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Challenge of Effectively Using Erythropoiesis-Stimulating Agents and Intravenous Iron
Challenge of Effectively Using Erythropoiesis-Stimulating Agents and Intravenous Iron Toros Kapoian, MD Clinicians who manage anemia in patients with chronic kidney disease, both on and off dialysis therapy, face several challenges: maintain stable hemoglobin (Hb) levels in their patients, avoid overshooting Hb targets, balance intravenous (IV) iron and erythropoiesis-stimulating agents (ESAs), and improve ESA response to use the lowest effective ESA dose. Special attention to ESA hyporesponsiveness, as well as the role of insufficient iron, is required. The efficacy of IV iron in managing these challenges, particularly in hemodialysis patients who have anemia despite adequate ESA doses, was shown in the randomized controlled Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) clinical trial and its 6-week follow-up extension study, DRIVE-II. These studies provide suggestive evidence of the ability of IV iron to reduce ESA requirements and maintain improved Hb levels in anemic hemodialysis patients with serum ferritin levels of 500 to 1,200 ng/mL and transferrin saturations of 25% or less. Am J Kidney Dis 52(S1):S21-S28. © 2008 by the National Kidney Foundation, Inc. INDEX WORDS: Anemia of chronic kidney disease; intravenous iron; erythropoiesis-stimulating agent.
T
he safety of higher hemoglobin (Hb) levels and the use of erythropoiesis-stimulating agents (ESAs) to target these levels is a concern in the nephrology community. Adverse outcomes have been reported in clinical trials investigating the effects of targeting Hb levels greater than 13 g/dL with an ESA in patients with chronic kidney disease (CKD).1-3 In 2007 the US Food and Drug Administration approved ESA boxed warnings and decreased its recommended Hb level range for ESA therapy.4 The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (KDOQI) updated its target Hb level range for ESAs.5 The Centers for Medicare & Medicaid Services (CMS) revised its Medicare claims policy for ESAs to include more conservative ESA dosing parameters in 2007.6
OVERSHOOTING Hb TARGETS Data from the US Renal Data System show that greater Hb levels are not uncommon in dialysis patients receiving ESAs, highlighting the need for improvement in maintaining Hb levels within the target range. The mean attained Hb level in dialysis patients 6 months after ESA therapy initiation was 12.2 g/dL in 2005, whereas mean weekly ESA doses 2 months after ESA therapy initiation were nearly 29,000 U/wk.7 The US Renal Data System also reported that 42% of patients achieve an Hb level of 14 g/dL or greater and 97% achieve an Hb level of 12 g/dL or greater 6 months after first attaining an Hb level of 11 g/dL.7 Overshooting the Hb level target is 3
to 4 times more common today than it was in 1997, whereas ESA dosing also has increased 3 to 4 times.7 These upward-trending Hb levels and ESA doses can be problematic for several reasons. Boxed warnings for ESAs state that patients experience greater risks of death and serious cardiovascular events when administered ESAs to target higher versus lower Hb levels.8,9 In addition, large increases in ESA doses intended to stimulate a better Hb response can lead to overshooting the Hb level target, increasing the patient’s risk of the adverse outcomes identified in clinical trials.1-3 Overshooting Hb levels in turn might spur a decision to withhold or scale back ESA therapy to restabilize Hb levels. This pattern of inconsistent ESA dosing can cause wide fluctuations in a patient’s Hb levels, putting the patient at further risk of poor outcomes.10,11
From UMDNJ–Robert Wood Johnson Medical School, New Brunswick, NJ. This article was published as part of a supplement sponsored by an educational grant from Watson Pharmaceuticals. Address correspondence to Toros Kapoian, MD, Department of Medicine/Nephrology, UMDNJ–Robert Wood Johnson Medical School, 1 Robert Wood Johnson Pl, MEB-412B, New Brunswick, NJ 08903. E-mail: tkapoian@ verizon.net © 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5206-0104$34.00/0 doi:10.1053/j.ajkd.2008.09.004
American Journal of Kidney Diseases, Vol 52, No 6, Suppl 1 (December), 2008: pp S21-S28
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assessed the impact of the degree of Hb level variability and number of months it persisted on mortality rates. The study reported that mortality risks became increasingly higher the longer patients’ Hb levels remained out of range, in particular, less than 11 g/dL.13
BENEFITS OF STABLE Hb LEVELS Maintaining stable Hb levels within the target range has been linked to the lowest hospital admission rates, fewest comorbidities, and shortest hospital stays.12 A study of 152,846 Medicare patients undergoing hemodialysis who were receiving ESAs and survived the first 6 months of 2003 evaluated the frequency with which these patients maintained Hb levels less than, within, and greater than the Hb target range recommended by the CMS at that time (11 to 12.5 g/dL).12 Patients with consistent target-range Hb levels had the lowest percentage of hospital admissions and admissions for infections and the shortest hospital stays (Table 1).12 Out-of-range Hb levels have been associated with reduced quality of life, impaired cardiac function, longer hospitalization stays, and greater risk of death.13-15 A prospective observational study of 1,428 patients with CKD from 119 centers found that maintaining Hb levels in the target range was associated with longer time to hospitalization and decreased adjusted mortality risk.14 In this study, Hb levels were predictive of 1-year survival and hospitalization, with a linear decrease in mortality risk as initial Hb levels increased from less than 10 to 12 g/dL. For Hb values of 11 to 12 g/dL, confidence intervals for the probability of 1-year survival and remaining free from hospitalization were 0.54 and 0.89, respectively. This was an improvement over the confidence intervals for lower Hb level ranges (0.34 and 0.77 for Hb ⬍ 10 g/dL and 0.47 and 0.82 for Hb of 10 to 11 g/dL).14 In an analysis of Medicare data for 159,720 ESA-treated hemodialysis patients who survived the first 6 months of 2004, patient Hb levels were classified according to 6 variability groups based on the lowest and highest Hb levels during a 6-month observation period.13 The investigators
APPROPRIATELY DOSING ESAs AND INTRAVENOUS IRON Although suboptimal Hb levels are undesirable, caution is advised when increasing ESA doses if faced with persistently low Hb levels.4,8,9 Data from an unpublished 1988 study conducted by J. Caro, as reported by Fishbane and Besarab16 in 2007, offer evidence that supports a conservative approach to making ESA dose adjustments to achieve target Hb levels. The study examined the endogenous response to blood loss from a rapid 2-unit phlebotomy in normal healthy male volunteers during 2 weeks. By the end of the first day, Hb levels decreased from a normal baseline value of 15 to 12 g/dL, whereas circulating mean endogenous erythropoietin levels increased 10-fold from 10 to 15 mU/mL at baseline to approximately 200 mU/mL. During the 2-week period, Hb levels progressively increased, partially correcting the anemia triggered by the blood loss, as endogenous erythropoietin levels decreased. It was determined that 50% of the red blood cell (RBC) deficit was corrected within the 2 weeks and the rest would be corrected during the next 6 weeks, while erythropoietin levels returned to normal concentrations. This type of response is preserved, although blunted, in hemodialysis patients.16 The study emphasizes the importance of providing sufficient time to allow Hb levels to respond to increased erythropoietin concentrations in ESA-treated patients before automatically increasing ESA doses.
Table 1. Lowest Hospitalization and Comorbidity Associated With Target-Range Hb Levels
Hb (g/dL)
Hospital Admission (%)
Admission for Infection (%)
Average Length of Stay (d)
Average Comorbidity (n)
Low (⬍11) Target (11-⬍12.5) High (ⱖ12.5)
69.2 25.3 29.8
29.5 6.2 7.4
12.7 1.9 2.2
2.4 1.1 1.2
Note: Hb in g/dL may be converted to g/L by multiplying by 10. Abbreviation: Hb, hemoglobin. Adapted with permission from Ebben et al.12
Effectively Using ESA and IV Iron
The phases of erythropoiesis itself point to the need for balance in anemia management strategies. Erythropoiesis is a process that requires both iron and erythropoietin. Erythropoietin steers the process by activating RBC production in the bone marrow, but iron is essential during the phase of RBC development. A sufficient supply of available iron during erythropoiesis ensures that RBCs are large enough and have sufficient oxygen-carrying capacity.17 The right balance between ESA and intravenous (IV) iron therapies, including appropriate dosing, therefore can optimize anemia treatment. For ESAs, full prescribing information provides a weight-based calculation to initiate therapy in patients with chronic kidney failure.8,9 It also is recommended that ESA dose increases should not be made more than once a month8,9 and ESA doses should be titrated by 25%.8,9 In addition, 4 weeks should be allowed between dose adjustments to provide sufficient time for changes in Hb levels in patients for whom the Hb level increase is less than 1 g/dL over 4 weeks and iron stores are adequate.8,9 For IV iron therapy administered to patients receiving ESAs, KDOQI guidelines5,15,18 recommend that before initiating ESA therapy, clinicians ensure that patients are iron replete. This includes evaluating patients for iron deficiency, consulting various laboratory markers to assess adequacy of iron for erythropoiesis, and determining the underlying causes of low Hb levels. In addition, it is recommended that after administering a repletion course of IV iron, clinicians assess ESA dosing. Clinicians also should avoid simultaneous adjustments to ESA and IV iron doses. To minimize the potential for risks when making ESA or IV iron dose adjustments, I recommend evaluating a patient’s entire clinical picture. For example, if an ESA-treated patient’s Hb levels are decreasing or not responding adequately to ESA therapy, determine the underlying cause of the decreasing or suboptimal Hb levels before increasing the ESA dose. Reasons for decreasing Hb levels might include an undetected source of blood loss that is causing decreased body iron content, such as bleeding from a vascular access site, bleeding in the intestines, or dialyzer-related blood retention. Also, monitor iron indices to determine whether a patient’s iron status is sufficient for erythropoiesis. Suboptimal
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Hb levels may result from iron deficiency, including a state of iron-restricted erythropoiesis. In patients with iron-restricted erythropoiesis, iron stores are used by ESA-driven erythropoiesis more quickly than they can be replenished. A similar scenario also may be seen in patients with inflammation-mediated processes, such as infection, which reduce/restrict the release of stored iron from the reticuloendothelial system to circulating transferrin. Several small studies of patients with CKD on dialysis therapy with ESA hyporesponsiveness and increased serum ferritin levels have investigated the utility of ascorbic acid supplementation.19-21 Vitamin C or ascorbic acid makes iron available for erythropoiesis by increasing its release from the reticuloendothelial system and from ferritin. Although KDOQI states that there is insufficient evidence to recommend the use of vitamin C, the European Best Practices Guidelines suggested that correction of impaired vitamin C status could reduce resistance to ESA therapy.22 Administration of 300 mg of ascorbic acid 3 times weekly on dialysis for less than 8 weeks duration appears to have only a modest effect on oxalate levels.20 Be alert to laboratory indicators of the mentioned causes of decreasing or low Hb levels: Iron loss related to bleeding may be signaled by decreased ferritin levels in the presence of either decreasing or stable Hb levels. Iron-restricted erythropoiesis may be suggested by a normal or increased serum ferritin level and low transferrin saturation (TSAT), and inflammation-mediated iron restriction may manifest as an increased serum ferritin level, decreased TSAT, low Hb level, increased ESA dose, and C-reactive protein level increased greater than 20 mg/L (generally a marker for inflammation in patients receiving hemodialysis).15,23,24 Complete your assessment of the patient’s clinical picture by evaluating the appropriateness of the patient’s IV iron dose, analyzing trends in the patient’s laboratory results and medical history, questioning the patient about such signs and symptoms as weakness or fatigue, and ruling out an active infection or another source of inflammation that may interfere with the efficacy of erythropoiesis.
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NEED FOR BALANCE BETWEEN IV IRON AND ESA It is important to remember that if iron and ESA dosing are not properly balanced, iron may not be available in sufficient quantities for effective erythropoiesis. This is not always a case of decreased total body iron content, as in a patient losing iron because of blood loss, but may be a problem of iron delivery resulting from infection, inflammation, or high-dose ESA therapy. In these situations, iron administration may be required to address the iron deficit.15 Carefully monitoring and addressing a patient’s iron status may help minimize the required ESA doses and maintain target-range Hb levels.15 KDOQI guidelines recommend frequent monitoring of iron status test results, combined with evaluation of the current Hb level and ESA dose and the trends in these over time.15 These management strategies are especially important because of the concerns associated with increasing ESA doses in patients who fail to achieve a corresponding hematologic response.1-3,25 The Food and Drug Administration revised product information labeling for ESAs in 2007 to incorporate guidance on treating patients who fail to achieve or maintain a response to ESA therapy, with an emphasis on minimizing the risks of unnecessarily high ESA doses in these patients.4,8,9,26 The revised label notes that insufficient iron is among the potential underlying causes of a poor response to ESA therapy that clinicians should consider.8,9 KDOQI guidelines state that iron deficiency is a common cause of a blunted ESA response.5,15,18 However, data from the CMS End-Stage Renal Disease Clinical Performance Measures Project for October to December 2004 point to a trend of administering the highest ESA doses to patients with the lowest Hb levels. In this report, weekly epoetin doses ranged from 400 to 550 U/kg/wk for patients with Hb levels less than 11 g/dL compared with 275 to 400 U/kg/wk for patients with Hb levels of 11 to 11.9 g/dL.27 DRIVE-II: ADDRESSING ANEMIA MANAGEMENT CHALLENGES The challenges of managing anemia in patients with CKD both on and off dialysis therapy are multifaceted: maintain stable Hb levels and
Toros Kapoian
avoid overshooting Hb level targets, balance IV iron and ESA therapy, and improve ESA response while using the lowest effective ESA doses. Evidence of the role of IV iron in managing these challenges, particularly in hemodialysis patients who have anemia despite adequate ESA doses, is found in the randomized controlled Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) clinical trial and its 6-week follow-up extension study, DRIVE-II.28,29 In DRIVE, a 6-week open-label randomized study, patients receiving hemodialysis with Hb levels of 11 g/dL or less, serum ferritin levels of 500 to 1,200 ng/mL, and TSATs of 25% or less and receiving adequate ESA doses were randomly assigned to receive IV iron (1 g of sodium ferric gluconate administered as 125-mg doses over 8 consecutive hemodialysis sessions) or no IV iron (control).28 Patients in both groups received a 25% increase in their ESA dose at the beginning of the first week, after which ESA doses were held constant for the next 6 weeks.28 DRIVE showed the efficacy of IV iron in this patient population.28 The IV iron group had a greater increase in Hb levels and greater percentage of patients with a clinically significant Hb level response (defined as at least a 2-g/dL increase in Hb level at any point during the study) compared with the control group.28 They also had a faster time to response compared with the control group.28 However, the 6-week duration of DRIVE was not sufficient for an analysis of whether the group that received IV iron would sustain the Hb level improvement or to observe effects on iron indices under the routine circumstances of anemia management.29 Additionally, because ESA doses were held constant in DRIVE, the study precluded investigation of the ESAsparing effects of IV iron.29 Therefore, DRIVE participants were enrolled in DRIVE-II, a 6-week observational study in which they resumed routine management of ESA and IV iron therapy.29 The primary objective of DRIVE-II was to investigate the effect of ferric gluconate administration on weekly ESA doses, with a secondary objective of analyzing changes in Hb levels, TSATs, and serum ferritin levels. There was no restriction on iron administration in either arm during DRIVE-II, and ESA doses were adjusted at the discretion of the treating nephrologists and
Effectively Using ESA and IV Iron
anemia managers to permit analysis of the effect of IV iron administration on weekly ESA doses.29
DRIVE-II: REDUCED ESA REQUIREMENTS IN THE FERRIC GLUCONATE GROUP The analysis duration included the 12-week period from the beginning of DRIVE to the end of DRIVE-II.29 Results showed that in patients undergoing hemodialysis who have serum ferritin levels of 500 to 1,200 ng/mL and TSATs of 25% or less, IV iron administered as a 1-g course of ferric gluconate during the DRIVE study safely and effectively decreased ESA doses during DRIVE-II while maintaining the improved Hb levels achieved with ferric gluconate during DRIVE.29 The ferric gluconate group experienced a mean decrease in ESA dose of about 21% from the DRIVE dose to the end of DRIVEII, a finding that was significant (P ⫽ 0.003; Fig 1). By week 12, the ESA dose of the ferric gluconate group was significantly less than that of the control group (P ⫽ 0.017). The final ESA dose of patients in the control group was significantly greater (P ⬍ 0.05) than that of patients in the ferric gluconate group, who had a final ESA dose similar to their baseline dose in DRIVE (before the 25% ESA dose increase).29 During the 6 weeks of DRIVE-II, significantly more patients in the ferric gluconate group than in the control group, 83.9% versus 67.9% (P ⬍
Mean ESA Dose, IU/wk
50,000
S25
0.05), maintained their Hb levels at greater than 11.0 g/dL despite decreases in their ESA dose (Fig 2).29 In both groups, there were no significant changes in Hb levels during the 6 weeks of DRIVE-II, again although the ferric gluconate group had a significantly decreased ESA dose compared with the DRIVE dose.29 Hb level change was 0.2 ⫾ 1.3 and 0.2 ⫾ 1.2 g/dL in the control and ferric gluconate groups from the end of DRIVE to the end of DRIVE-II, respectively (P ⫽ 0.432). There was also no significant change in TSATs during DRIVE-II in either group.29 The ferric gluconate group’s serum ferritin levels decreased significantly during the 6 weeks of the DRIVE-II study, whereas the control group’s serum ferritin levels increased, although not significantly (Fig 3).29 The ferric gluconate group’s serum ferritin levels initially increased (from 761 ng/mL at the beginning of DRIVE to 934 ng/mL at the end of DRIVE), then decreased by 92 ⫾ 217 ng/mL by the end of DRIVE-II (P ⫽ 0.009).29 This pattern of increasing serum ferritin levels followed by a decrease was similar to that after administration of 1 g of IV iron to patients who were overtly iron deficient.30,31 Regardless of whether patients’ baseline serum ferritin levels in DRIVE were 800 ng/mL or less or greater than 800 ng/mL, there was no significant difference between baseline serum ferritin levels and serum ferritin levels at the end
Control Group Ferric Gluconate Group
45,000
45.7
45.0 43.7
P = 0.017 40,000
36.1
36.0 35,000
34.9
30,000
Baseline Dose
DRIVE Dose
Dose at End o f DRIVE-II (Week 12)
Figure 1. Changes in mean weekly erythropoiesis-stimulating agent (ESA) dose in both the ferric gluconate and control groups from the base dose of the 6-week trial Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE)28 through the dose at the end of the 6-week extension study, DRIVE-II.29 At the beginning of week 1 of DRIVE, both groups received a 25% increase in ESA dose. ESA dose then was held constant through 6 weeks of DRIVE. The ferric gluconate group received 125 mg of intravenous ferric gluconate administered over 8 sessions in DRIVE. By week 12, ESA dose was significantly lower in ferric gluconate group than the control group. Adapted with permission from Kapoian et al.29
S26
Toros Kapoian 12.5
Hb, g/dL
12.0
Control Group Ferric Gluconate Group
11.9
12.1
11.6 11.5 11.4 11.0
10.5 10.3 10.1 10.0
DRIVE Baseline (Week 0)
End of DRIVE (Week 6)
End of DRIVE-II (Week 12)
Change from end of DRIVE to end of DRIVE-II: P = 0.432.
Figure 2. Changes in mean hemoglobin (Hb) values in the ferric gluconate and control groups from the baseline of the 6-week trial Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE)28 through the end of the 6-week extension study, DRIVE-II (week 12).29 During DRIVE, the ferric gluconate group experienced a significantly greater increase in mean Hb level than the control group.28 During DRIVE-II, significantly more patients in the ferric gluconate group than in the control group, 83.9% versus 67.9%, maintained their Hb levels at greater than 11.0 g/dL. Hb in g/dL may be converted to g/L by multiplying by 10. Adapted with permission from Kapoian et al.29
of DRIVE-II. Therefore, there was little impact of treatment on the numbers of patients with serum ferritin levels greater than 800 ng/mL.29
Serum Ferritin, ng/mL
DRIVE-II: FEWER ADVERSE EVENTS IN THE FERRIC GLUCONATE GROUP During the 12-week period of DRIVE-II, there was a significantly lower incidence of serious 1200
Control Group
1100
Ferric Gluconate Group
1000
adverse events in the ferric gluconate group.29 Although concerns have existed about the potential of IV iron administration to increase infection risk in patients who are undergoing hemodiaylsis and have increased serum ferritin levels, there were fewer hospitalizations for infections in the ferric gluconate group than the control group.29 No infection risk coinciding with the
934
900 800
761
802
752 700 582
585
600 500
DRIVE Baseline (Week 0)
End of DRIVE (Week 6)
End of DRIVE-II (Week 12)
Change from end of DRIVE to end of DRIVE-II: P = 0.459.
Figure 3. Changes in serum ferritin levels in the ferric gluconate and control groups from the baseline of the 6-week trial Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE)28 through the end of the 6-week extension study, DRIVE-II (week 12).29 The ferric gluconate group’s serum ferritin levels increased significantly during the 6 weeks of the DRIVE study, then decreased by the end of DRIVE-II. This was similar to effects observed with administering 1 g of iron to patients who were overtly iron deficient in previous studies.30,31 Ferritin levels expressed in ng/mL and g/L are equivalent. Reprinted with permission from Kapoian et al.29
Effectively Using ESA and IV Iron
administration of IV iron or occurring shortly thereafter was observed. The overall finding of fewer adverse events in the ferric gluconate group than in the control group, which did not receive IV iron during the 6 weeks of DRIVE, suggests the possibility that iron deficiency is associated with more adverse events.29
CONCLUSION In summary, the DRIVE-II study shows that IV iron minimizes ESA dose requirements while maintaining improved Hb levels as administered during the 6 weeks of DRIVE to hemodialysis patients who have TSATs of 25% or less and serum ferritin levels of 500 to 1,200 ng/mL and are receiving adequate ESA doses.29 These findings support the use of IV iron to manage the challenges in anemia management today: maintaining stable Hb levels and dosing IV iron and ESAs appropriately while using the lowest effective ESA dose. To minimize risks for patients, I recommend a balanced approach to ESA and IV iron therapy that recognizes the benefits of IV iron. ACKNOWLEDGEMENTS The author acknowledges the assistance of Regina Kelly in preparation of this manuscript. Support: None. Financial Disclosure: Within the past 3 years, Dr Kapoian reports having received researching grant support from Watson Pharmaceuticals, which markets an injectable sodium ferric gluconate compound, and from Roche, which markets an erythropoietin-stimulating agent.
REFERENCES 1. Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339:584-590, 1998 2. Drüeke TB, Locatelli F, Clyne N, et al: CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355:2071-2084, 2006 3. Singh AK, Szczech L, Tang KL, et al: CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355:2085-2098, 2006 4. US Food and Drug Administration and Center for Drug Evaluation and Research: Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA). Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/ RHE2007HCP.htm. Accessed February 25, 2008 5. National Kidney Foundation: KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for
S27 Anemia in Chronic Kidney Disease, 2007 Update of Hemoglobin Target. Am J Kidney Dis 50:471-530, 2007 6. Centers for Medicare & Medicaid Services. CMS Manual System. Pub 100-04 Medicare Claims Processing. Transmittal 1307. Change Request 5700. 7-20-2007. Available at: http://www.cms.hhs.gov/Transmittals/Downloads/ R1307CP.pdf. Accessed January 3, 2008 7. US Renal Data System: USRDS 2007 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007 8. FDA: Aranesp (darbepoetin alfa) for injection: Prescribing information. Silver Spring, MD, US Food and Drug Administration (USFDA), March 2008 9. FDA: Procrit (Epoetin alfa) for injection: Prescribing information. Silver Spring, MD, US Food and Drug Administration (USFDA), March 2008 10. Fishbane S, Berns JS: Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int 68:1337-1343, 2005 11. Yang W, Israni RK, Brunelli SM, Joffe MM, Fishbane S, Feldman HI: Hemoglobin variability and mortality in ESRD. J Am Soc Nephrol 18:3164-3170, 2007 12. Ebben JP, Gilbertson DT, Foley RN, Collins AJ: Hemoglobin level variability: Associations with comorbidity, intercurrent events, and hospitalizations. Clin J Am Soc Nephrol 1:1205-1210, 2006 13. Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury BD, Collins AJ: Hemoglobin level variability: Associations with mortality. Clin J Am Soc Nephrol 3:133138, 2008 14. Portolés J, López-Gómez JM, Aljama P: A prospective multicentre study of the role of anaemia as a risk factor in haemodialysis patients: The MAR Study. Nephrol Dial Transplant 22:500-507, 2007 15. National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S11-S145, 2006 (suppl 3) 16. Fishbane S, Besarab A: Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol 2:1274-1282, 2007 17. Petroff S: Evaluating traditional iron measures and exploring new options for patients on hemodialysis. Nephrol Nurs J 32:65-73, 2005 18. National Kidney Foundation: NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. Am J Kidney Dis 37:S182-S238, 2001 (suppl 1) 19. Gastaldello K, Vereerstraeten A, Nzame-Nze T, et al: Resistance to erythropoietin in iron-overloaded haemodialysis patients can be overcome by ascorbic acid administration. Nephrol Dial Transplant 10:S44-S47, 1995 (suppl 6) 20. Tarng DC, Wei YH, Huang TP, et al: Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia. Kidney Int 55:2477-2486, 1999 21. Attallah N, Osman-Malik Y, Frinak S, Besarab A: Effect of intravenous ascorbic acid in hemodialysis patients with EPO-hyporesponsive anemia and hyperferritinemia. Am J Kidney Dis 47:644-654, 2006
S28 22. Locatelli F, Aljama P, Barany P, et al: Revised European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 19 Suppl 2:ii1-47, 2004 23. Lin JL, Chang MY, Tan DT, Leu ML: Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients. Am J Nephrol 21:91-97, 2001 24. Wish JB: Assessing iron status: Beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 1:S4-S8, 2006 (suppl 1) 25. Regidor DL, Kopple JD, Kovesdy CP, et al: Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 17:1181-1191, 2006 26. US Food and Drug Administration and Center for Drug Evaluation and Research: Questions and Answers for Erythropoiesis-Stimulating Agents (ESAs) Labeling Changes. Available at: http://www.fda.gov/CDER/drug/infopage/RHE/ qa2007.htm. Accessed February 25, 2008 27. Centers for Medicare & Medicaid Services: 2005 Annual Report, End-Stage Renal Disease Clinical Performance Measures Project. Baltimore, MD, Department of
Toros Kapoian Health and Human Services, Centers for Medicare & Medicaid Services, Office of Clinical Standards and Quality, 2005 28. Coyne DW, Kapoian T, Suki W, et al: DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: Results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 18:975-984, 2007 29. Kapoian T, O’Mara NB, Singh AK, et al: Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol 19:372379, 2008 30. Warady BA, Zobrist RH, Wu J, Finan E; Ferrlecit Pediatric Study Group: Sodium ferric gluconate complex therapy in anemic children on hemodialysis. Pediatr Nephrol 20:1320-1327, 2005. 31. Nissenson AR, Lindsay RM, Swan S, Seligman P, Strobos J: Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial. Am J Kidney Dis 33:471-482, 1999
T
he safety of higher hemoglobin (Hb) levels and the use of erythropoiesis-stimulating agents (ESAs) to target these levels is a concern in the nephrology community. Adverse outcomes have been reported in clinical trials investigating the effects of targeting Hb levels greater than 13 g/dL with an ESA in patients with chronic kidney disease (CKD).1-3 In 2007 the US Food and Drug Administration approved ESA boxed warnings and decreased its recommended Hb level range for ESA therapy.4 The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (KDOQI) updated its target Hb level range for ESAs.5 The Centers for Medicare & Medicaid Services (CMS) revised its Medicare claims policy for ESAs to include more conservative ESA dosing parameters in 2007.6
OVERSHOOTING Hb TARGETS Data from the US Renal Data System show that greater Hb levels are not uncommon in dialysis patients receiving ESAs, highlighting the need for improvement in maintaining Hb levels within the target range. The mean attained Hb level in dialysis patients 6 months after ESA therapy initiation was 12.2 g/dL in 2005, whereas mean weekly ESA doses 2 months after ESA therapy initiation were nearly 29,000 U/wk.7 The US Renal Data System also reported that 42% of patients achieve an Hb level of 14 g/dL or greater and 97% achieve an Hb level of 12 g/dL or greater 6 months after first attaining an Hb level of 11 g/dL.7 Overshooting the Hb level target is 3
to 4 times more common today than it was in 1997, whereas ESA dosing also has increased 3 to 4 times.7 These upward-trending Hb levels and ESA doses can be problematic for several reasons. Boxed warnings for ESAs state that patients experience greater risks of death and serious cardiovascular events when administered ESAs to target higher versus lower Hb levels.8,9 In addition, large increases in ESA doses intended to stimulate a better Hb response can lead to overshooting the Hb level target, increasing the patient’s risk of the adverse outcomes identified in clinical trials.1-3 Overshooting Hb levels in turn might spur a decision to withhold or scale back ESA therapy to restabilize Hb levels. This pattern of inconsistent ESA dosing can cause wide fluctuations in a patient’s Hb levels, putting the patient at further risk of poor outcomes.10,11
From UMDNJ–Robert Wood Johnson Medical School, New Brunswick, NJ. This article was published as part of a supplement sponsored by an educational grant from Watson Pharmaceuticals. Address correspondence to Toros Kapoian, MD, Department of Medicine/Nephrology, UMDNJ–Robert Wood Johnson Medical School, 1 Robert Wood Johnson Pl, MEB-412B, New Brunswick, NJ 08903. E-mail: tkapoian@ verizon.net © 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5206-0104$34.00/0 doi:10.1053/j.ajkd.2008.09.004
American Journal of Kidney Diseases, Vol 52, No 6, Suppl 1 (December), 2008: pp S21-S28
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Toros Kapoian
assessed the impact of the degree of Hb level variability and number of months it persisted on mortality rates. The study reported that mortality risks became increasingly higher the longer patients’ Hb levels remained out of range, in particular, less than 11 g/dL.13
BENEFITS OF STABLE Hb LEVELS Maintaining stable Hb levels within the target range has been linked to the lowest hospital admission rates, fewest comorbidities, and shortest hospital stays.12 A study of 152,846 Medicare patients undergoing hemodialysis who were receiving ESAs and survived the first 6 months of 2003 evaluated the frequency with which these patients maintained Hb levels less than, within, and greater than the Hb target range recommended by the CMS at that time (11 to 12.5 g/dL).12 Patients with consistent target-range Hb levels had the lowest percentage of hospital admissions and admissions for infections and the shortest hospital stays (Table 1).12 Out-of-range Hb levels have been associated with reduced quality of life, impaired cardiac function, longer hospitalization stays, and greater risk of death.13-15 A prospective observational study of 1,428 patients with CKD from 119 centers found that maintaining Hb levels in the target range was associated with longer time to hospitalization and decreased adjusted mortality risk.14 In this study, Hb levels were predictive of 1-year survival and hospitalization, with a linear decrease in mortality risk as initial Hb levels increased from less than 10 to 12 g/dL. For Hb values of 11 to 12 g/dL, confidence intervals for the probability of 1-year survival and remaining free from hospitalization were 0.54 and 0.89, respectively. This was an improvement over the confidence intervals for lower Hb level ranges (0.34 and 0.77 for Hb ⬍ 10 g/dL and 0.47 and 0.82 for Hb of 10 to 11 g/dL).14 In an analysis of Medicare data for 159,720 ESA-treated hemodialysis patients who survived the first 6 months of 2004, patient Hb levels were classified according to 6 variability groups based on the lowest and highest Hb levels during a 6-month observation period.13 The investigators
APPROPRIATELY DOSING ESAs AND INTRAVENOUS IRON Although suboptimal Hb levels are undesirable, caution is advised when increasing ESA doses if faced with persistently low Hb levels.4,8,9 Data from an unpublished 1988 study conducted by J. Caro, as reported by Fishbane and Besarab16 in 2007, offer evidence that supports a conservative approach to making ESA dose adjustments to achieve target Hb levels. The study examined the endogenous response to blood loss from a rapid 2-unit phlebotomy in normal healthy male volunteers during 2 weeks. By the end of the first day, Hb levels decreased from a normal baseline value of 15 to 12 g/dL, whereas circulating mean endogenous erythropoietin levels increased 10-fold from 10 to 15 mU/mL at baseline to approximately 200 mU/mL. During the 2-week period, Hb levels progressively increased, partially correcting the anemia triggered by the blood loss, as endogenous erythropoietin levels decreased. It was determined that 50% of the red blood cell (RBC) deficit was corrected within the 2 weeks and the rest would be corrected during the next 6 weeks, while erythropoietin levels returned to normal concentrations. This type of response is preserved, although blunted, in hemodialysis patients.16 The study emphasizes the importance of providing sufficient time to allow Hb levels to respond to increased erythropoietin concentrations in ESA-treated patients before automatically increasing ESA doses.
Table 1. Lowest Hospitalization and Comorbidity Associated With Target-Range Hb Levels
Hb (g/dL)
Hospital Admission (%)
Admission for Infection (%)
Average Length of Stay (d)
Average Comorbidity (n)
Low (⬍11) Target (11-⬍12.5) High (ⱖ12.5)
69.2 25.3 29.8
29.5 6.2 7.4
12.7 1.9 2.2
2.4 1.1 1.2
Note: Hb in g/dL may be converted to g/L by multiplying by 10. Abbreviation: Hb, hemoglobin. Adapted with permission from Ebben et al.12
Effectively Using ESA and IV Iron
The phases of erythropoiesis itself point to the need for balance in anemia management strategies. Erythropoiesis is a process that requires both iron and erythropoietin. Erythropoietin steers the process by activating RBC production in the bone marrow, but iron is essential during the phase of RBC development. A sufficient supply of available iron during erythropoiesis ensures that RBCs are large enough and have sufficient oxygen-carrying capacity.17 The right balance between ESA and intravenous (IV) iron therapies, including appropriate dosing, therefore can optimize anemia treatment. For ESAs, full prescribing information provides a weight-based calculation to initiate therapy in patients with chronic kidney failure.8,9 It also is recommended that ESA dose increases should not be made more than once a month8,9 and ESA doses should be titrated by 25%.8,9 In addition, 4 weeks should be allowed between dose adjustments to provide sufficient time for changes in Hb levels in patients for whom the Hb level increase is less than 1 g/dL over 4 weeks and iron stores are adequate.8,9 For IV iron therapy administered to patients receiving ESAs, KDOQI guidelines5,15,18 recommend that before initiating ESA therapy, clinicians ensure that patients are iron replete. This includes evaluating patients for iron deficiency, consulting various laboratory markers to assess adequacy of iron for erythropoiesis, and determining the underlying causes of low Hb levels. In addition, it is recommended that after administering a repletion course of IV iron, clinicians assess ESA dosing. Clinicians also should avoid simultaneous adjustments to ESA and IV iron doses. To minimize the potential for risks when making ESA or IV iron dose adjustments, I recommend evaluating a patient’s entire clinical picture. For example, if an ESA-treated patient’s Hb levels are decreasing or not responding adequately to ESA therapy, determine the underlying cause of the decreasing or suboptimal Hb levels before increasing the ESA dose. Reasons for decreasing Hb levels might include an undetected source of blood loss that is causing decreased body iron content, such as bleeding from a vascular access site, bleeding in the intestines, or dialyzer-related blood retention. Also, monitor iron indices to determine whether a patient’s iron status is sufficient for erythropoiesis. Suboptimal
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Hb levels may result from iron deficiency, including a state of iron-restricted erythropoiesis. In patients with iron-restricted erythropoiesis, iron stores are used by ESA-driven erythropoiesis more quickly than they can be replenished. A similar scenario also may be seen in patients with inflammation-mediated processes, such as infection, which reduce/restrict the release of stored iron from the reticuloendothelial system to circulating transferrin. Several small studies of patients with CKD on dialysis therapy with ESA hyporesponsiveness and increased serum ferritin levels have investigated the utility of ascorbic acid supplementation.19-21 Vitamin C or ascorbic acid makes iron available for erythropoiesis by increasing its release from the reticuloendothelial system and from ferritin. Although KDOQI states that there is insufficient evidence to recommend the use of vitamin C, the European Best Practices Guidelines suggested that correction of impaired vitamin C status could reduce resistance to ESA therapy.22 Administration of 300 mg of ascorbic acid 3 times weekly on dialysis for less than 8 weeks duration appears to have only a modest effect on oxalate levels.20 Be alert to laboratory indicators of the mentioned causes of decreasing or low Hb levels: Iron loss related to bleeding may be signaled by decreased ferritin levels in the presence of either decreasing or stable Hb levels. Iron-restricted erythropoiesis may be suggested by a normal or increased serum ferritin level and low transferrin saturation (TSAT), and inflammation-mediated iron restriction may manifest as an increased serum ferritin level, decreased TSAT, low Hb level, increased ESA dose, and C-reactive protein level increased greater than 20 mg/L (generally a marker for inflammation in patients receiving hemodialysis).15,23,24 Complete your assessment of the patient’s clinical picture by evaluating the appropriateness of the patient’s IV iron dose, analyzing trends in the patient’s laboratory results and medical history, questioning the patient about such signs and symptoms as weakness or fatigue, and ruling out an active infection or another source of inflammation that may interfere with the efficacy of erythropoiesis.
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NEED FOR BALANCE BETWEEN IV IRON AND ESA It is important to remember that if iron and ESA dosing are not properly balanced, iron may not be available in sufficient quantities for effective erythropoiesis. This is not always a case of decreased total body iron content, as in a patient losing iron because of blood loss, but may be a problem of iron delivery resulting from infection, inflammation, or high-dose ESA therapy. In these situations, iron administration may be required to address the iron deficit.15 Carefully monitoring and addressing a patient’s iron status may help minimize the required ESA doses and maintain target-range Hb levels.15 KDOQI guidelines recommend frequent monitoring of iron status test results, combined with evaluation of the current Hb level and ESA dose and the trends in these over time.15 These management strategies are especially important because of the concerns associated with increasing ESA doses in patients who fail to achieve a corresponding hematologic response.1-3,25 The Food and Drug Administration revised product information labeling for ESAs in 2007 to incorporate guidance on treating patients who fail to achieve or maintain a response to ESA therapy, with an emphasis on minimizing the risks of unnecessarily high ESA doses in these patients.4,8,9,26 The revised label notes that insufficient iron is among the potential underlying causes of a poor response to ESA therapy that clinicians should consider.8,9 KDOQI guidelines state that iron deficiency is a common cause of a blunted ESA response.5,15,18 However, data from the CMS End-Stage Renal Disease Clinical Performance Measures Project for October to December 2004 point to a trend of administering the highest ESA doses to patients with the lowest Hb levels. In this report, weekly epoetin doses ranged from 400 to 550 U/kg/wk for patients with Hb levels less than 11 g/dL compared with 275 to 400 U/kg/wk for patients with Hb levels of 11 to 11.9 g/dL.27 DRIVE-II: ADDRESSING ANEMIA MANAGEMENT CHALLENGES The challenges of managing anemia in patients with CKD both on and off dialysis therapy are multifaceted: maintain stable Hb levels and
Toros Kapoian
avoid overshooting Hb level targets, balance IV iron and ESA therapy, and improve ESA response while using the lowest effective ESA doses. Evidence of the role of IV iron in managing these challenges, particularly in hemodialysis patients who have anemia despite adequate ESA doses, is found in the randomized controlled Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) clinical trial and its 6-week follow-up extension study, DRIVE-II.28,29 In DRIVE, a 6-week open-label randomized study, patients receiving hemodialysis with Hb levels of 11 g/dL or less, serum ferritin levels of 500 to 1,200 ng/mL, and TSATs of 25% or less and receiving adequate ESA doses were randomly assigned to receive IV iron (1 g of sodium ferric gluconate administered as 125-mg doses over 8 consecutive hemodialysis sessions) or no IV iron (control).28 Patients in both groups received a 25% increase in their ESA dose at the beginning of the first week, after which ESA doses were held constant for the next 6 weeks.28 DRIVE showed the efficacy of IV iron in this patient population.28 The IV iron group had a greater increase in Hb levels and greater percentage of patients with a clinically significant Hb level response (defined as at least a 2-g/dL increase in Hb level at any point during the study) compared with the control group.28 They also had a faster time to response compared with the control group.28 However, the 6-week duration of DRIVE was not sufficient for an analysis of whether the group that received IV iron would sustain the Hb level improvement or to observe effects on iron indices under the routine circumstances of anemia management.29 Additionally, because ESA doses were held constant in DRIVE, the study precluded investigation of the ESAsparing effects of IV iron.29 Therefore, DRIVE participants were enrolled in DRIVE-II, a 6-week observational study in which they resumed routine management of ESA and IV iron therapy.29 The primary objective of DRIVE-II was to investigate the effect of ferric gluconate administration on weekly ESA doses, with a secondary objective of analyzing changes in Hb levels, TSATs, and serum ferritin levels. There was no restriction on iron administration in either arm during DRIVE-II, and ESA doses were adjusted at the discretion of the treating nephrologists and
Effectively Using ESA and IV Iron
anemia managers to permit analysis of the effect of IV iron administration on weekly ESA doses.29
DRIVE-II: REDUCED ESA REQUIREMENTS IN THE FERRIC GLUCONATE GROUP The analysis duration included the 12-week period from the beginning of DRIVE to the end of DRIVE-II.29 Results showed that in patients undergoing hemodialysis who have serum ferritin levels of 500 to 1,200 ng/mL and TSATs of 25% or less, IV iron administered as a 1-g course of ferric gluconate during the DRIVE study safely and effectively decreased ESA doses during DRIVE-II while maintaining the improved Hb levels achieved with ferric gluconate during DRIVE.29 The ferric gluconate group experienced a mean decrease in ESA dose of about 21% from the DRIVE dose to the end of DRIVEII, a finding that was significant (P ⫽ 0.003; Fig 1). By week 12, the ESA dose of the ferric gluconate group was significantly less than that of the control group (P ⫽ 0.017). The final ESA dose of patients in the control group was significantly greater (P ⬍ 0.05) than that of patients in the ferric gluconate group, who had a final ESA dose similar to their baseline dose in DRIVE (before the 25% ESA dose increase).29 During the 6 weeks of DRIVE-II, significantly more patients in the ferric gluconate group than in the control group, 83.9% versus 67.9% (P ⬍
Mean ESA Dose, IU/wk
50,000
S25
0.05), maintained their Hb levels at greater than 11.0 g/dL despite decreases in their ESA dose (Fig 2).29 In both groups, there were no significant changes in Hb levels during the 6 weeks of DRIVE-II, again although the ferric gluconate group had a significantly decreased ESA dose compared with the DRIVE dose.29 Hb level change was 0.2 ⫾ 1.3 and 0.2 ⫾ 1.2 g/dL in the control and ferric gluconate groups from the end of DRIVE to the end of DRIVE-II, respectively (P ⫽ 0.432). There was also no significant change in TSATs during DRIVE-II in either group.29 The ferric gluconate group’s serum ferritin levels decreased significantly during the 6 weeks of the DRIVE-II study, whereas the control group’s serum ferritin levels increased, although not significantly (Fig 3).29 The ferric gluconate group’s serum ferritin levels initially increased (from 761 ng/mL at the beginning of DRIVE to 934 ng/mL at the end of DRIVE), then decreased by 92 ⫾ 217 ng/mL by the end of DRIVE-II (P ⫽ 0.009).29 This pattern of increasing serum ferritin levels followed by a decrease was similar to that after administration of 1 g of IV iron to patients who were overtly iron deficient.30,31 Regardless of whether patients’ baseline serum ferritin levels in DRIVE were 800 ng/mL or less or greater than 800 ng/mL, there was no significant difference between baseline serum ferritin levels and serum ferritin levels at the end
Control Group Ferric Gluconate Group
45,000
45.7
45.0 43.7
P = 0.017 40,000
36.1
36.0 35,000
34.9
30,000
Baseline Dose
DRIVE Dose
Dose at End o f DRIVE-II (Week 12)
Figure 1. Changes in mean weekly erythropoiesis-stimulating agent (ESA) dose in both the ferric gluconate and control groups from the base dose of the 6-week trial Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE)28 through the dose at the end of the 6-week extension study, DRIVE-II.29 At the beginning of week 1 of DRIVE, both groups received a 25% increase in ESA dose. ESA dose then was held constant through 6 weeks of DRIVE. The ferric gluconate group received 125 mg of intravenous ferric gluconate administered over 8 sessions in DRIVE. By week 12, ESA dose was significantly lower in ferric gluconate group than the control group. Adapted with permission from Kapoian et al.29
S26
Toros Kapoian 12.5
Hb, g/dL
12.0
Control Group Ferric Gluconate Group
11.9
12.1
11.6 11.5 11.4 11.0
10.5 10.3 10.1 10.0
DRIVE Baseline (Week 0)
End of DRIVE (Week 6)
End of DRIVE-II (Week 12)
Change from end of DRIVE to end of DRIVE-II: P = 0.432.
Figure 2. Changes in mean hemoglobin (Hb) values in the ferric gluconate and control groups from the baseline of the 6-week trial Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE)28 through the end of the 6-week extension study, DRIVE-II (week 12).29 During DRIVE, the ferric gluconate group experienced a significantly greater increase in mean Hb level than the control group.28 During DRIVE-II, significantly more patients in the ferric gluconate group than in the control group, 83.9% versus 67.9%, maintained their Hb levels at greater than 11.0 g/dL. Hb in g/dL may be converted to g/L by multiplying by 10. Adapted with permission from Kapoian et al.29
of DRIVE-II. Therefore, there was little impact of treatment on the numbers of patients with serum ferritin levels greater than 800 ng/mL.29
Serum Ferritin, ng/mL
DRIVE-II: FEWER ADVERSE EVENTS IN THE FERRIC GLUCONATE GROUP During the 12-week period of DRIVE-II, there was a significantly lower incidence of serious 1200
Control Group
1100
Ferric Gluconate Group
1000
adverse events in the ferric gluconate group.29 Although concerns have existed about the potential of IV iron administration to increase infection risk in patients who are undergoing hemodiaylsis and have increased serum ferritin levels, there were fewer hospitalizations for infections in the ferric gluconate group than the control group.29 No infection risk coinciding with the
934
900 800
761
802
752 700 582
585
600 500
DRIVE Baseline (Week 0)
End of DRIVE (Week 6)
End of DRIVE-II (Week 12)
Change from end of DRIVE to end of DRIVE-II: P = 0.459.
Figure 3. Changes in serum ferritin levels in the ferric gluconate and control groups from the baseline of the 6-week trial Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE)28 through the end of the 6-week extension study, DRIVE-II (week 12).29 The ferric gluconate group’s serum ferritin levels increased significantly during the 6 weeks of the DRIVE study, then decreased by the end of DRIVE-II. This was similar to effects observed with administering 1 g of iron to patients who were overtly iron deficient in previous studies.30,31 Ferritin levels expressed in ng/mL and g/L are equivalent. Reprinted with permission from Kapoian et al.29
Effectively Using ESA and IV Iron
administration of IV iron or occurring shortly thereafter was observed. The overall finding of fewer adverse events in the ferric gluconate group than in the control group, which did not receive IV iron during the 6 weeks of DRIVE, suggests the possibility that iron deficiency is associated with more adverse events.29
CONCLUSION In summary, the DRIVE-II study shows that IV iron minimizes ESA dose requirements while maintaining improved Hb levels as administered during the 6 weeks of DRIVE to hemodialysis patients who have TSATs of 25% or less and serum ferritin levels of 500 to 1,200 ng/mL and are receiving adequate ESA doses.29 These findings support the use of IV iron to manage the challenges in anemia management today: maintaining stable Hb levels and dosing IV iron and ESAs appropriately while using the lowest effective ESA dose. To minimize risks for patients, I recommend a balanced approach to ESA and IV iron therapy that recognizes the benefits of IV iron. ACKNOWLEDGEMENTS The author acknowledges the assistance of Regina Kelly in preparation of this manuscript. Support: None. Financial Disclosure: Within the past 3 years, Dr Kapoian reports having received researching grant support from Watson Pharmaceuticals, which markets an injectable sodium ferric gluconate compound, and from Roche, which markets an erythropoietin-stimulating agent.
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S27 Anemia in Chronic Kidney Disease, 2007 Update of Hemoglobin Target. Am J Kidney Dis 50:471-530, 2007 6. Centers for Medicare & Medicaid Services. CMS Manual System. Pub 100-04 Medicare Claims Processing. Transmittal 1307. Change Request 5700. 7-20-2007. Available at: http://www.cms.hhs.gov/Transmittals/Downloads/ R1307CP.pdf. Accessed January 3, 2008 7. US Renal Data System: USRDS 2007 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007 8. FDA: Aranesp (darbepoetin alfa) for injection: Prescribing information. Silver Spring, MD, US Food and Drug Administration (USFDA), March 2008 9. FDA: Procrit (Epoetin alfa) for injection: Prescribing information. Silver Spring, MD, US Food and Drug Administration (USFDA), March 2008 10. Fishbane S, Berns JS: Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int 68:1337-1343, 2005 11. Yang W, Israni RK, Brunelli SM, Joffe MM, Fishbane S, Feldman HI: Hemoglobin variability and mortality in ESRD. J Am Soc Nephrol 18:3164-3170, 2007 12. Ebben JP, Gilbertson DT, Foley RN, Collins AJ: Hemoglobin level variability: Associations with comorbidity, intercurrent events, and hospitalizations. Clin J Am Soc Nephrol 1:1205-1210, 2006 13. Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury BD, Collins AJ: Hemoglobin level variability: Associations with mortality. Clin J Am Soc Nephrol 3:133138, 2008 14. Portolés J, López-Gómez JM, Aljama P: A prospective multicentre study of the role of anaemia as a risk factor in haemodialysis patients: The MAR Study. Nephrol Dial Transplant 22:500-507, 2007 15. National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S11-S145, 2006 (suppl 3) 16. Fishbane S, Besarab A: Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol 2:1274-1282, 2007 17. Petroff S: Evaluating traditional iron measures and exploring new options for patients on hemodialysis. Nephrol Nurs J 32:65-73, 2005 18. National Kidney Foundation: NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. Am J Kidney Dis 37:S182-S238, 2001 (suppl 1) 19. Gastaldello K, Vereerstraeten A, Nzame-Nze T, et al: Resistance to erythropoietin in iron-overloaded haemodialysis patients can be overcome by ascorbic acid administration. Nephrol Dial Transplant 10:S44-S47, 1995 (suppl 6) 20. Tarng DC, Wei YH, Huang TP, et al: Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia. Kidney Int 55:2477-2486, 1999 21. Attallah N, Osman-Malik Y, Frinak S, Besarab A: Effect of intravenous ascorbic acid in hemodialysis patients with EPO-hyporesponsive anemia and hyperferritinemia. Am J Kidney Dis 47:644-654, 2006
S28 22. Locatelli F, Aljama P, Barany P, et al: Revised European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 19 Suppl 2:ii1-47, 2004 23. Lin JL, Chang MY, Tan DT, Leu ML: Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients. Am J Nephrol 21:91-97, 2001 24. Wish JB: Assessing iron status: Beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 1:S4-S8, 2006 (suppl 1) 25. Regidor DL, Kopple JD, Kovesdy CP, et al: Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 17:1181-1191, 2006 26. US Food and Drug Administration and Center for Drug Evaluation and Research: Questions and Answers for Erythropoiesis-Stimulating Agents (ESAs) Labeling Changes. Available at: http://www.fda.gov/CDER/drug/infopage/RHE/ qa2007.htm. Accessed February 25, 2008 27. Centers for Medicare & Medicaid Services: 2005 Annual Report, End-Stage Renal Disease Clinical Performance Measures Project. Baltimore, MD, Department of
Toros Kapoian Health and Human Services, Centers for Medicare & Medicaid Services, Office of Clinical Standards and Quality, 2005 28. Coyne DW, Kapoian T, Suki W, et al: DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: Results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 18:975-984, 2007 29. Kapoian T, O’Mara NB, Singh AK, et al: Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol 19:372379, 2008 30. Warady BA, Zobrist RH, Wu J, Finan E; Ferrlecit Pediatric Study Group: Sodium ferric gluconate complex therapy in anemic children on hemodialysis. Pediatr Nephrol 20:1320-1327, 2005. 31. Nissenson AR, Lindsay RM, Swan S, Seligman P, Strobos J: Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial. Am J Kidney Dis 33:471-482, 1999