 |
 |
 |
|
| home | CME | help | feedback | subscriptions | archive |
|
© 1996 The Journal of Bone and Joint Surgery, Inc. The Effects of Recombinant Human Erythropoietin on Perioperative Transfusion Requirements in Patients Having a Major Orthopaedic Operation*  , MOORESVILLE, INDIANA Investigation performed at The Center for Hip and Knee Surgery, Mooresville
Two hundred patients who were scheduled for a major elective orthopaedic operation were enrolled in a prospective study and were randomly assigned to one of three treatment groups. Group 1 consisted of sixty patients who received recombinant human erythropoietin, 300 international units per kilogram of body weight per day; Group 2, seventy-one patients who received recombinant human erythropoietin, 100 international units per kilogram of body weight per day; and Group 3, sixty-nine patients who received a placebo. A total of fifteen doses was given subcutaneously, beginning ten days before the operation and extending through the fourth postoperative day. Patients who declined or were unable to donate autologous blood preoperatively were included in the study and were maintained on iron supplementation orally. The decision to transfuse red blood cells depended on the physician; however, physicians were encouraged not to do so if the hematocrit was more than 0.27 (27 per cent), unless the clinical symptoms warranted it. Of the 185 patients who were evaluable with regard to efficacy, significantly fewer patients received homologous red-blood-cell transfusions in Groups 1 and 2 (17 per cent [nine] and 25 per cent [sixteen], respectively) than in Group 3 (54 per cent [thirty-six]) (p < 0.001). When the patients were stratified into two groups on the basis of the pre-treatment hemoglobin level (more than 100 to 130 grams per liter or more than 130 grams per liter), we found that patients who had received a placebo and had a baseline hemoglobin level of more than 100 to 130 grams per liter were at significantly higher risk for transfusion (78 per cent [twenty-one]) than those who had received a placebo and had a baseline level of more than 130 grams per liter (36 per cent [fourteen]). For patients who had a baseline hemoglobin level of more than 100 to 130 grams per liter, the higher dose of recombinant human erythropoietin appeared somewhat more effective than the lower dose, with 14 per cent (three) of the patients in Group 1 and 39 per cent (nine) in Group 2 needing a transfusion; however, the difference was not significant (p = 0.09). For patients who had a baseline hemoglobin level of more than 130 grams per liter, the two doses of recombinant human erythropoietin produced similar results, with 14 per cent (four) of the patients in Group 1 and 11 per cent (four) in Group 2 needing a transfusion; this was in contrast to a rate of transfusion of 36 per cent (fourteen) in Group 3 (the patients who received the placebo) (p = 0.03). The recombinant human erythropoietin was generally well tolerated, although one patient, who did not have a history of hypertension, had an increase in blood pressure, from a baseline level of 142/78 millimeters of mercury (18.93/10.40 kilopascals) to a level of 220/100 millimeters of mercury (29.33/13.33 kilopascals), after ten days of treatment with the higher dose. These data suggest that recombinant human erythropoietin, administered before and after major orthopaedic operations, can minimize the need for homologous red-blood-cell transfusion.
Human erythropoietin is a glycoprotein hormone that is a physiological regulator of erythropoiesis. It is secreted primarily by the kidneys, with a minor hepatic contribution occurring under conditions of extreme hypoxia or severe hemorrhagic stress. Because erythropoietin is secreted by the kidneys and stimulation of receptor sites occurs in bone marrow, it is considered a true hormone. Recombinant human erythropoietin is produced commercially in the ovarian cells of Chinese hamsters, into which the gene for human erythropoietin has been inserted. Recombinant human erythropoietin is identical in amino-acid sequence to endogenous human erythropoietin, but variations may occur in the carbohydrate side-chains19. In the United States, recombinant human erythropoietin has been approved for use in the treatment of anemia associated with chronic renal failure, in patients who are being managed with zidovudine (azidothymidine [AZT]) for the human immunodeficiency virus, and in patients who are receiving chemotherapy for a non-myeloid malignant tumor. It is administered subcutaneously or intravenously. In the presence of adequate iron stores, recombinant human erythropoietin improves the quality of life of patients who have chronic renal failure and maintains the level of hemoglobin so that the need for homologous transfusion is decreased or eliminated1,4,6,13,14,16,20,22. Recently, much interest has arisen regarding the use of recombinant human erythropoietin perioperatively, particularly for the preparation of certain patient populations for elective procedures. These may include patients who are unwilling or unable to accept homologous or autologous blood transfusions2,5,7,8,17. Recombinant human erythropoietin may also be used to increase the efficacy of preoperative autologous deposit programs9-12,21,23,24. With these ideas in mind, a double-blind, placebo-controlled, randomized study was performed to evaluate the safety and efficacy of the perioperative use of recombinant human erythropoietin and its relationship to the use of blood during this period.
The recombinant human erythropoietin that was used in this study was produced by recombinant DNA technology and provided by The R. W. Johnson Pharmaceutical Research Institute and Ortho Biotech, Incorporated (Raritan, New Jersey). The study protocol was approved by each involved hospital's institutional review board, and the study was carried out under the auspices of members of the American Erythropoietin Study Group. All patients were thoroughly educated as to the possible risks and benefits of the study protocol, and all signed an informed-consent form. Two hundred patients were enrolled in a multicenter, double-blind study and were randomly assigned to one of three treatment groups. Sixty patients (Group 1) received recombinant human erythropoietin, 300 international units per kilogram of body weight per day; seventy-one patients (Group 2) received recombinant human erythropoietin, 100 international units per kilogram of body weight per day; and sixty-nine patients (Group 3) received a placebo. The study medication was administered for fifteen consecutive days, beginning ten days before the operation and extending through the day of the operation through the fourth postoperative day. The investigators were blinded with regard to the identity of the medication (recombinant human erythropoietin or placebo). The medication was administered subcutaneously by a registered nurse at the patient's home or at a designated study site. All patients received iron supplementation (FeSo4, 325 milligrams or the equivalent, three times per day) orally throughout the study. The patients participating in this trial were scheduled to have a major orthopaedic procedure in which transfusion of two units or more of whole blood or red blood cells is usually required during or after the procedure. The selection of patients was limited to those who could not or did not choose to donate autologous blood preoperatively. All patients were more than eighteen years old. The women had been postmenopausal for at least one year, were sterile, or were using a reliable method of birth control and had had a negative pregnancy test immediately before being enrolled in the study. Patients were excluded if they had a history of primary hematological disease, clinically important disease or dysfunction of other major organ systems, seizures, uncontrolled hypertension, or an active infectious or neoplastic disease, or if they were candidates for autologous blood donation. The pre-study evaluation included a medical history and physical examination performed by an internal medicine specialist. The pre-study laboratory tests included a complete blood-cell count with reticulocyte count, serum chemistry studies, urinalysis, and testing of stool for occult blood. Determinations of the levels of folate, vitamin B12, iron, total iron-binding capacity, ferritin, erythropoietin antibody, and serum erythropoietin were also performed. Vital signs were monitored throughout the study. Hematological testing, including a reticulocyte count, was performed before the medication was administered and on the seventh day of the study. Twenty-four hours before the operation, hematological testing, serum chemistry determinations, and urinalysis were again performed. Hematological evaluation was done on each postoperative day until the patient was discharged and again in the second or third and the third or fourth weeks after the operation. A second sample for determination of the serum erythropoietin level was obtained on the third postoperative day, and a second sample for serum antibody analysis was obtained in the third or fourth week. Energy was assessed with use of a visual-analog scale, starting on the third postoperative day and extending to the time of discharge. At the time of discharge, the patients again had a physical examination; urinalysis; hematological and serum chemistry tests; and determinations of the levels of iron, total iron-binding capacity, and ferritin. All patients were closely evaluated for any adverse events during the course of administration of the study drug. Intraoperative and postoperative blood transfusions were performed at the discretion of the surgeon; however, every effort was made to avoid transfusion if the hematocrit level was more than 0.27 (27 per cent), unless the clinical situation warranted it.
Statistical Methods Summaries and analyses of efficacy were based on the evaluable patients, defined as those who had received at least fourteen of fifteen doses of the study medication and had had the scheduled operation. Summaries and analyses of safety were based on all patients. All statistical tests were performed at the 0.05 level of significance; however, the investigator-by-treatment interaction was performed at the 0.10 level. No adjustments for multiple comparisons were made, and multiple comparisons may yield spurious significant differences18.
Demographic Characteristics
Efficacy
In both groups of patients who received recombinant human erythropoietin, a significantly lower percentage (p
In Groups 1 and 2 (the patients managed with recombinant human erythropoietin), 17 and 25 per cent (nine and sixteen patients), respectively, received a red-blood-cell transfusion (Table III). In contrast, in Group 3 (the patients who were managed with a placebo), more than half (54 per cent [thirty-six patients]) received a homologous blood transfusion during or after the operation. This difference between the two groups that received recombinant human erythropoietin and the placebo group was significant (p
The mean number of units (and standard deviation) transfused for each patient was 0.37 ± 0.96 in Group 1, 0.58 ± 1.15 in Group 2, and 1.42 ± 1.67 in Group 3. Significant differences (p < 0.01) were observed between the two groups managed with recombinant human erythropoietin and the group that received the placebo. The difference between Groups 1 and 2 was not significant (p > 0.05) (Table III).
The patients were stratified into three groups according to whether the baseline hemoglobin level was 100 grams per liter or less, more than 100 to 130 grams per liter, or more than 130 grams per liter. Too few patients had a baseline hemoglobin level of 100 grams per liter or less to allow assessment of the effect of recombinant human erythropoietin on red-blood-cell transfusion. In the group of patients who had a baseline hemoglobin level of more than 100 to 130 grams per liter, recombinant human erythropoietin significantly reduced the proportion who received a red-blood-cell transfusion compared with the proportion in the group that received the placebo (14 per cent [three] in Group 1, 39 per cent [nine] in Group 2, and 78 per cent [twenty-one] in Group 3) (p
An analysis was also performed with use of a modified intent-to-treat patient population, defined as all patients who had received any amount of the study medication and who had had the operation. This population comprised fifty-four patients in Group 1, sixty-seven in Group 2, and sixty-seven in Group 3. In these patients, the over-all prevalence of red-blood-cell transfusion was 17, 27, and 54 per cent (nine, eighteen, and thirty-six) for Groups 1, 2, and 3, respectively (p < 0.001 for the two groups of patients who received recombinant human erythropoietin compared with the group that received the placebo). For the patients who had a baseline hemoglobin level of more than 100 to 130 grams per liter, the prevalence of red-blood-cell transfusion was 14 per cent (three) for Group 1, 44 per cent (nine) for Group 2, and 78 per cent (twenty-one) for Group 3. The rate of transfusion was significantly lower (p < 0.001) in the two groups of patients who received recombinant human erythropoietin compared with the group that received the placebo. In addition, the higher dose of recombinant human erythropoietin was significantly better (p = 0.03) than the lower dose in reducing the rate of transfusion in the patients who had this baseline hemoglobin level. For the patients who had a baseline hemoglobin level of more than 130 grams per liter, the over-all prevalence of transfusion was 14, 11, and 36 per cent (four, five, and thirty-six) for Groups 1, 2, and 3, respectively (p = 0.02 over-all). These data support and provide additional evidence for the conclusion that the higher dose of recombinant human erythropoietin is superior to the lower dose for patients who have a baseline hemoglobin level of more than 100 to 130 grams per liter. Of the patients who received a transfusion, 56 per cent (thirty-four) had the first transfusion on the day of the operation and 44 per cent (twenty-seven), in the days after the operation. The primary criterion for transfusion at both of these time-periods was the hematocrit value. The mean postoperative hematocrit at which a transfusion was performed (the transfusion trigger) was similar for the three treatment groups (0.25 [25 per cent] in Group 1, 0.27 [27 per cent] in Group 2, and 0.25 [25 per cent] in Group 3). No precise data on the intraoperative hematocrit transfusion trigger are available. When the data on transfusion were summarized according to the operative procedure, the difference between the two groups of patients who received recombinant human erythropoietin and the group that received the placebo was generally the same, for each type of procedure, as the difference between the groups for all types of procedures combined (Table V). The use of intraoperative and postoperative reinfusion systems was allowed in all three groups. There was no appreciable difference, among the three groups, with regard to the use of red-blood-cell salvage devices and reinfusion devices (54 per cent [twenty-nine] for Group 1, 45 per cent [twenty-nine] for Group 2, and 48 per cent [thirty-two] for Group 3). The mean estimated intraoperative blood loss for each patient was also comparable among the three groups (300 milliliters in Group 1,400 milliliters in Group 2, and 350 milliliters in Group 3).
Hematological Parameters
The mean reticulocyte counts increased, between the initiation of the therapy and the time of the operation, in both groups of patients managed with recombinant human erythropoietin. In Group 1, the mean reticulocyte count increased from a baseline level of 0.016 (1.6 per cent) to 0.054 (5.4 per cent) before the operation. In Group 2, it increased from a mean of 0.015 (1.5 per cent) to 0.046 (4.6 per cent). In both groups, these levels remained elevated until the patients were discharged from the hospital. In the patients who received the placebo (Group 3), the mean reticulocyte count remained at 0.016 (1.6 per cent) until four days postoperatively, when a measurable elevation was seen. In all three groups, the reticulocyte count returned to the baseline level by the third or fourth week after the operation (Fig. 3). In Group 3, the mean serum erythropoietin level increased from a baseline level of twenty-six international units per liter to 112 international units per liter three days after the operation. Taken together, these data suggest that erythropoietic recovery was delayed after the operation in the patients who received the placebo, whereas those who were managed with recombinant human erythropoietin had, at the time of the operation, an activated marrow that allowed erythropoietic recovery during the early postoperative period.
With regard to the hemoglobin level, hematocrit, and reticulocyte count, the changes that occurred between the pre-study and preoperative evaluations were significantly more (p  0.0001) in the two groups of patients who received recombinant human erythropoietin than in the group that received the placebo. The mean reticulocyte count in Group 1 was also significantly higher than that in Group 2 (p = 0.02) on the day before the operation. No difference in the assessment of energy, according to the serial visual-analog scale, was noted among the three treatment groups between the third postoperative day and the time of discharge.
Safety
Thrombotic and vascular events, including myocardial infarction, angina, deep-vein thrombosis, superficial phlebitis, and peripheral arterial thrombosis, were specifically analyzed. These events may be associated with rapid increases in the hemoglobin level and the hematocrit and are of special concern in patients who are managed with recombinant human erythropoietin. The over-all prevalences of thrombotic and vascular events in the two groups of patients who received recombinant human erythropoietin were not significantly different from the rate in the patients who received the placebo (p = 0.40; 3 per cent [two] in Group 1, 4 per cent [three] in Group 2, and 9 per cent [six] in Group 3) (Table VII). In addition, analysis according to the time of the event in relation to the operation (preoperatively or postoperatively) revealed no significant differences (p = 0.40) among the treatment groups.
Administration of the study medication was discontinued prematurely because of an adverse event in twelve patients (six in Group 1, four in Group 2, and two in Group 3; p > 0.05 for the among-group comparison) (Table VIII). It is unlikely that these widely varied events were related to the medication. However, hypertension was noted in three patients who were managed with the higher dose of recombinant human erythropoietin. Two of these patients, who had a history of hypertension, had elevated blood pressure (180/100 and 210/110 millimeters of mercury [23.99/13.33 and 27.99/14.66 kilopascals]) before the medication was administered, making any relationship to the medication unlikely. The third patient had a history of hypertension but was not taking any antihypertensive medication before the administration of the erythropoietin was initiated. The hemoglobin level and blood pressure increased in this patient, from 140 grams per liter and 142/78 millimeters of mercury (18.93/10.40 kilopascals) at baseline to 155 grams per liter and 220/100 millimeters of mercury (29.33/13.33 kilopascals) after ten days of administration of recombinant human erythropoietin, suggesting that the development of hypertension may have been related to rapid expansion of the erythroid mass. The orthopaedic procedure for this patient was canceled because the size of a pre-existing abdominal aneurysm had increased, necessitating repair.
No patient had evidence of antibodies against recombinant human erythropoietin at the pre-study or post-study examination, although one patient in Group 1 had a positive antibody titer against some component of the recombinant human erythropoietin formulation at those examinations.
Recombinant human erythropoietin has been approved for use in patients who have anemia associated with chronic renal failure, those who are receiving zidovudine (azidothymidine [AZT]) for the human immunodeficiency virus, and those who are receiving chemotherapy for cancer. Only recently has consideration been given to the possible benefits of recombinant human erythropoietin in the perioperative period. Several anecdotal reports have outlined its use for the preoperative preparation of patients, such as Jehovah's Witnesses, who refuse red-blood-cell transfusions2,5,7,8,17. In such patients, non-standardized dose schedules, derived from schedules used for patients who have chronic anemia, were implemented for four to six weeks preoperatively. More recently, controlled studies of the perioperative use of recombinant human erythropoietin demonstrated that the hormone may reduce the number of homologous red-blood-cell transfusions that are necessary during and after extensive cardiac procedures12,22,24. In a study by the Canadian Orthopedic Perioperative Erythropoietin Study Group3, recombinant human erythropoietin reduced perioperative transfusion requirements in patients who had a hip replacement. These investigators used a dose schedule of 300 international units per kilogram of body weight; the medication was administered beginning ten or five days before the operation and extending three days postoperatively. The rate of patients who needed a homologous red-blood-cell transfusion was 23 per cent in the patients who received recombinant human erythropoietin for fourteen days and 30 per cent in those who received it for nine days, compared with 44 per cent in the patients who received a placebo. Therapy with recombinant human erythropoietin was well tolerated in that study. In the current study, a single duration of therapy (fifteen days) was employed; however, the dose of recombinant human erythropoietin varied among groups. In both groups of patients who received recombinant human erythropoietin, the mean hemoglobin values rose throughout the ten-day preoperative period (by six and five grams per liter in Groups 1 and 2, respectively), whereas in the patients who received the placebo it declined five grams per liter. No hemoglobin values rose rapidly enough to necessitate phlebotomy preoperatively. The mean preoperative reticulocyte counts also rose substantially in both groups of patients who received recombinant human erythropoietin compared with the group that received the placebo (by 0.038 [3.8 percentage points], 0.031 [3.1 percentage points], and 0.000 [0.0 percentage point] in Groups 1, 2, and 3, respectively).
Of particular interest is the decrease in the rate of homologous transfusion in the two groups managed with recombinant human erythropoietin, compared with the rate in the group that received the placebo (17, 25, and 54 per cent [nine, sixteen, and thirty-six] in Groups 1, 2, and 3, respectively). These values in both Group 1 and Group 2 were significantly different from the value in Group 3 (p The recombinant human erythropoietin was well tolerated during the trial. There was no difference, with regard to the over-all rate of thrombotic or vascular events, between the patients who received recombinant human erythropoietin and those who received the placebo. However, in one patient who was managed with the higher dose of recombinant human erythropoietin, the blood pressure increased from 142/78 to 220/100 millimeters of mercury (18.93/10.40 to 29.33/13.33 kilopascals) after ten days of therapy. This increase in blood pressure in association with an increase in hemoglobin (from 140 to 155 grams per liter) suggests that a rapid increase in the erythroid mass may occasionally lead to hypertension, even if there is no history of hypertension. Thus, patients who are receiving recombinant human erythropoietin need to be carefully monitored and followed for evidence of hypertension. Possible sources of error in our study protocol include the fact that the investigators were not blinded with regard to the patient's preoperative reticulocyte count. If elevation of the reticulocyte count was a consideration in the decision to perform a transfusion, then bias favoring non-transfusion might have occurred in the two groups of patients receiving recombinant human erythropoietin. Blinding with regard to the reticulocyte count and the hemoglobin level was performed by the Canadian Orthopedic Perioperative Erythropoietin Study Group3; however, the results were very similar to those in the current study, suggesting that this was not a major problem. In summary, recombinant human erythropoietin was a safe adjunct in the preoperative preparation of patients scheduled for an elective orthopaedic procedure who may have needed a transfusion. The prevalence of transfusion in the over-all series of patients was decreased by approximately 50 per cent in association with therapy with recombinant human erythropoietin. The baseline hemoglobin level was a good indicator for identification of the risk of transfusion and the benefit that the patient would receive from the medication. The optimum dose may vary according to the patient's initial hemoglobin level. Patients who have a low baseline hemoglobin level may need a higher dose of recombinant human erythropoietin, whereas those who have a higher baseline level can receive a lower dose. Further evaluation of recombinant human erythropoietin is warranted, in order to define better its optimum role as a perioperative adjuvant to reduce the risk of exposure to homologous transfusion. Such studies should particularly be done in combination with the use of other blood-sparing modalities, such as autologous pre-deposit, normovolemic hemodilution, and red-blood-cell salvage procedures.
*Although none of the authors have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article, benefits have been or will be received but are directed solely to a research fund, foundation, educational institution, or other non-profit organization with which one or more of the authors are associated. Funds were received in total or partial support of the research or clinical study presented in this article. The funding source was the R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey.
  CiteULike  Connotea  Del.icio.us  Facebook  Technorati  Twitter What's this?
This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Top
Abstract
Introduction
| home | CME | help | feedback | subscriptions | archive | site index |
|
Stanford University Libraries' HighWire Press (TM) assists in the publication of JBJS Online. |