoperative intervals of 9 to 30 days in patients undergoing coronary artery bypass grafting are uncommon in the United States. A second lesson is that patients need to be selected for EPO therapy based on their likelihood of requiring transfusion. As D'Ambra and associates point out, their patients were mostly men scheduled for first-time coronary artery bypass grafting procedures, and only 39% of this cohort in the placebo group received allogeneic blood. Female patients, patients with initial hematocrit levels of 39% or less, and patients undergoing repeat operations or complex procedures benefit most from blood conservation strategies [10, 11].
Another important issue is that for EPO therapy to be most effective, it should be coupled with an autologous blood procurement strategy. In the current study, the EPO-treated (150 U/kg) patients had a 28% likelihood of allogeneic blood exposure, which is an unimpressive advance toward the goal of a bloodless operation, particularly when the cost of EPO (150 U/kg) therapy for a 70-kg patient approximates $1,000 over a 9-day interval. This problem also exists in the clinical trials of adjuvant EPO therapy in patients undergoing orthopedic joint replacement operations, in which 17% to 29% of EPO-treated patients were exposed to allogeneic blood [7, 12]. These transfusion outcomes are comparable with results reported nearly 10 years ago in patients who underwent routine autologous blood predeposit alone before orthopedic [13] and cardiac [14] operations. A recent European study of coronary artery bypass grafting surgical patients reported that the use of EPO (500 U/kg for five subcutaneous doses over 14 day), coupled with isovolemic hemodilution, was associated with an allogeneic exposure rate of only 11%, compared with 53% of placebo patients [15]. This reduction in allogeneic exposure is important clinically, and serves to illustrate how autologous blood procurement strategies and pharmacologic agents such as EPO can be used in tandem to take advantage of their individual benefits.
An unresolved question is the issue of safety for EPO therapy in cardiac surgery patients. The European trial [15] found no differences in mortality, thrombotic events, or serious adverse events among their 76 patients, and no differences in hemostatic parameters in their patients during the 14-day preoperative interval in which increased levels of hematocrit (42 ± 3% to 48 ± 3%) were demonstrated [16]. In fact, the investigators in the European trial were able to demonstrate that EPO-treated patients had improved extractable oxygen perioperatively, when compared with placebo-treated patients, that was also associated with a lower incidence of lactate acidosis in the EPO-treated patients [17]. However, although the present study [6] concludes that no differences in adverse events between EPO and placebo-treated patients were observed and that EPO therapy was well-tolerated, the description of adverse events and moralities in this report indicates that an uneven distribution of these events between the placebo and the EPO-treated groups cannot be ruled out to any degree of certainty. For example, given the cohort sizes in this study, even if the true mortality rate was 0% in the placebo group and 6% in the combined EPO groups, the probability is only 0.229 that the resulting data would produce a statistically significant p less than 0.05.
What is the current role of EPO therapy in cardiac surgery, particularly for the United States, in which cardiac and vascular operations are excluded as an indication for its use? This approach remains a valuable tool for patients with special requirements, such as Jehovah's Witness patients for whom blood transfusion is not an option [3]. Future trials of EPO therapy in cardiac operations in other countries will be helpful in providing additional information on the safety of EPO therapy in this setting. Until additional safety data are forthcoming, the off-label use of EPO in patients undergoing cardiac or vascular operations in the United States cannot be recommended.
In the meantime, for routine cardiac operations, a careful discussion of the risks of blood and the benefits of blood conservation needs to take place between patients and cardiothoracic surgeons and anesthesiologists. If patients really do want to minimize their likelihood of requiring allogeneic blood during their operation, then physicians should be prepared to alter their current practices: this would include a delay in the surgical date for the many procedures that really are elective, so that the use of oral iron supplementation has time for its effect, as well as the use of techniques such as "blood pooling" to take advantage of the higher preoperative hematocrit levels [18, 19].
Footnotes
Address reprint requests to Dr Goodnough, Division of Laboratory Medicine, Washington University School of Medicine, Box 8118, 660 S Euclid Ave, St. Louis, MO 63110-1093 (e-mail: goodnough{at}labmed.wustl.edu).
References
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  V. Alexi-Meskishvili, S. Ovroutski, I. Dahnert, and T. Fischer Correction of cor triatriatum sinistrum in a Jehovah's Witness infant Eur. J. Cardiothorac. Surg., December 1, 2000; 18(6): 724 - 726. [Abstract] [Full Text] [PDF]
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