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Effect of an intravenous iron dextran regimen on iron stores, hemoglobin, and erythropoietin requirements in hemodialysis patients
Effect of an Intravenous Iron Dextran Regimen on Iron Stores, Hemoglobin, and Erythropoietin Requirements in Hemodialysis Patients Laura Park, BScPhm, Tara Uhthoff, BScPhm, Michael Tierney, MSc, and Steven Nadler, MD, FRCPC ● Iron deficiency is a common cause of delayed or diminished response to erythropoietin (EPO) in hemodialysis patients. Although oral iron is often prescribed to replete iron stores, this approach to iron supplementation may not be adequate with chronic EPO therapy. Intravenous (IV) iron dextran may be an effective alternative approach to replete iron stores and may facilitate more cost-effective use of EPO. The purpose of this study was to evaluate an IV iron dextran regimen that consisted of a loading dose phase followed by monthly maintenance doses of iron dextran. The effect of this regimen on iron stores, hemoglobin, and EPO doses was evaluated. This was an open prospective study in adult hemodialysis patients who were iron deficient as defined by a serum ferritin less than 100 ng/mL or transferrin saturation (TSAT) of less than 20%. Patients were loaded with 1 g iron dextran in five divided doses and then received monthly maintenance doses of 100 mg for the 4-month study period. Values of serum ferritin, TSAT, hemoglobin, and EPO dose were followed for the 4-month study period. Thirty hemodialysis patients receiving EPO were identified as being iron deficient and were enrolled in the study. The mean serum ferritin increased significantly from 49 ng/mL at baseline to 225 ng/mL at the end of the study period (P F 0.0001). Mean TSAT also increased significantly from 27% to 33% (P ⴝ 0.002). Values for hemoglobin did not change significantly during the study period; however, there was a significant reduction in EPO dose from a mean baseline dose of 112 U/kg/wk to 88 U/kg/wk at the end of the study period (P ⴝ 0.009). Seventeen patients experienced an increase in hemoglobin or a decrease in EPO dose. Economic analysis showed that approximately $580 (Cdn) per patient per year could be saved by use of IV iron dextran. The administration of the IV iron dextran regimen in the iron-deficient hemodialysis population was effective at repleting and maintaining iron stores and reducing EPO use. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Iron deficiency; erythropoietin; IV iron dextran; chronic renal failure.
A
SIGNIFICANT AND debilitating anemia occurs in patients with end-stage renal disease.1 Many factors may contribute to this anemia, including increased hemolysis from the accumulation of uremic toxins, iron and folate deficiencies, and chronic blood loss that can occur through routine hemodialysis, frequent blood sampling, and gastrointestinal (GI) blood loss. Although all of these factors can play a role in the development of anemia, physiological deficiency of erythropoietin is unquestionably the primary cause of anemia.2 The use of recombinant erythropoietin (EPO) produces improvement in the signs and symptoms of anemia that are normally evident within 2 months of initiating EPO therapy.3,4 It is generally recommended that EPO be supplemented with oral iron to provide 150 to 200 mg elemental iron daily.5 Although oral iron is inexpensive and convenient to administer, it is plagued with many problems such as interactions with medications that alter iron absorption, gastric intolerance, which ultimately may lead to noncompliance and incomplete and erratic absorption.6,7
Intravenous (IV) iron provides an alternative route of administration. A number of studies in patients receiving EPO have indicated that approximately 40% to 60% of patients empirically started on oral iron supplementation continue to develop iron deficiency and eventually require parenteral iron dextran.8,9 Muirhead et al5 have recently published ‘‘evidence-based’’ recommendations for hemodialysis patients receiving EPO and suggest that a diagnosis of iron deficiency can be made if the serum ferritin is less than 100 ng/mL or transferrin saturation (TSAT) is less than 20%, or hypochromic red blood cells are greater than 10%.5 They recommend that if no improvement in iron From the Departments of Pharmacy and Medicine, Ottawa General Hospital, Ontario, Canada. Received March 14, 1997; accepted in revised form November 21, 1997. Address reprint requests to Michael Tierney, MSc, Pharmacy Department, Ottawa General Hospital, 501 Smyth Rd, Ottawa, Ontario, Canada K1H 8L6. E-mail: mtierney@ ogh.on.ca
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0013$3.00/0
American Journal of Kidney Diseases, Vol 31, No 5 (May), 1998: pp 835-840
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status has occurred after 4 to 8 weeks of oral iron therapy, it should be discontinued and IV iron dextran started as a 1-g loading dose followed by a maintenance dose of 100 to 200 mg monthly.5 This dosing strategy appears to be based on the estimated 1 to 2 g iron that are believed to be lost in renal failure patients each year. Because these recommendations were published as part of evidence-based recommendations, it might be assumed that they have been well validated by clinical trials. It is important to recognize that this is not the case. The objective of this study was to evaluate the efficacy of this standardized recommended dose of iron dextran as assessed by its effect on iron repletion, iron stores, hemoglobin, EPO requirements, and EPO costs. METHODS
Study Design The study was an open prospective study of patients in the Artificial Kidney Unit (AKU) of the Ottawa General Hospital who were receiving EPO.
Patient Selection Patients qualified for the study if they were receiving EPO for the anemia of chronic renal failure (CRF), were receiving regular hemodialysis, and were iron-deficient as defined by serum ferritin less than 100 ng/mL or transferrin saturation (TSAT) less than 20%. Patients who had received IV iron in the preceding 4 months were excluded from the study.
Protocol Baseline values for serum ferritin, TSAT, hemoglobin, EPO dose, vitamin B12, and red blood cell folate were recorded. If patients were on oral iron regimens, these were discontinued. All patients were dosed with IV iron dextran 200 mg for five consecutive dialysis sessions. Test doses of iron dextran were not administered because the rate of infusion was slower than that recommended for administration of test doses. After completion of this loading dose, each patient received monthly maintenance doses of 100 mg IV iron dextran. Patients were followed-up for 4 months. During the study period, adjustments in EPO doses were left to the discretion of the prescribing physician.
Outcomes Measured Primary end points were degree of change in iron stores as assessed by serum ferritin and TSAT, hemoglobin, and EPO dose. Data are presented as mean hemoglobin, serum ferritin, TSAT, and EPO dose/kg for the pretreatment and posttreatment periods. A positive outcome was defined as an increase in hemoglobin with no change in EPO dose, increase in
hemoglobin with decrease in EPO dose, or no change in hemoglobin with decrease in EPO dose. A neutral outcome was defined as an increase in hemoglobin with increase in EPO dose, no change in hemoglobin with no change in EPO dose, and a decrease in hemoglobin with a decrease in EPO dose. Finally, a negative outcome was defined as no change in hemoglobin with increase in EPO dose, decrease in hemoglobin with increase in EPO dose, and decrease in hemoglobin with no change in EPO dose.
Data Analysis All data were analyzed with a paired t-test to compare the pretreatment values with posttreatment values. A P value of 0.05 was used to determine statistical significance in all primary end points measured. A cost analysis was performed based on savings that would have been realized if the dosing at the end of the study period remained stable for a 1-year period. Costs are represented in Canadian dollars (the current exchange rate is $1.41 Cdn ⫽ $1 US). Dosing costs were based on the Ottawa General Hospital acquisition cost of $133.95/ 10,000-U vial for EPO and $25.00/100-mg vial for iron dextran. Changes in EPO cost were calculated based on the difference in EPO dosing at the start and end of the study. These data were then extrapolated to 1-year treatment costs, assuming that the monthly maintenance dose of IV iron at the end of the study would continue. One-year costs included the costs of the loading dose and the maintenance dose. Net savings were calculated by subtracting the costs of IV iron dextran from the savings in EPO costs and were calculated on a per-patient basis.
RESULTS
Thirty patients receiving EPO in the AKU were identified as being iron deficient. These 30 patients represented 31% of our hemodialysis population who were receiving EPO at the time of initiation of the study. Of these 30 patients, 29 had baseline serum ferritin of less than 100 ng/mL, and seven had a TSAT of less than 20%. There were 18 men and 12 women, and the mean age was 54 years (range, 24 to 80 years). Seventeen patients had already been taking oral iron supplementation and were still iron deficient despite at least 2 months of oral iron therapy. Patient characteristics are shown in Table 1. The average duration of EPO therapy was 2.3 years (range, ⬍1 to 5). During the course of the study, two patients were identified as being vitamin B12 deficient on the basis of a serum level below the normal range. No patients were identified as folic acid deficient. After receiving the loading dose of iron dextran and three monthly maintenance doses of iron dextran, 27 of the 30 patients achieved iron repletion. The values for serum ferritin rose from
EFFECT OF AN IV IRON DEXTRAN REGIMEN
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Table 1. Baseline Characteristics of Iron-Deficient Patients Receiving EPO Characteristic
All Patients
No. of patients Oral iron regimen No oral iron previously Male Female Age (yr) Serum ferritin (ng/mL) (normal, 100-300 ng/mL) Transferrin saturation (TSAT %) (normal, 20%-45%) Hemoglobin (g/L) EPO dose (U/kg/wk) Duration on erythropoietin (yr)
30 17 13 18 12 54 ⫾ 18* (24-80)† 49 ⫾ 31 (12-176) 27 ⫾ 8 (12-48) 115 ⫾ 12 (87-146) 112 ⫾ 62 (40-320) 2.3 ⫾ 1.3 (⬍1-5)
Abbreviation: EPO, erythropoietin. *Mean ⫾ SD. †Range.
a mean ⫾ SD of 49 ⫾ 31 ng/mL at baseline to 225 ⫾ 88 ng/mL at the end of the study period (P ⬍ 0.0001) (Table 2, Fig 1). Similarly, mean TSAT also rose from 27 ⫾ 8% to 33 ⫾ 9% (P ⫽ 0.002) (Fig 2). There was no significant change in hemoglobin. The mean hemoglobin was 115 ⫾ 12 g/L at baseline and 118 ⫾ 11 g/L at the end of the study (P ⫽ 0.209) (Fig 3). However, there was a significant change in the EPO dose, which decreased from 112 ⫾ 62 U/kg/wk to 88 ⫾ 69 U/kg/wk (P ⫽ 0.009) (Fig 4). Eight patients experienced an increase in he-
Fig 1. Mean serum ferritin during the study period (——, mean; ····, upper SD).
moglobin without a change in EPO dose, three patients’ EPO dose requirements decreased with a stable hemoglobin, and six patients’ hemoglobin increased and EPO dose decreased. Thus, a total of 17 of the 30 patients experienced a positive outcome after intervention with iron dextran. Nine patients experienced a neutral outcome, and four patients experienced a negative outcome (Table 3). IV iron dextran was well tolerated and convenient to administer in this population. No significant adverse reactions were reported, and in no instances was the dose regimen altered. The average EPO dose change from baseline to the end of the study was a reduction of 24 ⫾ 40 U/kg/wk. If one considers drug costs alone, this dose reduction extrapolated over 1 year of treatment would mean a savings of approximately $35,000 for the study population, or
Table 2. Measurements at Baseline and at 4 Months of Follow-Up End Point
Baseline Value
4-Month Value
Serum ferritin (ng/mL)
49 ⫾ 31
TSAT (%)
27 ⫾ 8
225 ⫾ 88 (P ⬍ 0.0001)* 33 ⫾ 9 (P ⫽ 0.0003)* 118 ⫾ 11 (P ⫽ 0.209) 88 ⫾ 69 (P ⫽ 0.009)*
Hemoglobin (g/L)
115 ⫾ 12
Dose of EPO (U/kg/wk)
112 ⫾ 62
Abbreviations: TSAT, transferrin saturation; EPO, erythropoietin. *Statistically significant difference.
Fig 2. Mean transferrin saturation during the study period (——, mean; ····, upper SD).
838
PARK ET AL Table 3. Change in Hemoglobin in Relation to Change in EPO Requirements Hemoglobin and EPO Dose
Increase in EPO dose No change in EPO dose Decrease in EPO dose Fig 3. Mean hemoglobin during the study period (——, mean; ····, upper SD).
$1,150 per patient. The cost to load the 30 patients with IV iron was approximately $7,500, and subsequent maintenance dose cost for the remainder of the year would have been approximately $9,400, to make a total of approximately $17,000 a year for the 30 patients or approximately $565 per patient per year. The net savings in reduced EPO requirements after subtracting the cost of iron dextran would be approximately $580 per patient per year. DISCUSSION
The ideal management of iron deficiency in hemodialysis patients treated with EPO remains uncertain. In CRF patients, prevention and treatment of iron deficiency is of utmost importance. These patients require large amounts of iron for new hemoglobin synthesis, but loss of blood through dialysis or GI bleeding often undermines attempts to replete iron stores by the oral route. The results of this study show that a standardized dosing regimen of IV iron dextran was very
Fig 4. Mean erythropoietin (EPO) dose during the study (——, mean; ····, upper SD).
Increase in Hemoglobin
No Change in Hemoglobin
Decrease in Hemoglobin
1
—
—
8*
6
4
6*
3*
2
*Positive response to iron dextran therapy.
effective at achieving iron repletion and in maintaining iron stores for at least 4 months in irondeficient patients. Normal indices for serum ferritin and TSAT were achieved for 90% of patients enrolled in the study. More than half of those patients had already been prescribed oral iron and had continued to be iron deficient despite at least 2 months of oral iron supplementation. Our results indicate that IV iron dextran is an effective means to achieve iron repletion in these patients. Most patients were iron replete by the first month of follow-up, and normal iron indices were maintained through the treatment period (Figs 1 and 2). To our knowledge, our study represents the first attempt to validate the recommendations for IV iron dextran dosing as published as part of a clinical practice guideline. The results support the use of this dosing strategy. Four patients in our study were judged to have not responded to the IV iron protocol in that we observed a decrease in hemoglobin despite a stable EPO dose. Of these, two had suspected bleeding from the GI tract during the study period (one patient had a diagnosis of Crohn’s disease, and the other was subsequently found to have carcinoma of the bowel). For the other two patients, follow-up at 1 year showed that these patients could be classified as responders. Reasons for their relatively slow response to IV iron were not apparent. Although there was no significant change in hemoglobin shown in this study, this may have reflected the relatively high baseline hemoglobin in the study population. Only six of the study patients had a baseline hemoglobin of less than 105 g/L, which is the low end of the target range for hemoglobin in our hemodialysis population
EFFECT OF AN IV IRON DEXTRAN REGIMEN
(target range, 105 to 115 g/L).5 In the study population, intervention with IV iron dextran seemed to allow patients to achieve the same hemoglobin while sparing EPO requirements. The mean EPO requirement decreased significantly from the beginning of the study to the end of the study, and when these results were assessed in terms of cost, significant savings in costs per patient were evident. Given the high economic cost of EPO, a mean decrease in dose by 24 U/kg/wk may have a substantial financial impact if applied to the large dialysis-dependent population. Our study followed patients for only 4 months. If longer follow-up confirms maintenance of iron stores with the studied dose, there will be a pronounced economic advantage in using iron dextran in patients maintained on EPO. Using this assumption, 1-year economic costs presented in this study show that iron dextran use (loading and maintenance doses) results in drug acquisition cost savings of $580 per patient. In subsequent years, there are potentially additional savings to be captured because the loading dose of iron dextran would not have to be repeated. Savings per patient per year could approach $800. Future pharmacoeconomic studies that incorporate all costs and include patient outcomes such as quality of life would be useful in evaluating the impact of IV iron dextran therapy. Although maintenance of iron stores is recognized to be an important component of effective therapy with EPO, the optimal method of doing so has not been definitively established. It is not known whether the intermittent loading doses or smaller, more frequent maintenance dosing is the preferred approach to replenish and maintain iron stores. Our results are consistent with other studies that have evaluated a variety of dosing strategies with iron dextran in hemodialysis patients.10-13 We employed monthly maintenance doses of 100 mg in accordance with recent recommendations that 100 to 200 mg of iron dextran each month was sufficient to maintain iron repletion.5 Because there appeared to be little clinical evidence to support this dosing recommendation, the results of our study can be used to assess the validity of this strategy. Over the course of the study, this regimen appeared to be effective at maintaining iron stores without the risk of iron
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tissue overload, and reductions in EPO dose were realized. Fishbane et al10 randomized 52 iron-replete patients to iron supplementation either orally (150 to 200 mg elemental iron daily) or intravenously (200 mg iron dextran weekly). After 4 months of study, patients in the IV iron dextran group had significantly higher mean hematocrit and ferritin. Also, the EPO dose decreased significantly in the IV iron dextran group, by approximately 3,500 U/dose. Although this study showed that iron dextran is superior to oral iron in maintaining iron stores and can reduce EPO requirements, they also found large increases in mean iron indices to a level of 750 ng/mL for serum ferritin and 75% for TSAT, raising concerns about tissue iron overload. This may have been because of the larger doses used compared to our regimen (3,200 mg v 1,400 mg over 4 months). The authors concluded that further studies were needed to determine whether lower doses of IV iron dextran would improve erythropoiesis without causing organ iron overload.10 Hemosiderosis is a potential risk of prolonged iron dextran therapy. Because there are risks such as liver cirrhosis and cardiac dysfunction associated with iron overload, future studies will be required to assess the long-term effects of maintenance dosing of IV iron. Laboratory abnormalities may indicate that iron overload is a TSAT of greater than 60% or serum ferritin level of greater than 300 ng/mL.14 By the end of our study, there were seven patients who achieved a serum ferritin or TSAT level above these values. However, these values are not specific for iron overload, and patients without iron overload also may have elevated values. Tissue damage from iron appears to be related more to the amount of iron deposited in parenchymal cells, which often results from ineffective erythropoiesis or increased intestinal iron absorption. However, iron introduced via the intravenous route preferentially deposits in the reticuloendothelial system, with less potential for end-organ damage.15 Nonetheless, ongoing monitoring and study are required to assess the potential for iron overload and toxicity in patients on long-term iron dextran therapy. Limitations of our study include the fact that there was no established protocol for adjustment
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of EPO doses during the study and a relatively short study period. Iron indices, hemoglobin, and changes in EPO dose are parameters that change slowly, and it is important to follow the trends in these parameters for a longer duration. Since completion of the study, we have performed a 1-year, retrospective follow-up of patients included in the study. Twenty-six of the 30 patients continued to receive monthly maintenance doses of 100 mg of IV iron dextran. Sixteen of the 26 continued to have a successful response, as assessed by iron indices. Six patients became iron deficient without any obvious reason, while another four patients required additional doses of iron in response to documented blood loss. These results support the utility of this recommended dose of iron dextran. CONCLUSION
The use of a standardized dose of IV iron dextran was effective in achieving iron repletion in more than 90% of hemodialysis patients deemed to be iron deficient. Use of iron dextran was associated with maintenance of hemoglobin despite a decrease in EPO dose. Economic analysis showed that approximately $580 per patient per year could be potentially saved in EPO costs by using IV iron dextran therapy. REFERENCES 1. Canadian Erythropoietin Study Group: Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis. Br Med J 300:573-576, 1990 2. Eschbach JW, Adamson JW: Modern aspects of the pathophysiology of renal anemia. Contrib Nephrol 66:6370, 1988
3. Humphries JE: Anemia of renal failure: Use of erythropoietin. Med Clin North Am 73:711-725, 1992 4. Watson A: Iron management during treatment with recombinant human erythropoietin in chronic renal failure. J Clin Pharmacol 33:1123-1138, 1993 5. Muirhead N, Bargman J, Burgess E, Jinda KK, Levin A, Nolin L, Parfrey P: Evidence-based recommendations for the clinical use of recombinant human erythropoietin. Am J Kidney Dis 26:S1-S23, 1995 (suppl 1) 6. Crosby WH: The rationale for treating iron deficiency anemia. Arch Intern Med 144:471-472, 1984 7. McEvoy GK (ed): AHFS Drug Information 96. Bethesda, MD, American Society of Health-System Pharmacists, 1996, pp 984-989 8. Lim VS, Kirchner PT, Fangman J, Richmond J, DeGowin RL: The safety and efficacy of maintenance therapy of recombinant human erythropoietin in patients with renal insufficiency. Am J Kidney Dis 14:496-506,1989 9. Eschbach JW, Kelly MR, Haley R, Abels RI: Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 321:158-163, 1989 10. Fishbane S, Frei GL, Maesaka J: Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 26:4146, 1995 11. Senger JM, Weiss RJ: Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment. ANNA J 23:319-323, 1996 12. Sepandj F, Jindal K, West M, Hirsch D: Economic appraisal of maintenance parenteral iron administration in treatment of anemia in chronic hemodialysis patients. Nephrol Dial Transplant 11:319-322, 1996 13. Fishbane S, Lynn RI: The efficacy of iron dextran for the treatment of iron deficiency in hemodialysis patients. Clin Nephrol 44:238-240, 1995 14. Powell LW, Isselbacher KJ: Hemochromotosis, in Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL (eds): Harrison’s Principles of Internal Medicine (ed 13). New York, NY, McGraw-Hill, 1994, pp 2069-2073 15. Halliday CE, Halliday JW, Powell LW: The clinical manifestations of chronic iron overload. Baillieres Clin Haematol 2:403-421,1989
A
SIGNIFICANT AND debilitating anemia occurs in patients with end-stage renal disease.1 Many factors may contribute to this anemia, including increased hemolysis from the accumulation of uremic toxins, iron and folate deficiencies, and chronic blood loss that can occur through routine hemodialysis, frequent blood sampling, and gastrointestinal (GI) blood loss. Although all of these factors can play a role in the development of anemia, physiological deficiency of erythropoietin is unquestionably the primary cause of anemia.2 The use of recombinant erythropoietin (EPO) produces improvement in the signs and symptoms of anemia that are normally evident within 2 months of initiating EPO therapy.3,4 It is generally recommended that EPO be supplemented with oral iron to provide 150 to 200 mg elemental iron daily.5 Although oral iron is inexpensive and convenient to administer, it is plagued with many problems such as interactions with medications that alter iron absorption, gastric intolerance, which ultimately may lead to noncompliance and incomplete and erratic absorption.6,7
Intravenous (IV) iron provides an alternative route of administration. A number of studies in patients receiving EPO have indicated that approximately 40% to 60% of patients empirically started on oral iron supplementation continue to develop iron deficiency and eventually require parenteral iron dextran.8,9 Muirhead et al5 have recently published ‘‘evidence-based’’ recommendations for hemodialysis patients receiving EPO and suggest that a diagnosis of iron deficiency can be made if the serum ferritin is less than 100 ng/mL or transferrin saturation (TSAT) is less than 20%, or hypochromic red blood cells are greater than 10%.5 They recommend that if no improvement in iron From the Departments of Pharmacy and Medicine, Ottawa General Hospital, Ontario, Canada. Received March 14, 1997; accepted in revised form November 21, 1997. Address reprint requests to Michael Tierney, MSc, Pharmacy Department, Ottawa General Hospital, 501 Smyth Rd, Ottawa, Ontario, Canada K1H 8L6. E-mail: mtierney@ ogh.on.ca
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0013$3.00/0
American Journal of Kidney Diseases, Vol 31, No 5 (May), 1998: pp 835-840
835
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status has occurred after 4 to 8 weeks of oral iron therapy, it should be discontinued and IV iron dextran started as a 1-g loading dose followed by a maintenance dose of 100 to 200 mg monthly.5 This dosing strategy appears to be based on the estimated 1 to 2 g iron that are believed to be lost in renal failure patients each year. Because these recommendations were published as part of evidence-based recommendations, it might be assumed that they have been well validated by clinical trials. It is important to recognize that this is not the case. The objective of this study was to evaluate the efficacy of this standardized recommended dose of iron dextran as assessed by its effect on iron repletion, iron stores, hemoglobin, EPO requirements, and EPO costs. METHODS
Study Design The study was an open prospective study of patients in the Artificial Kidney Unit (AKU) of the Ottawa General Hospital who were receiving EPO.
Patient Selection Patients qualified for the study if they were receiving EPO for the anemia of chronic renal failure (CRF), were receiving regular hemodialysis, and were iron-deficient as defined by serum ferritin less than 100 ng/mL or transferrin saturation (TSAT) less than 20%. Patients who had received IV iron in the preceding 4 months were excluded from the study.
Protocol Baseline values for serum ferritin, TSAT, hemoglobin, EPO dose, vitamin B12, and red blood cell folate were recorded. If patients were on oral iron regimens, these were discontinued. All patients were dosed with IV iron dextran 200 mg for five consecutive dialysis sessions. Test doses of iron dextran were not administered because the rate of infusion was slower than that recommended for administration of test doses. After completion of this loading dose, each patient received monthly maintenance doses of 100 mg IV iron dextran. Patients were followed-up for 4 months. During the study period, adjustments in EPO doses were left to the discretion of the prescribing physician.
Outcomes Measured Primary end points were degree of change in iron stores as assessed by serum ferritin and TSAT, hemoglobin, and EPO dose. Data are presented as mean hemoglobin, serum ferritin, TSAT, and EPO dose/kg for the pretreatment and posttreatment periods. A positive outcome was defined as an increase in hemoglobin with no change in EPO dose, increase in
hemoglobin with decrease in EPO dose, or no change in hemoglobin with decrease in EPO dose. A neutral outcome was defined as an increase in hemoglobin with increase in EPO dose, no change in hemoglobin with no change in EPO dose, and a decrease in hemoglobin with a decrease in EPO dose. Finally, a negative outcome was defined as no change in hemoglobin with increase in EPO dose, decrease in hemoglobin with increase in EPO dose, and decrease in hemoglobin with no change in EPO dose.
Data Analysis All data were analyzed with a paired t-test to compare the pretreatment values with posttreatment values. A P value of 0.05 was used to determine statistical significance in all primary end points measured. A cost analysis was performed based on savings that would have been realized if the dosing at the end of the study period remained stable for a 1-year period. Costs are represented in Canadian dollars (the current exchange rate is $1.41 Cdn ⫽ $1 US). Dosing costs were based on the Ottawa General Hospital acquisition cost of $133.95/ 10,000-U vial for EPO and $25.00/100-mg vial for iron dextran. Changes in EPO cost were calculated based on the difference in EPO dosing at the start and end of the study. These data were then extrapolated to 1-year treatment costs, assuming that the monthly maintenance dose of IV iron at the end of the study would continue. One-year costs included the costs of the loading dose and the maintenance dose. Net savings were calculated by subtracting the costs of IV iron dextran from the savings in EPO costs and were calculated on a per-patient basis.
RESULTS
Thirty patients receiving EPO in the AKU were identified as being iron deficient. These 30 patients represented 31% of our hemodialysis population who were receiving EPO at the time of initiation of the study. Of these 30 patients, 29 had baseline serum ferritin of less than 100 ng/mL, and seven had a TSAT of less than 20%. There were 18 men and 12 women, and the mean age was 54 years (range, 24 to 80 years). Seventeen patients had already been taking oral iron supplementation and were still iron deficient despite at least 2 months of oral iron therapy. Patient characteristics are shown in Table 1. The average duration of EPO therapy was 2.3 years (range, ⬍1 to 5). During the course of the study, two patients were identified as being vitamin B12 deficient on the basis of a serum level below the normal range. No patients were identified as folic acid deficient. After receiving the loading dose of iron dextran and three monthly maintenance doses of iron dextran, 27 of the 30 patients achieved iron repletion. The values for serum ferritin rose from
EFFECT OF AN IV IRON DEXTRAN REGIMEN
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Table 1. Baseline Characteristics of Iron-Deficient Patients Receiving EPO Characteristic
All Patients
No. of patients Oral iron regimen No oral iron previously Male Female Age (yr) Serum ferritin (ng/mL) (normal, 100-300 ng/mL) Transferrin saturation (TSAT %) (normal, 20%-45%) Hemoglobin (g/L) EPO dose (U/kg/wk) Duration on erythropoietin (yr)
30 17 13 18 12 54 ⫾ 18* (24-80)† 49 ⫾ 31 (12-176) 27 ⫾ 8 (12-48) 115 ⫾ 12 (87-146) 112 ⫾ 62 (40-320) 2.3 ⫾ 1.3 (⬍1-5)
Abbreviation: EPO, erythropoietin. *Mean ⫾ SD. †Range.
a mean ⫾ SD of 49 ⫾ 31 ng/mL at baseline to 225 ⫾ 88 ng/mL at the end of the study period (P ⬍ 0.0001) (Table 2, Fig 1). Similarly, mean TSAT also rose from 27 ⫾ 8% to 33 ⫾ 9% (P ⫽ 0.002) (Fig 2). There was no significant change in hemoglobin. The mean hemoglobin was 115 ⫾ 12 g/L at baseline and 118 ⫾ 11 g/L at the end of the study (P ⫽ 0.209) (Fig 3). However, there was a significant change in the EPO dose, which decreased from 112 ⫾ 62 U/kg/wk to 88 ⫾ 69 U/kg/wk (P ⫽ 0.009) (Fig 4). Eight patients experienced an increase in he-
Fig 1. Mean serum ferritin during the study period (——, mean; ····, upper SD).
moglobin without a change in EPO dose, three patients’ EPO dose requirements decreased with a stable hemoglobin, and six patients’ hemoglobin increased and EPO dose decreased. Thus, a total of 17 of the 30 patients experienced a positive outcome after intervention with iron dextran. Nine patients experienced a neutral outcome, and four patients experienced a negative outcome (Table 3). IV iron dextran was well tolerated and convenient to administer in this population. No significant adverse reactions were reported, and in no instances was the dose regimen altered. The average EPO dose change from baseline to the end of the study was a reduction of 24 ⫾ 40 U/kg/wk. If one considers drug costs alone, this dose reduction extrapolated over 1 year of treatment would mean a savings of approximately $35,000 for the study population, or
Table 2. Measurements at Baseline and at 4 Months of Follow-Up End Point
Baseline Value
4-Month Value
Serum ferritin (ng/mL)
49 ⫾ 31
TSAT (%)
27 ⫾ 8
225 ⫾ 88 (P ⬍ 0.0001)* 33 ⫾ 9 (P ⫽ 0.0003)* 118 ⫾ 11 (P ⫽ 0.209) 88 ⫾ 69 (P ⫽ 0.009)*
Hemoglobin (g/L)
115 ⫾ 12
Dose of EPO (U/kg/wk)
112 ⫾ 62
Abbreviations: TSAT, transferrin saturation; EPO, erythropoietin. *Statistically significant difference.
Fig 2. Mean transferrin saturation during the study period (——, mean; ····, upper SD).
838
PARK ET AL Table 3. Change in Hemoglobin in Relation to Change in EPO Requirements Hemoglobin and EPO Dose
Increase in EPO dose No change in EPO dose Decrease in EPO dose Fig 3. Mean hemoglobin during the study period (——, mean; ····, upper SD).
$1,150 per patient. The cost to load the 30 patients with IV iron was approximately $7,500, and subsequent maintenance dose cost for the remainder of the year would have been approximately $9,400, to make a total of approximately $17,000 a year for the 30 patients or approximately $565 per patient per year. The net savings in reduced EPO requirements after subtracting the cost of iron dextran would be approximately $580 per patient per year. DISCUSSION
The ideal management of iron deficiency in hemodialysis patients treated with EPO remains uncertain. In CRF patients, prevention and treatment of iron deficiency is of utmost importance. These patients require large amounts of iron for new hemoglobin synthesis, but loss of blood through dialysis or GI bleeding often undermines attempts to replete iron stores by the oral route. The results of this study show that a standardized dosing regimen of IV iron dextran was very
Fig 4. Mean erythropoietin (EPO) dose during the study (——, mean; ····, upper SD).
Increase in Hemoglobin
No Change in Hemoglobin
Decrease in Hemoglobin
1
—
—
8*
6
4
6*
3*
2
*Positive response to iron dextran therapy.
effective at achieving iron repletion and in maintaining iron stores for at least 4 months in irondeficient patients. Normal indices for serum ferritin and TSAT were achieved for 90% of patients enrolled in the study. More than half of those patients had already been prescribed oral iron and had continued to be iron deficient despite at least 2 months of oral iron supplementation. Our results indicate that IV iron dextran is an effective means to achieve iron repletion in these patients. Most patients were iron replete by the first month of follow-up, and normal iron indices were maintained through the treatment period (Figs 1 and 2). To our knowledge, our study represents the first attempt to validate the recommendations for IV iron dextran dosing as published as part of a clinical practice guideline. The results support the use of this dosing strategy. Four patients in our study were judged to have not responded to the IV iron protocol in that we observed a decrease in hemoglobin despite a stable EPO dose. Of these, two had suspected bleeding from the GI tract during the study period (one patient had a diagnosis of Crohn’s disease, and the other was subsequently found to have carcinoma of the bowel). For the other two patients, follow-up at 1 year showed that these patients could be classified as responders. Reasons for their relatively slow response to IV iron were not apparent. Although there was no significant change in hemoglobin shown in this study, this may have reflected the relatively high baseline hemoglobin in the study population. Only six of the study patients had a baseline hemoglobin of less than 105 g/L, which is the low end of the target range for hemoglobin in our hemodialysis population
EFFECT OF AN IV IRON DEXTRAN REGIMEN
(target range, 105 to 115 g/L).5 In the study population, intervention with IV iron dextran seemed to allow patients to achieve the same hemoglobin while sparing EPO requirements. The mean EPO requirement decreased significantly from the beginning of the study to the end of the study, and when these results were assessed in terms of cost, significant savings in costs per patient were evident. Given the high economic cost of EPO, a mean decrease in dose by 24 U/kg/wk may have a substantial financial impact if applied to the large dialysis-dependent population. Our study followed patients for only 4 months. If longer follow-up confirms maintenance of iron stores with the studied dose, there will be a pronounced economic advantage in using iron dextran in patients maintained on EPO. Using this assumption, 1-year economic costs presented in this study show that iron dextran use (loading and maintenance doses) results in drug acquisition cost savings of $580 per patient. In subsequent years, there are potentially additional savings to be captured because the loading dose of iron dextran would not have to be repeated. Savings per patient per year could approach $800. Future pharmacoeconomic studies that incorporate all costs and include patient outcomes such as quality of life would be useful in evaluating the impact of IV iron dextran therapy. Although maintenance of iron stores is recognized to be an important component of effective therapy with EPO, the optimal method of doing so has not been definitively established. It is not known whether the intermittent loading doses or smaller, more frequent maintenance dosing is the preferred approach to replenish and maintain iron stores. Our results are consistent with other studies that have evaluated a variety of dosing strategies with iron dextran in hemodialysis patients.10-13 We employed monthly maintenance doses of 100 mg in accordance with recent recommendations that 100 to 200 mg of iron dextran each month was sufficient to maintain iron repletion.5 Because there appeared to be little clinical evidence to support this dosing recommendation, the results of our study can be used to assess the validity of this strategy. Over the course of the study, this regimen appeared to be effective at maintaining iron stores without the risk of iron
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tissue overload, and reductions in EPO dose were realized. Fishbane et al10 randomized 52 iron-replete patients to iron supplementation either orally (150 to 200 mg elemental iron daily) or intravenously (200 mg iron dextran weekly). After 4 months of study, patients in the IV iron dextran group had significantly higher mean hematocrit and ferritin. Also, the EPO dose decreased significantly in the IV iron dextran group, by approximately 3,500 U/dose. Although this study showed that iron dextran is superior to oral iron in maintaining iron stores and can reduce EPO requirements, they also found large increases in mean iron indices to a level of 750 ng/mL for serum ferritin and 75% for TSAT, raising concerns about tissue iron overload. This may have been because of the larger doses used compared to our regimen (3,200 mg v 1,400 mg over 4 months). The authors concluded that further studies were needed to determine whether lower doses of IV iron dextran would improve erythropoiesis without causing organ iron overload.10 Hemosiderosis is a potential risk of prolonged iron dextran therapy. Because there are risks such as liver cirrhosis and cardiac dysfunction associated with iron overload, future studies will be required to assess the long-term effects of maintenance dosing of IV iron. Laboratory abnormalities may indicate that iron overload is a TSAT of greater than 60% or serum ferritin level of greater than 300 ng/mL.14 By the end of our study, there were seven patients who achieved a serum ferritin or TSAT level above these values. However, these values are not specific for iron overload, and patients without iron overload also may have elevated values. Tissue damage from iron appears to be related more to the amount of iron deposited in parenchymal cells, which often results from ineffective erythropoiesis or increased intestinal iron absorption. However, iron introduced via the intravenous route preferentially deposits in the reticuloendothelial system, with less potential for end-organ damage.15 Nonetheless, ongoing monitoring and study are required to assess the potential for iron overload and toxicity in patients on long-term iron dextran therapy. Limitations of our study include the fact that there was no established protocol for adjustment
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PARK ET AL
of EPO doses during the study and a relatively short study period. Iron indices, hemoglobin, and changes in EPO dose are parameters that change slowly, and it is important to follow the trends in these parameters for a longer duration. Since completion of the study, we have performed a 1-year, retrospective follow-up of patients included in the study. Twenty-six of the 30 patients continued to receive monthly maintenance doses of 100 mg of IV iron dextran. Sixteen of the 26 continued to have a successful response, as assessed by iron indices. Six patients became iron deficient without any obvious reason, while another four patients required additional doses of iron in response to documented blood loss. These results support the utility of this recommended dose of iron dextran. CONCLUSION
The use of a standardized dose of IV iron dextran was effective in achieving iron repletion in more than 90% of hemodialysis patients deemed to be iron deficient. Use of iron dextran was associated with maintenance of hemoglobin despite a decrease in EPO dose. Economic analysis showed that approximately $580 per patient per year could be potentially saved in EPO costs by using IV iron dextran therapy. REFERENCES 1. Canadian Erythropoietin Study Group: Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis. Br Med J 300:573-576, 1990 2. Eschbach JW, Adamson JW: Modern aspects of the pathophysiology of renal anemia. Contrib Nephrol 66:6370, 1988
3. Humphries JE: Anemia of renal failure: Use of erythropoietin. Med Clin North Am 73:711-725, 1992 4. Watson A: Iron management during treatment with recombinant human erythropoietin in chronic renal failure. J Clin Pharmacol 33:1123-1138, 1993 5. Muirhead N, Bargman J, Burgess E, Jinda KK, Levin A, Nolin L, Parfrey P: Evidence-based recommendations for the clinical use of recombinant human erythropoietin. Am J Kidney Dis 26:S1-S23, 1995 (suppl 1) 6. Crosby WH: The rationale for treating iron deficiency anemia. Arch Intern Med 144:471-472, 1984 7. McEvoy GK (ed): AHFS Drug Information 96. Bethesda, MD, American Society of Health-System Pharmacists, 1996, pp 984-989 8. Lim VS, Kirchner PT, Fangman J, Richmond J, DeGowin RL: The safety and efficacy of maintenance therapy of recombinant human erythropoietin in patients with renal insufficiency. Am J Kidney Dis 14:496-506,1989 9. Eschbach JW, Kelly MR, Haley R, Abels RI: Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 321:158-163, 1989 10. Fishbane S, Frei GL, Maesaka J: Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 26:4146, 1995 11. Senger JM, Weiss RJ: Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment. ANNA J 23:319-323, 1996 12. Sepandj F, Jindal K, West M, Hirsch D: Economic appraisal of maintenance parenteral iron administration in treatment of anemia in chronic hemodialysis patients. Nephrol Dial Transplant 11:319-322, 1996 13. Fishbane S, Lynn RI: The efficacy of iron dextran for the treatment of iron deficiency in hemodialysis patients. Clin Nephrol 44:238-240, 1995 14. Powell LW, Isselbacher KJ: Hemochromotosis, in Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL (eds): Harrison’s Principles of Internal Medicine (ed 13). New York, NY, McGraw-Hill, 1994, pp 2069-2073 15. Halliday CE, Halliday JW, Powell LW: The clinical manifestations of chronic iron overload. Baillieres Clin Haematol 2:403-421,1989