Recombinant Human Erythropoietin Utilization in Department of Veterans Affairs Dialysis Units

Recombinant Human Erythropoietin Utilization in Department of Veterans Affairs Dialysis Units Marsha Wolfson, MD, Diane J. Mundt, PhD, and Gerald G. Hawley, RN, MSN • This study was carried out to determine the use of recombinant human erythropoietin (rHuEPO) in the Veterans Affairs dialysis program and any strategies being carried out to enhance its effectiveness. The data were collected from a survey that was conducted using a questionnaire sent to all Veterans Affairs dialysis programs. The survey included all patients treated with hemodialysis or peritoneal dialysis for at least 3 months and who were receiving rHuEPO for at least 3 months. Patient diagnosis, age, length of time of dialysis, mode of dialysis, length of rHuEPO treatment, route of administration, assessment of iron stores, use of iron supplementation, and use of androgens were assessed by this questionnaire and analyzed for their effect on dose required to achieve a target hematocrit. Subcutaneous administration resulted in a significantly lower dose requirement compared with the dose required when rHuEPO was administered intravenously. Concomitant use of androgens resulted in a lower dose requirement for rHuEPO when it was given intravenously, but not when rHuEPO was given subcutaneously. The dose required to maintain the hematocrit at the designated level appeared to increase with time of treatment. This is a US government work. There are no restrictions on its use. INDEX WORDS: Recombinant human erythropoietin; utilization; anemia of renal failure; dialysis.

T

HE AVAILABILITY of recombinant human erythropoietin (rHuEPO) represents a major advance in the management of the anemia of renal failure. t - 3 Since being approved by the Food and Drug Administration, its use has increased; the cost of treating patients with endstage renal disease has also increased. The Department of Veterans Affairs (VA) noted a 63% increase in expenditures for rHuEPO between fiscal years 1990 and 1991. In fiscal year 1992, expenditures for this drug exceeded $9.1 million. This was a 24% increase over 1991, despite a reduction in unit cost of rHuEPO. However, few details regarding rHuEPO use in this large number of patients were available. The VA was especially interested in determining whether the route of administration (subcutaneous [SQ] v intravenous [IV]) resulted in any reduction in the dose required to maintain a desired hematocrit level. Other treatment modalities, such as concomitant androgen administration and iron supplementation with monitoring of iron stores, were also evaluated for their potential impact in reducing the dose of rHuEPO required to achieve a target hematocrit. All VA dialysis programs From The National Center for Cost Containment, Department of Veterans Affairs, Milwaukee, WI. Received September 30, 1993; accepted in revised form March 25, 1994. Address reprint requests to Marsha Wolfson, MD, Nephrology Section 111-C, Portland VA Medical Center, 3710 SW US Veterans Hospital Rd, PO Box 1034, Portland, OR 97207. This is a US government work. There are no restrictions on its use. 0272-6386/94/2402-0004$0.00/0 184

were surveyed to determine the clinical and economic efficacy of rHuEPO in the VA dialysis population. Patient-specific rHuEPO usage, dosage, and demographic information were requested from each dialysis site. MATERIALS AND METHODS A survey instrument (Appendix) was developed by a technical advisory committee consisting of physicians and nurses specializing in the care of dialysis patients, a hematologist, and a project manager from the VA National Center for Cost Containment. Patients were eligible for inclusion in the survey if they had been receiving continuous peritoneal or hemodialysis treatment for at least 3 months and were also receiving rHuEPO continuously for 3 or more months as of April 30, 1992. The survey included patient demographics and information on the type of dialysis, the route of administration of rHuEPO, the dose and frequency of administration, and the number of blood transfusions administered. The level of hematocrit targeted, as well as the initial and achieved hematocrit were requested for each patient. The survey tool also included the use of other treatment modalities and parameters that could potentially decrease the rHuEPO dosage requirement, such as iron supplementation, the state of the patients' iron stores, and concomitant androgen administration. The underlying cause of renal disease as well as other co-morbid conditions also were obtained. The survey instrument was sent to all 57 VA hospitals that had dialysis programs and to 25 VA satellite dialysis units and was completed by either a physician associated with the dialysis program or a designee. The results of the survey were tabulated by the VA National Center for Cost Containment. There were 1,054 unique patients for whom data were collected. Patient data were omitted from the analysis if the data records were incomplete (n = 39). At least 3 months and up to 6 months of data were collected for each patient. Data collected in the fourth month contained the largest single sample size in the survey (n = 812). Data were therefore analyzed for both month 4 and for those patients for whom the fulI 6 months of data were available (n = 605). There were no differences in the findings from the

American Journal of Kidney Diseases, Vol 24, No 2 (August), 1994: pp 184-191

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185

patients in the month 4 sample compared with those 605 patients for whom there were data for the entire 6 months. Data were analyzed by Student's I-test and ANOVA as appropriate. Statistical significance was defined as P < 0.05.

RESULTS

Sixty-nine of 82 dialysis programs (84%) responded to the survey, which supplied complete information on 1,015 maintenance dialysis patients who received rHuEPO according to the established criteria. Nine hundred nine patients surveyed (90%) were treated with maintenance hemodialysis and 106 were treated with peritoneal dialysis. The VA treated 2,890 dialysis patients annually as of March 31, 1992, and the centers submitting eligible patient record data provided dialysis to 2,514 patients, which represents 87% of the total active VA end-stage renal disease patient population. Patient demographic data and primary diagnoses for end-stage renal disease are shown in Tables 1 and 2. Ninety-seven percent of the patients were male, reflecting the preponderance of males in the veteran population. The average age of the patients was 61 years and 39% of patients were between 60 and 69 years of age. The two most prevalent underlying causes of renal disease reported were diabetes (28% of patients) and hypertension (25%). Overall, 52% of the dialysis patients were treated with rHuEPO in VA dialysis centers reTable 1. Demographic Characteristics of 1,015 Patients Seen in Veterans Administration Facilities for Dialysis Type of dialysis Hemodialysis Peritoneal dialysis Sex Females Males Age (yr) Not reported

<30 30-39 40-49 50-59 60-69 70-79 80-84 ~85

Average age (yr)

SO

909 (90%) 106 (10%) 27(3%) 988 (97%) 8(1%) 14 (1%) 60(6%) 147 (14%) 166 (16%) 394 (39%) 196 (19%) 22(2%) 8(1%) 60.5 12.5

Table 2. Primary Diagnoses of 1,015 Patients Seen in Veterans Administration Facilities for Dialysis

Primary diagnoses Diabetes Hypertension Unknown Glomerulonephritis Other, urologic Polycystic kidney disease Interstitial nephritis Pyelonephritis Other urologic

N

Percent Total

284 253 182 132 39 32 22 8 63

28 25 18 13 4 3 2 1 6

sponding to the survey. This is in contrast to 83% of patients receiving rHuEPO in community dialysis centers.4 The number of patients treated with rHuEPO varied widely among the individual dialysis programs, ranging from 100% to less than 10%. There was no correlation between the number of patients treated with rHuEPO in an individual dialysis program and the number of patients on dialysis in that program. No differences were found in the results of the statistical analyses when the data were expressed as either number of units per kilogram per week or total number of units per week. There also was no correlation between body weight and rHuEPO dose. There was a very small but significant difference in kilogram body weight between the patients who received rHuEPO via the SQ route compared with those who received it via the IV route (76 ± 15 kg v 73 ± 17 kg; P < 0.05). Data are presented as number of units per kilogram per week to be consistent with prior publications and recommended dosing schedules, and to correct the dose for patient weight. Tables 3 to 5 summarize the effect of several possible strategies that might decrease the dose required to achieve a target hematocrit. These strategies included the route of administration, the monitoring of iron stores, the provision of iron supplementation, and the concomitant use of androgen therapy. Because transfusion requirements might have affected the rHuEPO dose, patients who received red blood cell transfusions were analyzed as a separate group. Hemodialysis patients who never received blood transfusions were given the drug an average

186

WOLFSON, MUNDT, AND HAWLEY

Table 3. Comparison of Mean Dose of Recombinant Human Erythropoietin Adjusted for Weight by Transfusion Status, Stratified for Mode of Dialysis and Route of Administration N

Subgroup

Hemodialysis-IV Transfusion No transfusion Hemodialysis-Sa Transfusion No transfusion Continuous ambulatory peritoneal dialysis Transfusion No transfusion

Mean Dose ± SD (U/kg/wk)

Probability Value

116 478

171 ± 96 134 ± 82

<0.01

44 250

151 ± 110 103 ± 73

<0.01

9 84

146 ± 115 91 ± 73

<0.01

of 2.8 times per week via the IV route and 2.4 times per week via the SQ route (P < 0.01). The dose by route ofrHuEPO administration (SQ v IV) was evaluated among those patients receiving packed red blood cell transfusions and among those receiving no transfusions. Using data from month 4 of data collection, hemodialysis patients who were never transfused and received the drug via the IV route required a 23% higher dose compared with those receiving rHuEPO SQ (134 ± 82 U/kg/wk IV v 103 ± 73 U/kg/wk SQ; P < 0.001; Table 3). There were no significant differences in the average hematocrit prior to the use of rHuEPO (23.6% IV v 24.5% SQ), the hematocrit achieved in data collected from month 4 (29.9% IV v 29.6% SQ), or in the target hematocrit (31.0% IV v 31.3% SQ). In patients for whom data were obtained for the entire 6-month period, the total weekly dose averaged 137 ± 83 U/kg/wk in the 338 hemodialysis patients who never required transfusions and received rHuEPO IV and 99 ± 65 U/kg/wk for the 146 hemodialysis patients who never required a blood transfusion and who received rHuEPO SQ (P < 0.01). Over the entire 6-month survey period, in patients who received at least

one red blood cell transfusion during the survey period, the SQ dose was significantly lower than the IV dose (173 ± 102 U/kg/wk IV v 121 ± 45 U /kg/wk SQ; P < 0.01). Again, there were no differences in average hematocrit, achieved hematocrit, or target hematocrit prior to EPO administration. The majority of patients had iron stores assessed, either by measuring the percent saturation of iron binding protein or by measurement of serum ferritin concentrations. However, 10% of the patients had no reported assessment of iron stores. Eighty-five percent of patients were given some form of iron supplementation, most often via the oral route. This is perhaps because IV iron was not commercially available during the period of the survey. The rHuEPO dose was significantly lower for those patients who were given the drug SQ compared with the dose when given IV, whether or not the serum ferritin levels were greater or less than 100 ng/mL (Table 4). Whether use of androgens affected the rHuEPO dosage was also assessed (Table 5). Seventy-three patients (9%) were given androgen supplementation as well as rHuEPO. Almost all patients received androgens intramuscularly. Nontrans-

Table 4. Effect of Iron Supplementation and Serum Ferritin Levels on Dose by Route of Administration Subgroup

IV Iron Iron

sa

Iron Iron

N

Mean Dose ± SD (U/kg/wk)

+ ferritin>

100 ng/mL

219 136

135 ± 85 141 ± 82

+ ferritin>

100 ng/mL

110 66

104 ± 65 110 ± 71

+ ferritin < 100 ng/mL + ferritin < 100 ng/mL

• By ANOVA, by route of administration.

Probability Value'

<0.001

187

ERYTHROPOIETIN UTILIZATION Table 5. Comparison of Mean Dose of Recombinant Human Erythropoietin Adjusted for Weight and Stratified by Androgen Therapy, Transfusion Status, and Route of Administration

Subgroup

No transfusion-IV Androgen No androgen No transfusion-Sa Androgen No androgen Transfusion-IV Androgen No androgen Transfusion-Sa Androgen No androgen

N

Mean Dose ± SD (U/kg/wk)

Probability Value

49 374

118 ± 76 139 ± 83

0.04

7 230

107 ± 72 105 ± 74

0.47

15 88

132 ± 77 178 ± 100

0.05

2 40

265 ± 99 146 ± 109

0.07

fused patients receiving rHuEPO IV with androgen therapy required a lower dose to achieve the target hematocrit compared with patients receiving rHuEPO IV who were not given androgens (Table 5). This was true also for IV rHuEPO patients who received transfusions during the survey period (Table 5). However, androgens did not have an effect on the rHuEPO dose in patients receiving the drug SQ (Table 5). Red blood cell transfusions were required at some point in 173 of the 1,015 patients. A significantly greater proportion (19%) of patients receiving IV rHuEPO required at least one blood transfusion compared with 14% of patients receiving SQ rHuEPO (P < 0.05). The reasons provided for blood transfusions, when given (n = 15), were usually acute or chronic gastrointestinal bleeding. All patients who received at least one red blood cell transfusion required higher doses of rHuEPO compared with patients who never needed a blood transfusion. Among patients who received red blood cell transfusions, there was no significant difference in the dose given IV compared with SQ for data collected in month 4 (P < 0.14). The mode of dialysis treatment was evaluated to determine whether this had an effect on rHuEPO requirements. In month 4, there was a tendency for the dose to be lower in patients on continuous ambulatory peritoneal dialysis who never received a transfusion compared with SQ hemodialysis patients who never received a

transfusion (91 ± 61 U/kg/wk v 103 ± 73 U/kg/ wk; P = 0.08). Whether length of treatment with rHuEPO affected the dose requirement was also evaluated. Hemodialysis patients who did not require transfusions and who received rHuEPO SQ for 6 to 12 months and for 12 to 24 months prior to data collection required lower doses compared with similar patients who received rHuEPO for 3 to 6 months (95 ± 66 and 87 ± 67 v 123 ± 55; P < 0.01). However, there also was an increase in the SQ rHuEPO requirements over time, as the dose increased again to 128 ± 94 U/kg/wk for patients treated for more than 24 months (P < 0.01). Target hematocrit values were unchanged over the course of the study. No increase in dose after 24 months was observed in patients given rHuEPO IV who did not require blood transfusions. The achieved hematocrit level at the end of month 4 and the dose administered were also analyzed (Table 6). In patients who had never been transfused and who received rHuEPO IV, the weekly dose was inversely related to the achieved hematocrit level. The highest doses of rHuEPO were given to patients with the lowest hematocrit and lower doses were given to those patients with higher hematocrit. In those patients who were given rHuEPO SQ and never received a transfusion, there was no correlation between the dose given and the hematocrit level. There also was no correlation between dose and hematocrit in transfused patients independent of route of administration. This lack of correlation between dose and hematocrit in the patients given rHuEPO SQ may be due to the smaller range of doses used in the SQ group compared with the range of doses administered IV (500 to 10,000 U SQ v 500 to 14,000 U IV). Certain patient characteristics also were evaluated to determine whether any of these had an impact on dose requirements. There was a significant difference in dose requirement based on age in those hemodialysis patients who did not require transfusions and who were given rHuEPO SQ. Patients less than 40 years of age (N = 15) required a significantly higher dose of rHuEPO than those in any other age group (151 ± 60 U / kg/wk; P < 0.04 as compared with older patients), although both target and achieved hematocrits were similar in all patient groups. In the patients

188

WOLFSON, MUNDT, AND HAWLEY Table 6. Comparison of Mean Dose of Recombinant Human Erythropoietin Adjusted for Weight by Achieved Hematocrit, Stratified by Mode of Dialysis, Route of Administration, and Transfusion Status Subgroup

Hemodialysis-IV No transfusion

Hemodialysis-Sa No transfusion

Hemodialysis-IV Transfusion

Hemodialysis-Sa Transfusion

Mean Dose ± SD (U/kg/wk)

Achieved Hematocrit

N

::0;23 >23-25 >25-28 >28-32 >32

15 49 89 180 145

202 ± 181 ± 138 ± 130 ± 114 ±

80 112 71 81 67

::0;23 >23-25 >25-28 >28-32 >32

19 16 55 100 60

117 ± 102 ± 118 ± 94 ± 101 ±

96 54 94 60 66

0.29

::0;23 >23-25 >25-28 >28-32 >32

25 15 33 28 15

196 190 158 160 158

± 105 ± 118 ± 77 ± 103 ± 78

0.49

::0;23 >23-25 >25-28 >28-32 >32

8 15 13 11 7

117 148 175 171 117

± ± ± ± ±

0.67

given rHuEPO IV, there was a tendency, not significant, for the highest dose to be administered to those patients younger than 40 years (147 ± 87 U/kg/wk; P < 0.16). Dose requirements in patients with diabetes mellitus were not different from those of patients without diabetes in all patient groups. The length oftime patients were on dialysis also did not affect rHuEPO dose requirements. DISCUSSION

Recombinant human erythropoietin represents a major advance in the management of the anemia of renal failure,I-3 However, this treatment is very costly. Between fiscal years 1991 and 1992, the VA noted a 63% increase in expenditures for rHuEPO, and the cost to the VA is approaching $10 million per year. The means of reducing costs should be examined. Several recent studies5-7 suggest that the drug may be more efficacious when administered via the SQ compared with the IV route. In pharmacologic studies ofrHuEPO, the SQ route resulted in lower blood levels but a longer duration of effective

50 42 146 143 32

Probability Value

<0.01

blood concentration. 5.6 Lim et al studied predialysis patients and demonstrated that the dose was lower when the drug was given SQ compared with IV.7 However, concern that the dose requirement may decrease over time independent of the route of administration and complaints by patients of discomfort with SQ injection 8 have led to resistance on the part of some caregivers to administer the drug SQ and of patients to accept SQ administration. The present survey was carried out to determine whether, in a large number of patients treated in a routine clinical setting, there were differences in the dose required to achieve a target hematocrit based on the route of administration. In this survey, 84% of VA dialysis programs responded, making it likely that the survey is representative of the overall VA dialysis population. This survey, unlike previous studies,5,7 included patients who were already stabilized on a specific dosing regimen. Thus, it is unlikely that dose requirements were changing during the period of observation. Sixty-seven percent of the patients in this survey received the drug IV, despite

ERYTHROPOIETIN UTILIZATION

published data suggesting that the SQ route is more efficacious. 5- 7 Those patients who received rHuEPO via the SQ route required 23% to 29% less drug compared patients with who received the drug IV with no significant difference in achieved hematocrit. These data confirm the findings of the earlier studies. 5-7 Other information also was gained from this survey. Although the survey excluded patients not treated with rHuEPO, the patients surveyed were very similar to the dialysis population of the United States as reported by the US Renal Data System for 1991,9 with the exception that the majority of the VA patients were male. Thus, it is likely that the findings from this study may be generally attributable to dialysis patients everywhere. There was a notable difference in rHuEPO utilization in the VA population compared with patients treated in community dialysis programs. Only 52% of VA patients were treated with rHuEPO compared with 83% of hemodialysis patients treated in the private sector. 4 The reasons for this discrepancy in rHuEPO utilization is not clear from the survey data. Since the survey did not include patients who did not receive rHuEPO, it is not possible to determine how the anemia of renal failure was managed in these latter patients. This survey also provided information on the effect of several strategies that might affect the dose required to achieve and maintain a target hematocrit. The use of iron administration and the monitoring of iron stores were assessed by the survey questionnaire. There were no differences in weekly dose based on iron stores or supplementation in patients given rHuEPO. This is difficult to explain. However, it is perhaps because the survey analyzed dose in relation to ferritin levels rather than percent of iron saturation, which may better reflect available iron stores. Alternatively, it may be due to the cross-sectional nature of the survey. Patients who were given iron supplementation generally received it orally. This is probably because availability of injectable iron was limited during the survey period. However, iron was not administered to 15% of the patients. Since adequate body iron stores are needed for optimum response to rHuEPO, it might be expected that most patients would require iron supplementation after 3 months of rHuEPO treatments. 10.1 1 As almost all patients

189

(90%) had routine assessment of iron stores, it is possible that those patients not treated with iron had evidence of iron overload, which is a consequence of repeated blood transfusions. 12 Adequate iron stores are clearly necessary for an optimum response to rHuEPO and although this survey failed to demonstrate the importance of adequate iron stores on dose, it should not be concluded that iron stores are not important in the dose response to rHuEPO. Androgen therapy was used in a small percentage of patients surveyed. Concomitant androgen treatment did result in a reduced rHuEPO dose in patients who received rHuEPO IV, but did not result in any differences in the required rHuEPO dose with SQ administration. Androgen administration improves the anemia of renal failure in most patients with native kidneys, but generally is not effective in patients who have undergone bilateral nephrectomy. 12-14 However, there are potentially serious adverse effects from its use, including virilization, which limits their use in females and children. 12.15 Although there is a report that androgens may potentiate the effect oflow-dose rHuEPO therapy on the anemia of renal failure, 16 the potential for adverse effects should be considered before instituting androgen therapy. Since, in the present survey, the SQ dose was not reduced by androgen therapy, androgens should probably not be used to treat anemia in patients who are given rHuEPO SQ. It is possible that androgens also should not be used to treat anemia of renal failure with IV rHuEPO, since the patients are exposed to additional risks from androgens when either an increased dose of rHuEPO or a switch to SQ administration would accomplish the same end. It may be that the 48% of VA patients not in this survey are receiving androgens. If so, consideration of the adverse effects should be made, even in patients who respond to androgens and are believed to not require rHuEPO. Not surprisingly, patients who required blood transfusions required higher doses of rHuEPO. The data also demonstrated that for patients on hemodialysis given rHuEPO IV, there was an inverse relationship between hematocrit achieved and dose required. However, this was not seen in the hemodialysis patients receiving SQ rHuEPO. This relationship also was not seen in patients who required transfusions, regardless of the route

190

of administration. The reason for this lack of relationship in the nontransfused patients given SQ rHuEPO is not clear from these survey data. The range of doses when rHuEPO was given SQ was smaller than the range of doses administered by the IV route (data not shown). It is possible that smaller doses were used in the SQ group because of difficulty in administering large doses into the skin. No data are available from this survey on the length of time needed to achieve a target hematocrit. However, the response to rHuEPO with regard to length of time patients were receiving the drug was analyzed. There were no differences in dose among patients who received rHuEPO IV from 3 to 6, 6 to 12, 12 to 24, or longer than 24 months. However, in patients who were given rHuEPO SQ, the dose decreased after 6 months of treatment. It increased again in patients treated for longer than 24 months. Thus, it appears that over long time periods, the dose requirement may increase. This is in contrast to the study by Lim et al in predialysis patients7 in which the dose decreased after patients were switched from IV therapy to SQ therapy and continued to decline despite the fact that in the latter months of the study, rHuEPO was only administered once weekly. It is possible that the dose increase after 24 months in the present survey is due to the development of iron deficiency, but this cannot be determined from the survey. Other variables that might affect the rHuEPO dose were examined. These included age, length and type of dialysis, and presence of diabetes. Since all peritoneal dialysis patients were given rHuEPO via the SQ route, they were compared with hemodialysis patients given SQ rHuEPO. Despite the blood loss associated with hemodialysis, there was no difference in dose required in the hemodialysis patients when compared with patients treated with peritoneal dialysis. These data lend further support to the conclusion that the SQ route is more efficacious than the IV route. The rHuEPO requirement according to patient age was evaluated. There were no differences in dose requirements according to age in the hemodialysis patients who were not transfused and who received IV rHuEPO. In the patients who were never transfused and received rHuEPO SQ, age over 40 years was associated with a significantly lower dose. The reason for this finding is

WOLFSON, MUNDT, AND HAWLEY

not clear from the survey. The elderly appear to have decreased hematopoiesis. 17 Studies of the use of rHuEPO in the elderly suggest a greater requirement with advanced age, 17.18 although this is controversial. 19 In the present survey, patients who were under 40 years of age required higher doses, but this was a very small group of patients. No other studies have described a higher requirement in younger patients. This survey provides information on the routine utilization of rHuEPO in a large number of patients treated in VA dialysis programs. Hemodialysis patients given rHuEPO via the SQ route required a dose that was 23% to 29% lower than hemodialysis patients given the drug IV. These data support other studies that were much smaller in scale. It is likely that the response of the patients in this survey is very similar to the response of patients in most other clinical settings. Thus, it is reasonable to conclude that the administration of rHuEPO would be most efficacious when given via the SQ route. However, this report represents the results of a survey, not a study. A prospective, controlled trial examining this question should be performed. APPENDIX: SURVEY INSTRUMENT Name of VA Medical Center: Station no. : Total no. of hemodialysis patients receiving rHuEPO: Total no. of peritoneal dialysis patients receiving rHuEPO: Patient social security no. (last four digits, eg, H2031): Date of birth (eg, 6/9/91): Sex (0 = female, I = male): Date of dialysis initiation (eg, 4/12/91): Date epogen administration initiated (eg, 10/1/91): Patient hematocrit prior to initiating rHuEPO: Target hematocrit: As of April 30, 1992, identify the following: Primary diagnosis (DXLS) Co-morbid condition I Co-morbid condition 2 Co-morbid condition 3 Co-morbid condition 4 Hemodialysis (yes, no): Peritoneal dialysis (yes, no): For the duration of the study period, identify the following: Iron measured as percent saturation (yes, no): Iron supplementation (yes, no): Type of iron supplementation (oral or IV): Ferritin level measured (yes, no): Ferritin level maintained> 100 ng/mL (yes, no): Serum aluminum level measured (yes, no): Elevated serum aluminum level controlled with deferoxamine (DFO) (yes, no): Androgen supplementation (yes, no):

ERYTHROPOIETIN UTILIZATION

Androgen supplementation type (oral or intramuscularly): Monthly data collection (November 1991 through April 1992) rHuEPO dose (units) as measured on last day of month route of administration (IV, SQ) Number of doses per week (eg, I, 2) Hematocrit percent achieved as measured on last day of month Patient dry weight (kilogram) as measured on last day of month Number of transfusion units required during month (eg, 0, 1,3)

ACKNOWLEDGMENT The authors express their gratitude to Mary T. Bates and Frances L. Vosburg, Data Analysts, National Center for Cost Containment, Milwaukee, WI, for administrative and technical support and to Dr Sandford Krantz for his helpful suggestions regarding the manuscript. They also thank all the Medical Directors and staff of the Department of Veterans Affairs Dialysis Centers who responded to the survey and without whom this work could not have been accomplished.

REFERENCES I. Mohini R: Clinical efficacy of recombinant human erythropoietin in hemodialysis patients. Semin Nephrol 9:1621. 1989 (suppl I) 2. Eschbach JW. Abdulhadi MH. Browne JK, Delano BG, Downing MR. Egrie JC, Evans RW, Friedman EA, Graber SE, Haley NR, Korbet S. Krantz SB, Lundin AP, Nissenson AR. Ogden DA, Paganini EP, Rader B, Rutsky EA. Stivelman J, Stone WJ, Teschan P. Van Stone JC, Van Wyck DB, Zuckerman K. Adamson JW: Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter trial. Ann Intern Med III :992-1000, 1989 3. Carbide S: Anemia and erythropoietin in hemodialysis and continuous ambulatory peritoneal dialysis. Kidney Int 43:S-11-S-119. 1993 4. Greer JW: Erythropoietin use by dialysis modality. J Am Soc Nephrol 3:425, 1992 (abstr) 5. Besarab A, Flaharty KK. Erslev AH. McCrea JB. Vlasses BH. Medina F, Caro J, Morris E: Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: The case for subcutaneous administration. J Am Soc NephroI2:1405-1416. 1992 6. Kampf 0, Eckardt KU, Fischer HC, Schmalisch C, Ehmer B, Schostak M: Pharmacokinetics of recombinant human

191 erythropoietin in dialysis patients after single and multiple subcutaneous administration. Nephron 61 :393-398. 1992 7. Lim VS. Kirchner PT. Fangman J, Richmond J, Degowin RL: The safety and efficiency of maintenance therapy of recombinant human erythropoietin in patients with renal insufficiency. Am J Kidney Dis 14:496-506, 1989 8. Granolleras C, LeskopfW, Shaldon S, Fourcade J: Experience of pain after subcutaneous administration of different preparations of recombinant human erythropoietin: A randomized. double-blind crossover study. Clin Nephrol 36:294298, 1991 9. US Renal Data System, USRDS 1991 Annual Data Report: Bethesda, MD. The National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases, 1991 10. Van Wyck DB: Iron deficiency in patients with diaiysisassociated anemia during erythropoietin replacement therapy: Strategies for assessment and management. Semin Nephrol 9:21-24. 19,1989 (suppI2) II. Van Wyck DB, Stivelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA: Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 35:712-716, 1989 12. Watson AJ: Adverse effects of therapy for the correction of the anemia in hemodialysis patients. Semin Nephrol 9:3034, 1989 (suppl I) 13. Shahidi NT: Androgens and erythropoiesis. N Engl J Med 289:72-80, 1973 14. Neff MS, Goldberg J, Slifkin FR, Eiser AR, Calamia V, Kaplan M, Baez A, Gupra S, Mattoo N: A comparison of androgens for anemia in patients on hemodialysis. N Engl J Med 304:871-875. 1981 15. Hendler ED. Goffinet SA. Ross S, Longnecker RE, Bakovic V: Controlled study of androgen therapy in anemia of patients on maintenance hemodialysis. N Engl J Med 291: 1046-1051,1974 16. Ballal SH, Domoto DT, Polack DC, Marciulonis P. Martin KJ: Androgens potentiate the effects of erythropoietin in the treatment of anemia of end-stage renal disease. Am J Kidney Dis 17:29-33, 1991 17. Lipschitz DA. Udupa KB. Milton KY, Thompson CO: Effect of age on hematopoiesis in man. Blood 63:502-509, 1984 18. Udupa KB. Lipschitz DA: Erythropoiesis in the aged mouse: I. Response to stimulation in vivo. J Lab Clin Med 103:574-580, 1984 19. Shank WA. Balducci L: Recombinant hematopoietic growth factors: Comparative hematopoietic response in younger and older subjects. J Am Geriatr Soc 40: 151-154, 1992