Resolving the paradigm crisis in intravenous iron and erythropoietin management

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1 & 26 International Society of Nephrology Resolving the paradigm crisis in intravenous and erythropoietin management A Besarab 1 1 Henry Ford Hospital, Detroit, Michigan, USA Despite the proven benefits of intravenous (i.v.) therapy in anemia management, it remains underutilized in the hemodialysis population. Although overall i.v. usage continues to increase slowly, monthly usage statistics compiled by the US Renal Data System suggest that clinicians are not implementing continued dosing regimens following repletion of stores. Continued therapy with i.v. represents a key opportunity to improve patient outcomes and increase the efficiency of anemia treatment. Regular administration of low doses of i.v. prevents the recurrence of deficiency, enhances response to recombinant human erythropoietin therapy, minimizes fluctuation of hemoglobin levels, hematocrit levels, and stores, and may reduce overall costs of care. This article reviews the importance of i.v. dosing on a regular basis in the hemodialysis patient with -deficiency anemia and explores reasons why some clinicians may still be reluctant to employ these protocols in the hemodialysis setting.. doi:1.138/sj.ki.545 EYWORDS: i.v. ; deficiency; anemia; repletion dosing; continued dosing; erythropoietin Correspondence: A Besarab, Henry Ford Hospital, 2799 West Grand Blvd, CFP511, Detroit, Michigan 4822, USA. abesarab@ghsrenal.com or abesara1@hfhs.org According to the National idney Foundation s idney Disease Outcomes Quality Initiative (/DOQI) guidelines, target hemoglobin (Hgb) and hematocrit (Hct) levels can be achieved and maintained in the majority of patients through a standard of anemia care that includes both recombinant human erythropoietin (EPO) and intravenous (i.v.) therapy. 1 I.v. therapy is needed in patients on hemodialysis for several reasons: patients experience ongoing blood () losses, efficient erythropoiesis requires both and EPO, oral fails to maintain adequate stores, use of i.v. will help improve and hematologic parameters, and health benefits of i.v. outweigh the potential adverse effects. 1 Despite the proven benefits of i.v. therapy, there is still a substantial percentage of clinicians who do not prescribe i.v. on a regular basis for their hemodialysis patients. According to Medicare claims data from the US Renal Data System (USRDS), only about 85% of the more than 24 hemodialysis patients on EPO therapy received at least one dose of i.v. in 22 (Figure 1). 2 However, more disconcerting is the poor adoption of a continued i.v. protocol, as recommended by the /DOQI guidelines. According to the USRDS data, only slightly more than half of hemodialysis patients receive i.v. therapy at least once a month. These statistics demonstrate that although i.v. therapy is being administered to the majority of hemodialysis patients, i.v. therapy is not being used on a regular basis (Figure 1). 2 BENEFITS OF A CONTINUED I.V. IRON PROTOCOL Nephrologists have varied approaches to the type of i.v. protocol employed, with two basic approaches including a repletion program and a continued dosing regimen. Although a repletion schedule is important as a catch up mechanism in patients with absolute deficiency, a more physiological approach is to administer doses of i.v. on a regular basis in order to maintain sufficient patient stores. Sole reliance on a repletion protocol to supply the patient s ongoing requirements raises several potential problems, most notably the development of functional deficiency leading to fluctuations in Hgb/Hct levels that occur between dosing periods (Table 1). 1,3 Functional deficiency is one cause of Hgb cycling. 4 Therefore, continued i.v. therapy, along with EPO and repletion S13

2 A Besarab: Intravenous and EPO in anemia management I.v. use (%) At least one i.v. dose for the year At least one i.v. dose per month Table 2 Benefits of continued i.v. therapy Stabilizes Hgb and Hct levels over the long term Reduces fluctuations in stores Allows for more efficient erythropoiesis/reduces risk of resistance to EPO Provides a constant supply of readily bioavailable Allows benefits to be achieved at lowest effective doses of EPO Prevents the emergence of clinical signs and symptoms of anemia EPO, erythropoietin; Hct, hematocrit; Hgb, hemoglobin; i.v., intravenous Figure 1 Trends in i.v. usage among US hemodialysis patients, Although nearly 85% of all hemodialysis patients on EPO therapy received i.v. at least once during 22, only 55% received i.v. at least monthly, indicating a failure to implement routine i.v. continued protocols as established by the /DOQI guidelines. 2 Table 1 Implications of using an i.v. repletion regimen without continued therapy Reduced supply of bioavailable. Iron uptake is rapid, not only in erythroid progenitor cells but also in the reticuloendothelial system. Iron deposited into the reticuloendothelial system as hemosiderin is less easily accessible for erythropoiesis Inadequate maintenance of Hgb/Hct and TSAT/serum ferritin levels. Repletion regimens are often ineffective for maintaining target Hgb, Hct, TSAT, and serum ferritin levels between dosing intervals. In one study of 28 patients with absolute deficiency who were given i.v. repletion regimens, 15 required additional i.v. within 1 weeks to raise the serum ferritin level 41 ng/ml 3 Rollercoastering of levels. Clinicians may respond to the initial increase in Hgb/Hct by decreasing the patient s dosage of recombinant human EPO, which can lead to a decrease in Hgb/Hct after stores become depleted. This leads to a state of continuing instability in Hgb/Hct levels (i.e., cycling) 4 EPO, erythropoietin; Hgb/Hct, hemoglobin/hematocrit; i.v., intravenous; TSAT, transferrin saturation. protocols, should be considered an indispensable component of the anemia management plan. 1 Administration of i.v. therapy on a regular basis provides a number of key benefits that are not adequately achieved with the use of repletion protocols (Table 2). Prevents absolute and functional deficiency Continued i.v. therapy provides on an ongoing basis, so patients can achieve and maintain adequate total stores, thereby preventing absolute deficiency in the patient. The demands placed on the hemodialysis patient to maintain adequate stores can be enormous. Annual losses in individuals vary depending on factors such as weight and menstrual status, and may be augmented by events such as surgical procedures. Although annual losses of up to 8 g have been reported in hemodialysis patients, 5 the majority of the data estimate losses at between 2 and 4 g/year. 1,6 Furthermore, a continuous source of is needed to optimize the body s supply of bioavailable. In the healthy individual, the circulating pool of (i.e., bound to Storage Iron in Hgb Healthy individual Storage Iron in Hgb HD patient before EPO therapy Storage Iron in Hgb HD patient during EPO therapy Figure 2 Functional deficiency following the initiation of EPO therapy. The supraphysiologic rate of erythropoiesis with EPO results in a depleted pool of storage, as is moved into the erythroid marrow for incorporation into new red blood cells. Hgb, hemoglobin; HD, hemodialysis. Adapted from Excerpta Medica International Congress Series No. 366, 1975, pp transferrin) consists of only 3 4 mg of. 7 This pool is extraordinarily active; in order to provide the average 24 mg of necessary for daily red blood cell production, the entire pool is turned over six times. In the hemodialysis patient receiving EPO therapy, this level of turnover must be maintained despite decreased transferrin levels and the blockade of at least some amount of in the cells of the reticuloendothelial system owing to underlying inflammation. 7 Regular i.v. administration reverses the imbalance in body stores that results in a state of functional deficiency by supplying new to occupy non-heme storage sites (Figure 2). 6 Stabilizes Hgb and Hct levels The lower doses and consistent administration schedule of i.v. therapy help to avoid large swings in stores and Hgb/Hct levels, phenomena known as seesawing or rollercoastering (Figure 3). 8 These states occur when multiple doses of i.v. are given within a short period of time (as is the case with a repletion regimen of 1 mg over 8 1 dialysis sessions) and then is withheld for several months, at which time the cycle is repeated. 9 Following a rapid restoration of serum stores and Hgb/Hct, the patient will experience a similarly sharp drop in these measures if continued i.v. therapy is not given to consolidate these initial benefits. 4 Table 3 shows the sharp decline experienced by a group of hemodialysis patients given 4 months of repletion therapy and then withdrawn from i.v. therapy altogether. 1 The patients in this study rapidly returned to a state of functional deficiency. It is not surprising that intermittent repletion therapy several times a year is associated with Hgb cycling. 4 S14

3 A Besarab: Intravenous and EPO in anemia management I.v. administration (mg/kg) Month Figure 3 Graphic representation of intermittent repletion (solid bar) versus repletion followed by ongoing (dotted line) approaches to i.v. therapy. An intermittent repletion regimen results in a rollercoastering effect on stores. Reprinted with permission from Nephron 1999; 81: Table 3 Decrease in levels following termination of i.v. therapy a1 Baseline Month 4 Unlike intermittent administration, continued administration of i.v. therapy stabilizes Hgb/Hct levels. Earlier studies observed that, once a target Hgb or Hct level is obtained, these levels can best be maintained without the use of inappropriately higher EPO doses if replacement is given on a regular basis (e.g., weekly or biweekly) to counteract the effects of continued blood loss. 9 Although anemia management guidelines may suggest the possibility of using oral, repeated assessments have demonstrated that oral is usually inadequate to replenish the patient s ongoing needs. 11 Oral is associated with gastrointestinal irritation, is poorly absorbed (especially in hemodialysis patients, where underlying inflammation and the use of protect-pump inhibitors further impairs absorption), and cannot deliver sufficient to reverse a state of functional deficiency. Reduces risk of EPO resistance Consistent administration of i.v. therapy is important because a patient s erythropoietic response is poor in the presence of inadequate stores, even with ongoing administration of EPO therapy. 1 Continued EPO administration without addressing the patient s needs is the primary reason for the development of EPO resistance, characterized by poor Hgb/Hct response despite increasing EPO doses. Regular use of i.v. overcomes EPO resistance, resulting in more efficient erythropoiesis. Numerous clinical trials have demonstrated that improved response to EPO can 8 Month 8 (4 months after termination of i.v. ) Serum ferritin (7s.d.) TSAT (%) (7s.d.) a Twenty hemodialysis patients treated with i.v., 2 mg/week for 4 months. i.v., intravenous; TSAT, transferrin saturation. be achieved with continued dosing regimens of i.v. therapy (Table 4). 1,12 16 The association between i.v. use and better response to EPO therapy is also reflected in the national Medicare statistics from 22 on i.v. usage among hemodialysis patients. 2 These data show Hgb levels lower than the national average, despite the use of high doses of EPO, in geographic regions that generally had the lowest percentages of i.v. treated patients. In contrast, higher Hgb levels were achieved with lower mean EPO doses in areas where i.v. therapy was used in a higher percentage of patients. 2 STRIING THE RIGHT BALANCE BETWEEN I.V. IRON AND EPO: CONTINUED THERAPY PROTOCOLS Determining an effective dose An appropriately balanced approach to i.v. and EPO therapy involves adherence to a program that uses ongoing and consistent administration of therapy. The /DOQI guidelines provide a framework for which to develop a continued i.v. protocol, but allow for substantial flexibility in the actual dose regimen. A thrice weekly, weekly, every other week, or once monthly schedule can be used to provide 25 1 mg of i.v. within 12 weeks. However, with any administration protocol, the determining factor in treatment is not the stated dose or dose range, but rather the patient s erythropoietic response and his/her need for. The goal is to provide an ongoing dose of i.v. in hemodialysis patients that will replace ongoing losses and allow the patient to maintain the target Hgb/Hct level at a safe and stable level. 1 Continued i.v. therapy, given with careful attention to the patient s Hgb/Hct response, has an impressive number of positive effects in the treatment of hemodialysis patients, which encouragingly have been seen with the use of a number of different dosing regimens. Various dosing regimens ranging from 25 to 125 mg/week of continued i.v. therapy have helped patients to overcome EPO resistance as well as to improve response to EPO therapy. 1,12 16 A study by Canavese et al. 8 demonstrated that ongoing low-dose administration of i.v. therapy resulted in continually repleted levels and improved response to EPO therapy. The authors concluded that the improvement in efficacy of EPO therapy might be mainly owing to a better approach to i.v. therapy (i.e., continued use of i.v. therapy and the use of EPO only when necessary). In a continued i.v. -dosing regimen, frequency of administration can vary from small doses being given with each hemodialysis treatment to a single dose monthly, and dose size can vary from 5 to 1625 mg/month, with the latter dose being used in patients with ongoing gastrointestinal blood loss (e.g., angiodysplasia). In a 16-week direct comparison of intermittent and continued i.v. regimens involving 26 patients with adequate stores, patients receiving ongoing i.v. therapy of mg of sodium ferric gluconate per hemodialysis session had significantly improved Hgb levels over baseline compared with patients S15

4 A Besarab: Intravenous and EPO in anemia management Table 4 Improved response to EPO with continued i.v. regimens Hgb or Hct TSAT (%) Serum ferritin Baseline Follow-up Baseline Follow-up Baseline Follow-up Change in Hgb/Hct (%) Hgb (g/dl) NA NA Hct (%) NA NA EPO, erythropoietin; Hgb, hemoglobin; Hct, hematocrit; i.v., intravenous; NA, not available; TSAT, transferrin saturation. Mean Hgb (g/dl) Continued therapy Intermittent therapy 1. Baseline Week 4 Week 8 Week 12 Week 16 *P<.5 vs baseline. Figure 4 Change in mean Hgb levels with a continued low-dose regimen of sodium ferric gluconate versus an intermittent regimen. Reprinted with permission from Am J Nephrol 22; 22: receiving an intermittent regimen of every 1 4 weeks (Figure 4). 17 The strategy adopted is influenced by the labor and costs involved; less labor and cost is needed to administer the drug at weekly to monthly intervals than with each dialysis treatment. In the United States, where dialysis centers suffer from chronic nursing shortage, the tendency is to administer parenteral weekly to monthly. Continued dosing with i.v. can also provide substantial cost savings related to enhanced EPO response. One study demonstrated expected improvements in blood indices of anemia with an aggressive i.v. regimen of 1 mg/week via bolus to a maximum serum ferritin level of 1 ng/ml. Although the aggressive regimen increased total i.v. expenses by more than $38, a dramatic improvement in EPO response was achieved, resulting in a net cost savings of more than $35 (Figure 5). 18 Importantly, improved response to EPO therapy has been achieved with a much less aggressive i.v. therapy regimen of 1 mg/month. 19 Besarab et al. 9 noted that in terms of costs, an ongoing i.v. protocol was revenue neutral at the level of the dialysis unit but produced a cost savings at the level of the healthcare provider. When to measure status Determining the proper time to test for status is an important consideration when developing an effective * I.v. expenditure ($US) 72 I.v. expenditure Mean EPO dose Nov Dec Jan Feb Mar 1998 Apr 1998 May 1998 June July Aug Sept Oct Nov Figure 5 I.v. expenditures compared with reductions in EPO requirements with an aggressive i.v. continued regimen (1 mg/week via bolus). Although i.v. expenditures increased in this population of 116 hemodialysis patients by $38 5, the reduction in EPO dosages translated into a net cost savings of $362. Adapted with permission from Am J idney Dis 1999; 34(Suppl 2): S4 S protocol that promotes a practical balance between i.v. and EPO therapy. A well-formed therapy protocol should emphasize the systematic measurement and documentation of indices. Serum ferritin, transferrin saturation (TSAT), and Hgb/Hct levels should be determined when a patient is initially diagnosed with renal disease and then at routine intervals. Routine monitoring can help increase the clinician s understanding of the factors that affect laboratory measures and improve their ability to distinguish among different clinical situations (e.g., functional deficiency and inflammatory block) that may resemble each other in presentation (see first article of this supplement). In addition, close monitoring of and hematologic parameters can help determine the appropriate dose of continued i.v. therapy, allowing the clinician to titrate the dose of in order to keep the parameters within the target range. The protocol shown in Figure 6 is used at Henry Ford Health System (HFHS). HFHS believes that proper anemia management requires monthly testing of both indices and Hgb levels so that both can be adjusted appropriately, if needed, on a monthly basis. In addition, HFHS has added the use of reticulocyte hemoglobin content to help detect the early development of functional deficiency. Mean EPO dose (U/week) S16

5 A Besarab: Intravenous and EPO in anemia management Iron and anemia management protocol: ongoing therapy Measure TSAT/ferritin monthly TSAT >5% TSAT >25% TSAT <25% <3 < Hold Hold q 4 weeks q 2 weeks 125 mg q Rx X4 75 mg q week q week q 2 weeks Use CHr to fine tune >2 Consecutive months in this path Consult MD >2 Consecutive months in this path Figure 6 Continued therapy and anemia management protocol used by the Henry Ford Health System. TSAT, transferrin saturation. Implementing a protocol to provide ongoing, consistent therapy The reason for the slow growth in i.v. usage after 1997 is unclear, particularly because this coincides with the initial release of the /DOQI guidelines for anemia management, which made recommendations for the use of i.v. in hemodialysis patients. Although it may be that a certain percentage of patients continue to maintain adequate stores, the dramatically low consistent use of i.v. therapy indicates a certain level of resistance to implementing such protocols. 2 Further study is needed to pinpoint the precise reasons; however, misconceptions about i.v. (see second article of this supplement) and the perceived added burden of initiating and maintaining a policy of chronic i.v. supplementation may cause many clinicians to reject this approach. The added resources that may be needed to implement a clinic-wide i.v. continued dosing protocol may also mitigate against its adoption. Several excellent models for the successful incorporation of i.v. -continued therapy regimens have been developed for the clinician who is unfamiliar with the logistical aspects of developing these protocols. Organization of a continuous quality improvement initiative provides the opportunity to assess current anemia treatment practices, identify opportunities for improvement, initiate a plan of intervention, evaluate the results in a systematic fashion, and revise the plan based on the need for continued improvement. Although the initial creation of such an initiative may require a substantial commitment of time and resources, the benefits are numerous, and include improved patient health, safety, and satisfaction; reduced variability in practice; reduced costs and wastage; increased Table 5 Improvements in anemia/ indices following a 6-month continuous quality improvement program with i.v. sodium ferric gluconate Index Baseline value (May 24) (n=116) Continued therapy with sodium ferric gluconate (December 24) (n=145) % of patients with Hgb g/dl Mean i.v. dose (mg/ month) Mean EPO dose (U/ month) % of patients on i.v Adapted from Nephrol Nurs J 25; 32: EPO, erythropoietin; Hgb, hemoglobin; i.v., intravenous. unit revenue; and fewer problems with insurance reimbursement. An excellent example of a continuous quality improvement process has been published by Bowe and Ammel. 2 Employing the principles developed in this protocol enabled the anemia management team to increase the use of continued i.v. therapy and lower the mean i.v. and EPO dosages, while improving mean Hgb (Table 5). 2 CONCLUSION This supplement has demonstrated that, in an effort to improve outcomes in hemodialysis patients, clinicians need to take a proactive approach to managing anemia. The first step is to implement an anemia management program that S17

6 A Besarab: Intravenous and EPO in anemia management includes a balanced approach to i.v. and EPO therapy. Studies have shown that i.v. therapy is critical for effective erythropoiesis in this patient population and, that low-dose i.v. administration on a regular basis can enhance the patient s response to EPO therapy and prevent the recurrence of deficiency. In addition to continued i.v. therapy, a successful anemia management program should require early evaluation of status (i.e., before EPO therapy is initiated) as well as ongoing monitoring of indices. Because of the challenges associated with interpreting some of the markers, especially serum ferritin levels, which can be falsely elevated by inflammation, clinicians should have a complete understanding of the conditions that can negatively impact accurate assessment of status. Owing to the limitations of the available markers, anemia management should be guided by several principles, including administering i.v. to improve erythropoiesis and not to attain specific levels of TSAT or serum ferritin, and making treatment decisions based on an evaluation of the whole patient rather than a single laboratory value. New markers, such as reticulocyte hemoglobin content, may also be useful in detecting functional deficiency. Finally, when initiating an anemia management plan, it may be necessary to address some common misconceptions that could hinder the execution of a practical balance between i.v. and EPO therapy. For example, potential concerns surrounding a very high serum ferritin level or fear of oxidative stress should not be considered as obstacles to implementing a continued i.v. protocol, given that the doses used for such a regimen are small. In an effort to improve anemia management through the use of a balanced approach to i.v. and EPO therapy, clinicians must overcome the boundaries of the current philosophy surrounding anemia treatment. A strategy that achieves superior results with minimum, effective doses administered on a regular basis is one soundly rooted in the good practice of medicine, and a clinician would be hard-pressed to justify a decision not to pursue this approach. REFERENCES 1. National idney Foundation. /DOQI clinical practice guidelines for anemia of chronic kidney disease. Am J idney Dis 21; 37(Suppl 1): S182 S St. Peter WL, Obrador GT, Roberts TL, Collins AJ. Trends in intravenous use among dialysis patients in the United States ( ). Am J idney Dis 25; 46: Fishbane S, Lynn RI. The efficacy of dextran for the treatment of deficiency in hemodialysis patients. Clin Nephrol 1995; 44: Fishbane S, Berns JS. 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