American Journal of Health-System Pharmacy

doi: 10.1093/ajhp/64.suppl_8.23pmid: N/A

Learning Objectives After studying these articles, the reader should be able to: Quantify the prevalence of chronic kidney disease (CKD) and anemia in the United States, define anemia, classify the CKD stage based on renal function, and describe the relationship between renal function and hemoglobin concentration in patients with CKD. Explain the etiology and consequences of anemia, and name a clinical benefit and an economic benefit of correcting anemia in patients with CKD. Discuss the current recommendations of the National Kidney Foundation (NKF) for treating anemia in patients with CKD, including laboratory monitoring, the use of erythropoietin-stimulating agents (ESA) and iron supplements, and patient evaluation for an inadequate response to ESA. Describe the dosing, frequency and route of administration, efficacy, and safety of ESA, iron supplements, continuous erythropoiesis receptor activator (CERA), and other investigational anemia therapies for patients with CKD. Identify a possible barrier to the treatment of anemia in patients with CKD and suggest a strategy that pharmacists can use to overcome the barrier. Self-assessment questions For each question there is only one best answer. The number of Americans with CKD and anemia is estimated to be: 150,000. 600,000. 1 million. 4 million. The proportion of patients with CKD who have anemia at the time they initiate dialysis is approximately: One in four. One in three. Two in three. Three in four. Which of the following statements best describes the relationship between serum creatinine (SCr) and hematocrit in patients with CKD? As the SCr decreases, the hematocrit decreases, with the greatest decreases in hematocrit in the early stages of CKD. As the SCr increases, the hematocrit decreases, with the greatest decreases in hematocrit in the early stages of CKD. As the hematocrit decreases, the SCr decreases, with the greatest decreases in SCr in the late stages of CKD. As the hematocrit increases, the SCr decreases, with the greatest decreases in SCr in the late stages of CKD. In addition to worsening CKD, which of the following are components of the cardiorenal syndrome in patients with CKD? Worsening anemia and worsening cognition. Worsening anemia and worsening angina. Worsening anemia and worsening congestive heart failure (CHF). Worsening angina and worsening CHF. Which of the following changes most closely reflects improved cardiac function from anemia correction in predialysis patients with CKD? Increased glomerular filtration rate. Increased pulmonary capillary wedge pressure. Increased cardiac output. Reduced left ventricular mass index. Which of the following has been associated with cost savings in patients with CKD and anemia? Normalizing hemoglobin concentrations instead of using a more conservative target of 11–12 g/dL. Use of a conservative hemoglobin concentration of 11–12 g/dL instead of normalizing hemoglobin concentrations. Converting from subcutaneous (s.c.) to intravenous (i.v.) epoetin alfa therapy. Converting from i.v. to s.c. epoetin alfa therapy. Which of the following factors should be taken into consideration when determining whether a particular hemoglobin concentration constitutes anemia? Living at a low altitude. Cur rent or recent cigarette smoking. A high ambient temperature when the blood sample was obtained. Fasting before the blood sample was obtained. Which of the following is a contraindication to ESA use? Uncontrolled hypertension. A history of seizures. Compromised nutritional status. Vascular access occlusion. Which of the following statements best characterizes NKF recommendations for the route of administration for ESAs in patients with CKD? The i.v. route is preferred for predialysis patients, and the s.c. route is preferred for hemodialysis patients. The s.c. route is preferred for predialysis patients, and the i.v. route is preferred for hemodialysis patients. The i.v. route is preferred for both predialysis and hemodialysis patients. The s.c. route is preferred for both predialysis and hemodialysis patients. Which of the following ESAs has the longest elimination half-life? Epoetin alfa. Darbepoetin alfa. CERA. Epoetin alfa, darbepoetin alfa, and CERA have similar half-lives. Which of the following is the least likely cause of an inadequate response to darbepoetin alfa? Antibody-mediated pure red cell aplasia. Iron deficiency. Inflammation. Catheter use. Which of the following statements best characterizes NKF recommendations for the route of administration for iron supplements in patients with CKD? The i.v. route is preferred for both predialysis and hemodialysis patients. The oral route is preferred for both predialysis and hemodialysis patients. The i.v. or oral route may be used for predialysis patients, but the i.v. route is preferred for hemodialysis patients. The i.v. or oral route may be used for predialysis patients, but the oral route is preferred for hemodialysis patients. Which of the following is the upper limit for the serum ferritin concentration recommended by NKF during iron supplementation in patients with anemia and CKD? 12 g/dL. 13 g/dL. 500 ng/mL. 800 ng/mL. Which of the following investigational anemia therapies is particularly attractive because of its oral route of administration? CERA. FG-2216. Hematide. Ferumoxytol. Which of the following led to the development of an investigational inhaled formulation of erythropoietin? Conjugation of recombinant human erythropoietin to the Fc component of a human immunoglobulin G molecule. Conjugation of recombinant human erythropoietin with polyethylene glycol. Creation of a semi-synthetic carbohydrate-coated iron oxide. Transfer of the gene that encodes erythropoietin into muscle cells. Failure to assess iron status in patients with CKD is attributed to: Difficulty interpreting iron laboratory values and identifying iron deficiency. A lack of laboratory assays for iron status. A lack of knowledge about the role of iron deficiency in erythropoiesis. Patient failure to keep laboratory appointments. Which of the following statements about iron supplementation in patients with CKD is correct? It is needed only for patients with iron deficiency. It is needed for patients receiving ESAs, even if iron deficiency is not present. It is needed only for patients undergoing hemodialysis. It is needed only for predialysis and peritoneal dialysis patients. Which of the following is recommended for a predialysis patient who complains of gastrointestinal upset from oral iron supplements? Take the supplement at bedtime. Try an immediate-release product instead of an extended-release product. Take the supplement two hours before or one hour after a meal. Try a combination product that contains docusate sodium. Which of the following is an advantage of i.v. iron supplements in patients with CKD? The rapid administration. The convenience. The lack of toxicity. The lack of concern about bioavailability. Which of the following is a possible barrier to the treatment of anemia in patients with CKD? A lack of effective therapies. A lack of consensus among clinicians on a therapeutic approach. A high risk of harm from available therapies. A lack of clinician familiarity with clinical practice recommendations. AJHP continuing education AJHP CE Process Continuing education (CE) credit for this AJHP supplement is free for both members and nonmembers. Successful completion of a CE test is required to obtain CE credit. The CE test can only be taken online through ASHP’s CE Testing Center. After successful completion (score of 70% or better), you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your entire transcript through the CE Testing Center. Instructions for the CE Testing Center Go to http://ce.ashp.org and select “Enter CE Testing Center” ASHP members and registered customers: Type in either your 8-digit ASHP ID or your user name, and password. Click on “Register for Tests”. Follow instructions to select the desired supplement or, an easy way to search, click on “Edit”; select “Find on this Page”; type in a word or phrase in the title. Nonmembers: Click on the “Become a Registered User” link at the bottom of the page. Fill out the information requested and create your password. Go back to http://ce.ashp.org and select “Enter CE Testing Center” You will automatically be logged into the center. To view the complete list of available AJHP CE articles and supplements go to www.ashp.org, click on “Continuing Education” on the left menu, and then click on “AJHP CE Publications” under “Self- Study Programs”. While many of these are free to nonmembers, some are not. To have access to all the CE AJHP has to offer for free, consider becoming a member of ASHP. To find out more about the benefits of being an ASHP member, go to www.ashp.org and click on “Member Center” on the left menu. Supplement: New therapeutic approaches to improving clinical and economic outcomes in patients with chronic kidney disease and anemia ACPE #: 204-000-07-006-H01 CE credit: 2.0 hours (0.2 CEUs) Expiration date: July 1, 2010 The American Society of Health- System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education Questions? Call ASHP Processing Center: 866-279-0681 (toll free) +1-240-646-7082 (international callers) Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved. Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Grabe, Darren, W.

doi: 10.2146/ajhp070182pmid: 17591995

Abstract Purpose. The National Kidney Foundation (NKF) clinical practice recommendations for treating anemia in chronic kidney disease (CKD) and the dosing, route and frequency of administration, efficacy, and safety of currently available and investigational drug therapies for anemia in patients with CKD, including the erythropoietin-stimulating agents (ESAs) iron replacement, and adjuvants, are described. Summary. The NKF recommendations for ESA use are general and include dosing based on the measured and target hemoglobin concentrations, the rate of increase in hemoglobin, and clinical circumstances, with the route and frequency of administration determined by the CKD stage, treatment setting, efficacy, and ESA class. A serum ferritin concentration of 100–500 ng/mL is the target during oral and intravenous (i.v.) iron therapy for predialysis and peritoneal dialysis patients, but use of the i.v. route of administration and a target serum ferritin concentration of 200–500 ng/mL is recommended for hemodialysis patients by NKF. Iron deficiency and inflammation are possible causes of inadequate response to ESAs. The safety profile of epoetin alfa and darbepoetin alfa are similar, but the longer half-life of darbepoetin alfa permits administration on a once-monthly basis in patients with CKD and anemia. Extended dosing of CERA also appears safe and effective in dialysis patients with CKD. Several investigational anemia therapies with a variety of mechanisms of action are in development. Conclusion. Efforts by the NKF to update their clinical practice recommendations provide clinicians with insight into the optimal therapeutic approach to treating anemia in patients with CKD. Clinical research has resulted in the development of new therapeutic modalities to improve outcomes in patients with CKD and anemia. Anemia, Continuous erythropoiesis receptor activator, Darbepoetin alfa, Dialysis, Dosage, Dosage schedules, Drugs, investigational, Epoetin alfa, Half-life, Hematopoietic agents, Iron, Iron preparations, Kidney diseases, National Kidney Foundation, Protocols, Toxicity In 2006, the National Kidney Foundation (NKF) released clinical practice guidelines and recommendations for treating anemia in patients with chronic kidney disease (CKD) as part of its Kidney Disease Outcomes Quality Initiative. 1 Some of these guidelines and recommendations reflect important changes since a previous NKF document was released in 2002.2 NKF guidelines and recommendations According to NKF, hemoglobin concentrations should be measured annually in patients with CKD. The NKF recommends monitoring hemoglobin levels at least monthly during treatment with an erythropoietin-stimulating agent (ESA).1 The NKF guidelines for ESA dosing represent a departure from previous guidelines, which provided specific recommendations.2 By contrast, the 2006 guidelines are more general and recommend that ESA dosing be based on the patient’s measured and target hemoglobin concentrations, the rate of increase in hemoglobin, and clinical circumstances. If the hemoglobin concentration rises too high, a reduction in ESA dosage, but not necessarily withholding the drug, is recommended by NKF. Stopping and restarting an ESA can be problematic since this may lead to cycling of anemia control. In other words, because of the lifespan of red blood cells, the effect of stopping a dose of an ESA and restarting treatment at a lower dose would not be fully realized until some time later. This may lead to less than optimal control of hemoglobin within a target range. The NKF recommends administering missed ESA doses as soon as possible.1 Continuation of ESA therapy is recommended by NKF in ESA-dependent patients during hospitalization.1 The product labeling for ESAs lists uncontrolled hypertension (and known hypersensitivity to any component of the ESA) as a contraindication because of the risk of increases in blood pressure during therapy, although controlled hypertension is not a contraindication.3,–5 The NKF was concerned that ESAs might be withheld unnecessarily from patients who stand to benefit. The NKF guidelines state that hypertension, vascular access occlusion, inadequate dialysis, a history of seizures, or compromised nutritional status are not contraindications to ESA use.1 According to the NKF, the route of ESA administration should be determined by the CKD stage (see the preceding article by Dowling in this supplement), treatment setting, efficacy, safety, and class of ESA used.1 The NKF prefers the subcutaneous (s.c.) route of administration because of convenience in predialysis patients with CKD (i.e., patients with stage 2, 3, or 4 CKD who do not yet require hemodialysis). However, the NKF prefers the intravenous (i.v.) route of administration for hemodialysis patients with CKD (i.e., stage 5) also because of convenience. The NKF guidelines state that the frequency of ESA administration should be determined by the CKD stage, treatment setting, efficacy considerations, and class of ESA.1 In-frequent administration is preferred by NKF because of convenience, particularly in predialysis patients with CKD. Many patients also prefer infrequent administration because of its convenience.6 Administration of darbepoetin alfa as infrequently as once monthly has produced an adequate hemoglobin response in patients with anemia and CKD or heart failure.7,8 Iron supplementation Iron is required for hemoglobin synthesis and erythropoiesis.9 The initial assessment of anemia in patients with CKD should include the serum ferritin concentration (a measure of iron stores) and either the serum transferrin saturation (TSAT) or the content of hemoglobin in reticulocytes (CHr), which reflect the adequacy of iron for erythropoiesis.1 The CHr is a new test that has not gained widespread acceptance due to unfamiliarity with its use. Iron supplementation should be provided to maintain adequate iron stores and support erythropoiesis in patients with CKD who are receiving an ESA. In the past, a serum ferritin concentration greater than 100 ng/mL and a TSAT greater than 20% were conservative therapeutic targets for iron supplementation in patients with CKD who are receiving an ESA. The 2006 NKF guidelines state that these targets are appropriate for predialysis and peritoneal dialysis patients, and iron therapy may be administered by the i.v. or oral route in these patients.1 However, in patients receiving hemodialysis, a target serum ferritin concentration of more than 200 ng/mL is recommended by NKF based on efficacy and safety data from iron studies in this patient population. The lower target of 100 ng/mL might provide inadequate iron stores for a patient with inflammation, which suppresses erythropoiesis, so the higher target of 200 ng/mL was recommended. A target TSAT of more than 20% and a target CHr of more than 29 pg/cell are recommended by NKF for hemodialysis patients (achieving either target suffices in an individual).1 The i.v. route of administration is recommended by NKF for iron supplementation in hemodialysis patients.1 An upper limit of 500 ng/mL for the serum ferritin concentration is recommended by NKF during iron supplementation for all patients with CKD because of a lack of efficacy and safety data supporting the routine use of iron therapy at higher ferritin levels.1 According to NKF, decisions regarding iron administration to patients with a serum ferritin level greater than 500 ng/mL should take into consideration ESA responsiveness, the hemoglobin and TSAT levels, and clinical status (i.e., iron therapy is not necessarily contraindicated when the serum ferritin exceeds 500 ng/mL, and decisions to administer iron are made on an individual basis).1 Adjuvants to ESA therapy in hemodialysis The 2006 NKF guidelines address several adjuvants used to enhance the response to or reduce dosage requirements for ESA therapy in hemodialysis patients with CKD.1 These adjuvants include L-carnitine, vitamin C, and androgens. The NKF found insufficient evidence to recommend the use of L-carnitine or vitamin C. A strong recommendation was made by NKF that androgens should not be used as an adjuvant to ESA treatment in anemic patients with CKD because of concerns about adverse effects and limited evidence of efficacy. Androgens were routinely used in hemodialysis patients before ESAs were introduced. Increased erythropoietin production, increased sensitivity of erythroid progenitors to the effects of erythropoietin, and increased red blood cell survival rate are among the purported mechanisms of action of androgens.1 The NKF considered the results of studies of various modifications to the hemodialysis treatment. For example, ultrapure dialysate solutions have been used to avoid exposing patients to dialysate solutions contaminated with endotoxins or bacteria, which could cause the release of inflammatory cytokines that interfere with erythropoiesis. The response to ESA treatment may be enhanced or ESA dosage requirements may be reduced by the use of ultrapure dialysate solutions.1 Daily and nocturnal hemodialysis have been used instead of conventional hemodialysis with some success in increasing hemoglobin concentrations.1 However, the NKF did not make specific recommendations for the use of ultrapure dialysate solutions, daily or nocturnal hemodialysis, or other modifications to hemodialysis treatment. ESA hyporesponsiveness An inadequate response to ESA therapy is a common problem that is associated with morbidity and mortality.1 The NKF guidelines state that patients with anemia and CKD should undergo evaluation for specific causes if the hemoglobin concentration is inappropriately low for the ESA dose administered. Examples of such scenarios identified by NKF include the need for a substantial increase in the ESA dosage to maintain a consistent hemoglobin level, a substantial decrease in hemoglobin level when the ESA dosage is unchanged, and failure of the hemoglobin level to exceed 11 g/dL despite an ESA dosage equivalent to epoetin alfa dosages exceeding 500 units/kg/week.1 Antibody-mediated pure red cell aplasia is a rare cause of ESA hypo-responsiveness reported primarily in patients receiving an epoetin alfa formulation that is not available in the United States.1 The reaction results from the formation of antibodies that neutralize ESA and endogenous erythropoietin. Iron deficiency is a common cause of ESA hyporesponsiveness, especially in the predialysis population. Oral iron therapy causes constipation and stomach upset, which reduce patient adherence.10 The need to take iron on an empty stomach and concerns about drug interactions also present challenges in the use of oral iron therapy. Although i.v. iron administration is feasible, administration by that route is time consuming.11,–13 Other possible causes of ESA hyporesponsiveness include hospitalization, temporary or permanent catheter use, hypoalbuminemia, elevated C-reactive protein concentrations, and miscellaneous (e.g., gastrointestinal bleeding, hemodialysis) causes. Many of these etiologies (e.g., catheter use, hospitalization for infection, elevated C-reactive protein concentrations) reflect inflammation, which interferes with iron absorption, the release of iron from storage sites, erythropoietin production, and the bone marrow response to erythropoietin (i.e., erythropoiesis).9 Currently available therapies Currently available ESAs include two similar epoetin alfa products and darbepoetin alfa. Iron formulations for i.v. administration include iron dextran, sodium ferric gluconate, and iron sucrose, but the use of iron dextran is limited by adverse effects.11,–13 Oral iron products include ferrous sulfate, ferrous fumarate, and ferrous gluconate.10 These products will be discussed in the Gilmartin article in this supplement. Epoetin alfa. The initial epoetin alfa dosage recommended in the product labeling is 150–300 units/kg/week i.v. or s.c. in three divided doses.3,4 Maintenance doses in patients with CKD who are not on dialysis are between 75 and 150 units/kg/week. The usual initial epoetin alfa dosage for adult patients with CKD not on dialysis and with anemia recommended by the Albany Nephrology Pharmacy (ANephRx) Group, a private practice, is 80–120 units/kg/week s.c with a typical weekly dose of 6000–10000 units.3,4 Most patients with predialysis CKD, followed by the ANephRx Group receive weekly epoetin alfa doses, with some patients receiving two or three doses each week. The hematopoietic response to epoetin alfa therapy is monitored by the ANephRx Group every one to two weeks after initiating or adjusting therapy, and both hemoglobin and hematocrit are used to evaluate the hematopoietic response. A hemoglobin of 11–12 g/dL is targeted (a target hemoglobin not to exceed 12 g/dL is recommended in the product labeling).3,4 A 25–50% increase in epoetin dose is recommended by the ANephRx group if the hemoglobin and hematocrit do not increase within two to four weeks following initiation of therapy. For example, if the hematocrit does not increase by two percentage points within two to four weeks or the hemoglobin increases less than 1 g/dL, after initiating epoetin alfa and iron stores are adequate, the ANephRx Group would recommend increasing the epoetin alfa dosage by 25–50% (a 25% dosage increase is recommended in the product labeling if the hemoglobin does not increase by at least 1 g/dL in a four-week period).3,4 A 25% decrease in epoetin alfa dose is recommended if the hemoglobin or hematocrit increases too rapidly. For example, if the hemoglobin increased by more than 2 g/dL or hematocrit by more than eight percentage points within a four-week period, the ANephRx Group would recommend reducing the epoetin alfa dosage by 25% (the product labeling recommends such a dosage reduction if the hemoglobin increases by more than 1 g/dL in a two-week period). The ANephRx Group recommends monitoring the hematopoietic response to epoetin alfa every two to four weeks once the hematocrit is stable. Hypertension affected one in four patients with CKD who received epoetin alfa in clinical trials, possibly because of an excessively rapid rate of increase in hemoglobin concentration. 3,4 Initiation of or increases in antihypertensive therapy in conjunction with dietary restriction may be required to control blood pressure during epoetin alfa therapy. If these measures are inadequate, a reduction in the epoetin alfa dosage may be necessary. Seizures were reported during epoetin alfa clinical trials of patients with CKD, possibly because of an excessively rapid increase in hemoglobin concentration.3,4 Epoetin alfa has been linked with an increased risk of thrombotic events (e.g., vascular access thrombosis) when efforts were made to normalize the hematocrit (i.e., increase the hematocrit beyond the usual target) in patients with CKD and ischemic heart disease or congestive heart failure.3,4 Whether epoetin alfa therapy increases the risk of thrombotic events when the target hemoglobin concentration recommended by NKF is used is unclear and controversial. The risk of hyperkalemia from epoetin alfa appears small, although it is difficult to quantify because hyperkalemia is not uncommon in patients with CKD.3,4 Moreover, many patients receive other drug therapies that can cause hyperkalemia (e.g., angiotensin converting-enzyme inhibitors, angiotensin receptor blockers) and fail to adhere to restrictions on dietary potassium intake. The ANephRx Group uses several strategies to optimize s.c. epoetin alfa therapy. Epoetin alfa is available in a variety of strengths that allow flexibility (1-mL, preservative-free, single-dose vials containing 2000 units/ mL, 3000 units/mL, 4000 units/mL, 10,000 units/mL, and 40,000 units/ mL; 2-mL multi-dose vials containing 10,000 units/mL with a preservative, and 1-mL multi-dose vials containing 20,000 units/mL with a preservative). 3,4 Use of a needle with the smallest possible bore (e.g., 29 gauge) and a product in a multi-dose vial with a high concentration for s.c. injections minimizes pain at the injection site by allowing the administration of a small volume. The preservative, benzyl alcohol, may act as a local anesthetic. Administering s.c. doses as infrequently as possible (e.g., once weekly) and rotating injection sites among the upper arm, thigh, and abdominal wall are among the strategies used by the ANephRx Group to optimize s.c. epoetin alfa therapy. Darbepoetin alfa. The terminal half-life of darbepoetin alfa is 2-3-fold greater than that of epoetin alfa in patients with CKD.14 This difference allows less frequent administration, fewer office visits, and less disruption to patient lives when darbepoetin alfa is used. The recommended initial darbepoetin alfa dosage is 0.45 μg/kg s.c. or i.v. once weekly.5 The target hemoglobin is not to exceed 12 g/dL, and increases and decreases in dosage by 25% are recommended for an inadequate or excessive hematopoietic response, respectively.5 Darbepoetin alfa dosages in patients switching from epoetin alfa therapy are based on the previous weekly epoetin alfa dosage (Table 11). The darbepoetin alfa dosing frequency is weekly if epoetin alfa was given two or three times weekly and every other week if epoetin alfa was given once weekly. Table 1. Weekly Darbepoetin Alfa Dosages for Adults with CKD Previously Managed with Epoetin Alfa5,a Previous Epoetin Alfa Dosage (units/week) Darbepoetin Alfa Dosage (μg/week) aCKD = chronic kidney disease <2500 6.25 2500–4999 12.5 5000–10,999 25 11,000–17,999 40 18,000–33,999 60 34,000–89,999 100 ≥90,000 200 Previous Epoetin Alfa Dosage (units/week) Darbepoetin Alfa Dosage (μg/week) aCKD = chronic kidney disease <2500 6.25 2500–4999 12.5 5000–10,999 25 11,000–17,999 40 18,000–33,999 60 34,000–89,999 100 ≥90,000 200 Open in new tab Table 1. Weekly Darbepoetin Alfa Dosages for Adults with CKD Previously Managed with Epoetin Alfa5,a Previous Epoetin Alfa Dosage (units/week) Darbepoetin Alfa Dosage (μg/week) aCKD = chronic kidney disease <2500 6.25 2500–4999 12.5 5000–10,999 25 11,000–17,999 40 18,000–33,999 60 34,000–89,999 100 ≥90,000 200 Previous Epoetin Alfa Dosage (units/week) Darbepoetin Alfa Dosage (μg/week) aCKD = chronic kidney disease <2500 6.25 2500–4999 12.5 5000–10,999 25 11,000–17,999 40 18,000–33,999 60 34,000–89,999 100 ≥90,000 200 Open in new tab Darbepoetin alfa is supplied in single-dose, preservative-free 25 μg, 40 μg, 60 μg, 100 μg, 150 μg, 200 μg, 300 μg, and 500 μg vials, prefilled syringes, and autoinjector syringes. The syringes have 27 gauge needles. In a typical 70-kg patient who is initiating darbepoetin alfa therapy, the ANephRx Group often uses 25-μg vials for once-weekly administration and 60-μg vials for administration every other week. The 60-μg vials also are commonly used for darbepoetin alfa administration every other week to patients previously receiving once-weekly epoetin alfa doses. The safety profile of darbepoetin alfa is similar to that of epoetin alfa.15 Initiation of or an increase in antihypertensive therapy and dietary restriction may be required because of increases in blood pressure during darbepoetin alfa therapy.5 Darbepoetin alfa dosage reduction may be necessary if these efforts are inadequate. Avoidance of an excessively rapid increase in hemoglobin concentration (i.e., more than 1 g/dL in a two-week period) is recommended during darbepoetin alfa therapy because of the possible link with hypertension and seizures.5 Whether darbepoetin alfa increases the risk for thrombotic effects is unclear.5 The use of extended dosing intervals (i.e., administration less frequently than once every two weeks) for darbepoetin alfa has been explored in patients with CKD and anemia. In a randomized double-blind study of 213 patients with CKD receiving hemodialysis and stable doses of recombinant human erythropoietin, i.v. administration of darbepoetin alfa every two weeks was noninferior to once-weekly i.v. epoetin alfa dosing.16 The safety profiles of darbepoetin alfa and epoetin alfa were similar. In another study, 54 dialysis patients with stable hemoglobin concentrations of 10–13 g/dL who had been receiving darbepoetin alfa s.c. or i.v. every two weeks were switched to treatment once every three weeks for 20 weeks and then if hemoglobin values remained stable, once every four weeks for an additional 20 weeks.17 The target hemoglobin was maintained in 30 (83%) of 36 evaluable patients who made the switch to treatment once every four weeks. These 30 patients represent 56% of all enrolled patients. The incidence and prevalence of adverse effects were similar in patients receiving treatment once every three weeks and patients treated once every four weeks. In a multicenter, open-label study, 128 predialysis patients with CKD who had not received an ESA within 12 weeks before enrollment (i.e., ESA-naïve patients) were given darbepoetin alfa 0.75 μg/kg s.c. once every two weeks.18 A total of 115 patients completed the trial, and 97% (n = 111) of these patients achieved the target hemoglobin concentration of at least 11 g/dL after 21 weeks of treatment. The median dose was 60 μg every other week. The patients who achieved the hemoglobin target were then converted to once monthly dosing using a dose equivalent to the amount received over the preceding month. An interim analysis showed that the target hemoglobin was maintained in 85 (85%) of 100 evaluable patients using a median monthly dose of 118 μg. Darbepoetin was well tolerated in the study. The findings of this study support the use of darbepoetin alfa on a once-monthly basis in patients with CKD and anemia regardless of whether they receive dialysis. The product labeling for darbepoetin alfa is expected to be modified to reflect the use of this extended dosing interval in the near future. The average wholesale price of treatment with epoetin alfa and darbepoetin alfa is similar when the dose and dosing frequency are taken into consideration.19 However, the drug acquisition costs may vary because of differences in contract prices negotiated by institutions. Investigational agents Continuous erythropoiesis receptor activator. Continuous erythropoiesis receptor activator (CERA) is a new drug that stimulates erythropoiesis and is expected to receive approval from the Food and Drug Administration in 2007. It is a large molecule created by integrating a single polymer chain (polyethylene glycol) into recombinant human erythropoietin.20,–22 The mass of this pegylated erythropoietin is twice that of erythropoietin.20 The elimination half-life (135 hours) of CERA after i.v. or s.c. administration is considerably longer than the half-life of either epoetin alfa or darbepoetin alfa, allowing a long dosing interval for CERA.20 The efficacy and safety of CERA were evaluated in a 12-week, dose-finding, open-label study of 61 ESA-naïve patients with CKD who were receiving dialysis.23 After a four-week run-in period, patients were randomly assigned to receive s.c. 0.15 μg/ kg/week, 0.30 μg/kg/week, or 0.45 μg/ kg/week. Patients in each group were further assigned on a random basis to treatment once weekly, once every two weeks, or once every three weeks (e.g., patients in the 0.15 μg/kg/week group were randomly assigned to receive 0.15 μg/kg once weekly, 0.30 μg/kg every two weeks, or 0.45 μg/kg every three weeks). A hematopoietic response (i.e., an increase from baseline in hemoglobin concentration ≥1 g/dL) was observed in 72%, 90%, and 79% of patients in the 0.15 μg/kg/week, 0.30 μg/kg/week, and 0.45 μg/kg/week groups, respectively. The response rate was not related to the dosing interval. The median response time decreased with increases in dosage from 51 days in the 0.15 μg/ kg/week group to 38 days in the 0.30 μg/kg/week group and 31 days in the 0.45 μg/kg/week group. The drug was well tolerated. Hypertension was reported by 8% of patients, all of whom were in the highest dosage group. This incidence of hypertension is lower than that observed in epoetin alfa or darbepoetin trials, but it may reflect the small patient population or inclusion and exclusion criteria.3,–5 Comparative clinical trials are needed to determine the risk of hypertension from CERA and other ESAs. Three s.c. CERA doses (0.15 μg/ kg; 0.30 μg/kg; 0.45 μg/kg) and three dosing intervals (once weekly, once every three weeks, and once every four weeks) were compared in 137 dialysis patients with CKD who were not ESA-naïve.24 After 19–21 weeks of treatment, the target hemoglobin concentration (10–13 g/dL) was maintained with a dosing interval of once every four weeks. CERA was well tolerated in the study. In two 12-month studies of a total of 109 dialysis patients who had been treated previously with epoetin alfa, i.v. treatment with CERA once weekly or every other week (study 1) or s.c. treatment with CERA once weekly, every three weeks, or every four weeks (study 2) was effective for maintaining stable hemoglobin concentrations regardless of gender, age, race, or diabetes status.25 Few dosing adjustments were required during the studies. CERA was well tolerated, with hypotension and muscle cramps being the most commonly reported adverse effects. The findings of these clinical studies suggest that extended dosing of CERA is safe and effective in dialysis patients with CKD. The drug appears safe and effective regardless of prior ESA use. Other investigational therapies. Erythropoiesis is regulated by hypoxiainducible factor-1α (HIF-1α), a transcription factor that stimulates erythropoiesis and iron mobilization and utilization.26,27 Prolyl hydroxylase enzymes serve as a negative feedback by breaking down HIF-1α and reducing its activity.27 Several inhibitors of HIF-prolyl hydroxylase, FG-2216 and FG-4592, have been developed to stabilize HIF-1α, upregulate expression of the erythropoietin gene (i.e., increase endogenous erythropoietin synthesis), and assist in the mobilization and utilization of iron stores.21,28 These HIF-prolyl hydroxylase inhibitors are noteworthy because they are administered orally, which is convenient. The potential for these agents to promote cancer progression is a concern because HIF-1α is overexpressed in many cancers, especially metastatic cancers. 29 Cancer progression during use of these agents has not been observed in clinical trials of HIF-prolyl hydroxylase inhibitors, but the possibility warrants concern. The HIF-prolyl hydroxylase inhibitor known as FG-2216 was evaluated in a phase IIa placebo-controlled study of nine ESA-naïve predialysis patients with CKD.30 After a twoweek screening period, patients were randomly assigned in a 2:1 ratio to receive the active drug or placebo orally three times a week for four weeks, with a two-week follow-up period. Substantial increases from baseline in hemoglobin concentration were observed after three weeks and six weeks (i.e., at the end of the follow-up period) in the five evaluable patients who received FG-2216, although decreases from baseline were observed in the three placebo-treated patients over the same periods. The mean increase from baseline in hemoglobin concentration was 1.0 g/dL after three weeks and 1.4 g/dL after six weeks in the active treatment group. The mean decrease from baseline in hemoglobin in the placebo group was 0.6 g/dL after three weeks and 0.5 g/dL after six weeks. These findings suggest that FG-2216 may be a useful oral therapy for patients with CKD and anemia. Further research is needed. Hematide is a pegylated synthetic peptide-based ESA developed from research in erythropoietin-mimetic peptides.21 In animals, the drug binds to and activates the erythropoietin receptor and causes proliferation and differentiation of erythroid progenitor cells.31 In 28 healthy male volunteers, single 0.1-mg/kg i.v. doses of Hematide produced significantly greater increases from baseline in hemoglobin concentration than placebo, and the increases were sustained for more than one month.32 The doses were well tolerated.32 Phase II trials of Hematide for the treatment of anemia associated with CKD are under way.33 Ferumoxytol is a semi-synthetic carbohydrate-coated iron oxide that was developed initially for magnetic resonance imaging. In a randomized, double-blind, ascending-dose study of 41 normal volunteers and an open-label, ascending-dose study of 20 hemodialysis patients, rapid i.v. injection of ferumoxytol at a rate of 60 mg iron/min produced significant increases in transferrin saturation and serum iron and ferritin concentrations.34 The drug was well tolerated. In another study, 21 predialysis or peritoneal dialysis patients with CKD were randomly assigned to receive four ferumoxytol doses containing 255 mg iron over two weeks or two ferumoxytol doses containing 510 mg iron over one to two weeks by rapid i.v. injection at a rate of 30 mg iron/sec.35 The mean hemoglobin concentration increased significantly from a baseline level of 10.4 g/dL to a maximum value of 11.4 g/dL after six weeks. The mean serum ferritin increased significantly from a baseline value of 232 ng/mL to a maximum value of 931 ng/mL after two weeks, with a value of 295 ng/mL maintained after eight weeks. Five patients reported constipation, chills, tingling, a gastrointestinal viral syndrome, delayed pruritic erythematous rash, and transient pain at the injection site that might have been related to ferumoxytol. These findings suggest that ferumoxytol might be a convenient alternative to conventional i.v. and oral iron therapy for patients with CKD and anemia, although additional clinical experience is needed with the drug. A phase III trial comparing ferumoxytol with oral iron therapy for the treatment of anemia in hemodialysis patients is in progress.36 A new i.v. iron product, VIT 45, has been developed. Two phase III clinical trials of the drug are under way. One study is designed to compare oral iron with VIT 45 in the treatment of anemia in predialysis patients with CKD.37 The other study is a long-term safety study of VIT 45 for the treatment of anemia in the same patient population. 38 As with other i.v. iron products, hemodialysis does not remove significant amounts of VIT 45.11,12,39,40 Other investigational therapies for the treatment of anemia in patients with CKD include an inhaled formulation of erythropoietin created by conjugating recombinant human erythropoietin to the Fc component of a human immunoglobulin G molecule.41 Preliminary testing of this formulation has been performed in chimpanzees and healthy male volunteers, but additional research is needed. In an animal model of severe anemia associated with chronic renal failure, transfer of the gene that encodes erythropoietin into muscle cells increased gene expression and serum erythropoietin and hematocrit levels without causing severe hypertension. 42 Whether erythropoietin gene transfer might be useful in humans with anemia and CKD remains to be determined. Conclusion Clinical practice recommendations of the NKF provide clinicians with guidance to optimize the treatment of anemia in patients with CKD. Research has led to the development of new therapeutic modalities with the potential to improve convenience, efficacy, safety, and outcomes in this patient population. Footnotes Based on the proceedings of symposia held December 4 and 5, 2006, during the ASHP Midyear Clinical Meeting in Anaheim, CA, and supported by an educational grant from Roche Pharmaceuticals. Dr. Grabe received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Grabe reports that he has no affiliation with or financial interest in a commercial organization that pose a conflict of interest with this article. References 1 National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis . 2006 ; 47 (5 suppl 3): S11 –145. Crossref Search ADS PubMed 2 National Kidney Foundation. Kidney/ Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis . 2002 ; 39 (2 suppl 1): S1 –266. PubMed 3 Procrit package insert. Raritan, NJ: Ortho Biotech Products, L.P.; December 2006 . 4 Epogen package insert. Thousand Oaks, CA: Amgen; December 2006 . 5 Aranesp package insert. Thousand Oaks, CA: Amgen; December 2006 . 6 Hoggard J, Crouch T, McMurray S et al. Preference for monthly darbepoetin alfa dosing in patients with chronic kidney disease not receiving dialysis. Curr Med Res Opin . 2006 ; 22 : 2023 –30. Crossref Search ADS PubMed 7 Cleland JG, Sullivan JT, Ball S et al. Once-monthly administration of darbepoetin alfa for the treatment of patients with chronic heart failure and anemia: a pharmacokinetic and pharmacodynamic investigation. J Cardiovasc Pharmacol . 2005 ; 46 : 155 –61. Crossref Search ADS PubMed 8 Ling B, Walczyk M, Agarwal A et al. Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol . 2005 ; 63 : 327 –34. Crossref Search ADS PubMed 9 Adamson JW. Iron deficiency and other hypoproliferative anemias. In: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005 :586–92. 10 McEvoy GK, ed. Iron preparations, oral. In: AHFS Drug Information 2007. Bethesda, MD: American Society of Health-System Pharmacists; 2007 :1410–7. 11 McEvoy GK, ed. Iron dextran. In: AHFS Drug Information 2006. Bethesda, MD: American Society of Health-System Pharmacists; 2006 :1418–21. 12 McEvoy GK, ed. Sodium ferric gluconate. In: AHFS Drug Information 2007. Bethesda, MD: American Society of Health-System Pharmacists; 2007 :1418–22. 13 McEvoy GK, ed. Iron sucrose. In: AHFS Drug Information 2007. Bethesda, MD: American Society of Health-System Pharmacists; 2007 :1417–8. 14 Zamboni WC, Stewart CE. An overview of the pharmacokinetic disposition of darbepoetin alfa. Pharmacotherapy . 2002 ; 22 (9 pt 2): 133S –140S. Crossref Search ADS PubMed 15 Nissenson AR, Swan SK, Lindberg JS et al. Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients. Am J Kidney Dis . 2002 ; 40 : 110 –8. Crossref Search ADS PubMed 16 Locatelli F, Villa G, Backs W et al. Aranesp (darbepoetin alfa) maintains hemoglobin levels in hemodialysis patients at extended dosing intervals regardless of previous recombinant human erythropoietin dosing frequency [abstract]. American Society of Nephrology 2004 [PUB254]. J Am Soc Nephrol . 2004 ; 15 (abstracts): 816A 17 Jadoul M, Vanrenterghem Y, Foret M et al. Darbepoetin alfa administered once monthly maintains haemoglobin levels in stable dialysis patients. Nephrol Dial Transplant . 2004 ; 19 : 898 –903. Crossref Search ADS PubMed 18 Silver MR, Ayus CJ, Dhingra R et al. Once-monthly (QM) Aranesp (darbepoetin alfa) maintains target hemoglobin (Hb) levels in patients with chronic kidney disease who are converting from every-other-week (Q2W) administration. J Am Soc Nephrol. 2005 ; 16 : 762A . Abstract SA–PO940. 19 Drug Topics Red Book. Montvale, NJ: Medical Economics; 2003 . 20 Bunn HF. New agents that stimulate erythropoiesis. Blood . 2007 ; 109 : 868 –73. PubMed 21 Macdougall IC. Recent advances in erythropoietic agents in renal anemia. Semin Nephrol . 2006 ; 26 : 313 –8. Crossref Search ADS PubMed 22 Macdougall IC. CERA (continuous erythropoietin receptor activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep . 2005 ; 4 : 436 –40. PubMed 23 de Francisco AL, Sulowicz W, Klinger M et al. Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomised, multicentre, multiple-dose, phase II study. Int J Clin Pract . 2006 ; 60 : 1687 –96. Crossref Search ADS PubMed 24 Locatelli F, Villa G, Arias M et al. CERA (continuous erythropoiesis receptor activator) maintains hemoglobin levels in dialysis patients when administered subcutaneously up to once every four weeks. Presented at the 37th Annual Meeting and Scientific Exposition of the American Society of Nephrology, St. Louis, MO: October 29–November 1, 2004 . Abstract SU-PO051. 25 Dutka P, Tilocca P. CERA (continuous erythropoietin receptor activator) maintains stable hemoglobin concentrations in dialysis patients irrespective of gender, age, race, or diabetic status. Presented at the American Nephrology Nurses’ Association 37th National Symposium; Nashville, TN: April 2–5, 2006 . 26 Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov . 2003 ; 2 : 803 –11. Crossref Search ADS PubMed 27 Melnikova I. Anaemia therapies. Nat Rev Drug Discov . 2006 ; 5 : 627 –8. Crossref Search ADS PubMed 28 Liu DY, Neff TB, Guenzler V et al. Novel and beneficial pharmacodynamic properties of endogenous EPO and ‘complete erythropoiesis’ induced by selective HIF prolyl hydroxylase inhibitors. J Am Soc Nephrol . 2005 ; 16 : 761A . 29 Zhong H, De Marzo AM, Laughner E et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res . 1999 ; 59 : 5830 –5. PubMed 30 Günzler V, Muthukrishnan E, H.H. Neumayer KS et al. FG-2216 increases hemoglobin concentration in anemic patients with chronic kidney disease. J Am Soc Nephrol . 2005 ; 16 : 758A . 31 Fan A, Leuther KK, Holmes CP et al. Pre-clinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol . 2006 ; 34 : 1303 –11. Crossref Search ADS PubMed 32 Stead RB, Lambert J, Wessels D et al. Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers. Blood . 2006 ; 108 : 1830 –4. Crossref Search ADS PubMed 33 Efficacy and safety of Hematide™ injection in the treatment of anemia in patients with chronic kidney disease. www.clinicaltrials.gov/ct/show/NCT00314795 (accessed 2007 Feb 10). 34 Landry R, Jacobs PM, David R et al. Pharmacokinetic study of ferumoxytol: a new iron replacement therapy in normal subjects and hemodialysis patients. Am J Nephrol . 2005 ; 25 : 400 –10. Crossref Search ADS PubMed 35 Spinowitz BS, Schwenk MH, Jacobs PM et al. The safety and efficacy of ferumoxytol therapy in anemic chronic kidney disease patients. Kidney Int . 2005 ; 68 : 1801 –7. Crossref Search ADS PubMed 36 Ferumoxytol versus oral iron in the treatment of anemia in hemodialysis patients. www.clinicaltrials.gov/ct/show/NCT00233597?order=1 (accessed 2007 Feb 10). 37 VIT45 versus oral iron in the treatment of anemia in non-dialysis dependent chronic kidney disease. www.clinicaltrials.gov/ct/show/NCT00317239?order=3 (accessed 2007 Feb 10). 38 Long term safety study of (VIT45) extension study: treatment of anemia in non-dialysis dependent chronic kidney disease. www.clinicaltrials.gov/ct/show/NCT00317226?order=2 (accessed 2007 Feb 10). 39 Venofer package insert. Shirley, NY: American Regent, Inc; October 2005 . 40 Manley HJ, McClaran ML. Determination of VIT 45 (IND#63,243 - American Regent) removal by closed loop in vitro hemodialysis system. Int J Artif Organs . 2006 ; 29 : 1062 –6. Crossref Search ADS PubMed 41 Dumont JA, Bitonti AJ, Clark D et al. Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway. J Aerosol Med . 2005 ; 18 : 294 –303. Crossref Search ADS PubMed 42 Ataka K, Maruyama H, Neichi T et al. Effects of erythropoietin-gene electrotransfer in rats with adenine-induced renal failure. Am J Nephrol . 2003 ; 23 : 315 –23. Crossref Search ADS PubMed Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Dowling, Thomas, C.

doi: 10.2146/ajhp070181pmid: 17591994

Abstract Purpose. The prevalence of chronic kidney disease (CKD) and anemia in the United States, classification scheme for CKD, definition of anemia, etiology and consequences of anemia in patients with CKD, and the clinical and economic benefits of correcting anemia are described. Summary. Approximately 20 million people in the United States population have CKD, and 2–4 million of these may also have anemia, which often goes undetected and untreated. Patients with CKD are now classified into five stages based on the degree of kidney function impairment. Here, anemia is caused by insufficient erythropoietin production, and may occur as early as stage 3 CKD. Potential consequences of anemia include cognitive impairment, angina, and the cardiorenal anemia syndrome, a triad of worsening anemia, worsening CKD, and worsening congestive heart failure. Treatment of anemia in predialysis patients with stage 2–4 CKD may slow renal disease progression and improve energy, work capacity, health-related quality of life, and cardiac function. Optimizing the hemoglobin or hematocrit value before initiating dialysis may reduce mortality. Anemia contributes to significant healthcare costs associated with CKD. Substitution of the subcutaneous route of administration for the intravenous route of administration for epoetin alfa can reduce drug acquisition and healthcare costs, the two largest components of healthcare costs in CKD patients. Efforts to slow the progression of CKD could also have a substantial impact on hospitalizations and costs. Conclusion. Correcting anemia has the potential to improve clinical and economic outcomes in patients with CKD. Anemia, Classification, Costs, Drug administration routes, Economics, Epidemiology, Epoetin alfa, Hematopoietic agents, Injections, Kidney diseases, Mortality, Quality of life Erythropoiesis is the process of red blood cell formation from stem cells in the bone marrow. The process begins with the proliferation and differentiation of stem cells to form progenitor cells (i.e., burst-forming units-erythroid, colony-forming units-erythroid), which contain erythropoietin receptors. Hemoglobin synthesis in these progenitor cells leads to the formation of mature erythrocytes. The entire process of erythropoiesis takes approximately five days and is regulated by the hormone erythropoietin, which is synthesized in the kidneys. In healthy persons, erythropoietin is released in response to a low hemoglobin concentration or hematocrit. However, patients with chronic kidney disease (CKD) are unable to produce erythropoietin in response to decreases in hemoglobin or hemotocrit.1 The extent to which erythropoietin synthesis is impaired by kidney disease depends on the degree of renal impairment. Increases in serum creatinine (SCr) concentration (i.e., deterioration in renal function) correlate with decreases in hematocrit (Figure1).2 The greatest declines in hematocrit are observed in the early stages of kidney disease (e.g., SCr up to 5 mg/dL) and smaller hematocrit reductions in patients with moderate renal failure (SCr 5–10 mg/dL) and advanced renal failure (SCr >10 mg/dL).2 Thus, early detection and monitoring of anemia is required in CKD patients. Figure 1. Open in new tabDownload slide Figure 1. Open in new tabDownload slide Classification of CKD and anemia The National Kidney Foundation (NKF) defines CKD as the presence of kidney damage (i.e., pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies), or a decreased level of kidney function (i.e., a glomerular filtration rate [GFR] <60 mL/min/1.73 m2) for three or more months, regardless of the presence of kidney damage.3 Patients with CKD are classified into one of five stages based on the degree of kidney impairment, regardless of the diagnosis (Table 11).3 Analysis of data from the third National Health and Nutrition Examination Survey revealed that roughly 10% of the U.S. population has CKD.3 Many of these people are in stage 1 and do not realize that they have kidney damage. The largest group of patients with CKD are classified in stage 3, which is where complications such as anemia and calcium and phosphate imbalances manifest, and healthcare resource utilization becomes substantial. 4 Earlier recognition of CKD is therefore needed to monitor and slow the progression of CKD from stage 1 to stage 5. Stage 5 includes patients with end-stage renal disease (ESRD) who are undergoing dialysis or awaiting transplantation. This stage represents a substantial part of healthcare resource utilization because of the high cost of dialysis, much of which is covered by Medicare, and accounts for nearly $20 billion annually.5 Table 1. Classification and Prevalence of Chronic Kidney Disease in the United States3,a Stage Description Estimated GFR (mL/min/1.73 m2) Prevalence in millions (%) aGFR = glomerular filtration rate 1 Kidney damage with normal or ↑GFR ≥90 5.9 (3.3) 2 Kidney damage with mild ↓ GFR 60–89 5.3 (3.0) 3 Moderate ↓ GFR 30–59 7.6 (4.3) 4 Severe ↓ GFR 15–29 0.4 (0.2) 5 Kidney failure (end-stage renal disease) <15 (or on dialysis) 0.3 (0.1) Stage Description Estimated GFR (mL/min/1.73 m2) Prevalence in millions (%) aGFR = glomerular filtration rate 1 Kidney damage with normal or ↑GFR ≥90 5.9 (3.3) 2 Kidney damage with mild ↓ GFR 60–89 5.3 (3.0) 3 Moderate ↓ GFR 30–59 7.6 (4.3) 4 Severe ↓ GFR 15–29 0.4 (0.2) 5 Kidney failure (end-stage renal disease) <15 (or on dialysis) 0.3 (0.1) Open in new tab Table 1. Classification and Prevalence of Chronic Kidney Disease in the United States3,a Stage Description Estimated GFR (mL/min/1.73 m2) Prevalence in millions (%) aGFR = glomerular filtration rate 1 Kidney damage with normal or ↑GFR ≥90 5.9 (3.3) 2 Kidney damage with mild ↓ GFR 60–89 5.3 (3.0) 3 Moderate ↓ GFR 30–59 7.6 (4.3) 4 Severe ↓ GFR 15–29 0.4 (0.2) 5 Kidney failure (end-stage renal disease) <15 (or on dialysis) 0.3 (0.1) Stage Description Estimated GFR (mL/min/1.73 m2) Prevalence in millions (%) aGFR = glomerular filtration rate 1 Kidney damage with normal or ↑GFR ≥90 5.9 (3.3) 2 Kidney damage with mild ↓ GFR 60–89 5.3 (3.0) 3 Moderate ↓ GFR 30–59 7.6 (4.3) 4 Severe ↓ GFR 15–29 0.4 (0.2) 5 Kidney failure (end-stage renal disease) <15 (or on dialysis) 0.3 (0.1) Open in new tab Anemia definition Anemia is defined by NKF as a hemoglobin concentration less than 12.0 g/dL in women and less than 13.5 g/dL in men.6 However, these thresholds are based on adult women and men of all races and ethnic groups living at a relatively low altitude (<3000 feet above sea level). The mean hemoglobin concentration decreases between the ages of 50 and 75 in men, but not in women. Levels remain stable in women between the ages of 20 and 80. The mean hemoglobin concentration in pediatric patients varies widely with age. Other factors, such as smoking, may cause a compensatory increase in hemoglobin concentration, reducing the risk for anemia in current and past smokers. Persons living at high altitudes have higher hemoglobin concentrations, due in part to low atmospheric oxygen tension, resulting in reduced oxygen saturation (~90%) and increased erythropoietin production.6 Therefore, the threshold for anemia should be higher in persons living at high altitudes than in those who live at low altitudes. Hemoglobin concentrations and the prevalence of anemia in patients with CKD vary according to race or ethnicity.6 For example, African Americans have been reported to have lower hemoglobin concentrations, and a higher prevalence of anemia associated with CKD, than Caucasians. Etiology and consequences of anemia Insufficient erythropoietin production is the primary cause of anemia in patients with CKD. Various secondary causes can contribute to anemia, including a deficiency of iron, folate, or vitamin B12; gastrointestinal bleeding; severe hyperparathyroidism; inflammatory conditions; and shortened red blood cell survival due to uremia.1,7 Deficiencies of folate and vitamin B12 cause macrocytic anemia. Elevated parathyroid hormone concentrations and acute and chronic inflammation suppress erythropoiesis in the bone marrow.7 The normal life span of red blood cells is 120 days, but red blood cell survival is reduced to 60 days in patients with renal failure.8 Cardiovascular complications of anemia include worsening heart failure, left ventricular hypertrophy, and angina. Anemia impairs oxygen delivery to tissues, and the resulting tissue hypoxia can adversely affect organ function, particularly cardiac function.9 Here, cardiac output increases in an attempt to compensate for tissue hypoxia, resulting in cardiac enlargement. It has been reported that 39% of predialysis patients with CKD have left ventricular hypertrophy. 10 In patients with ESRD who require dialysis, left ventricular hypertrophy is associated with a 20% five-year survival rate compared with a 50% five-year survival rate in patients with ESRD who do not have left ventricular hypertrophy.10 Prolonged left ventricular hypertrophy can further lead to congestive heart failure. A triad of worsening anemia, worsening CKD, and worsening CHF create a vicious cycle referred to as the cardiorenal anemia syndrome. Therefore, treating anemia in patients with heart failure can interrupt the cycle, leading to reduced cardiac complications and a slower rate of CKD progression. Angina is another potential complication of anemia. In a study of 253 elderly patients (age ≥ 75 years) with stable, symptomatic coronary artery disease, the presence of anemia was an independent predictor of death and major adverse clinical events over a four-year follow-up period.11 Reduced tissue oxygen delivery can also result in cerebral hypoxia. This can lead to common symptoms of anemia such as lethargy, decreased cognition and reduced mental acuity. Prevalence of anemia The prevalence of anemia (defined as a hemoglobin concentration <12 g/dL) was assessed in 5222 patients with CKD.12 Women with an SCr of 1.5–6.0 mg/dL and men with an SCr of 2.0–6.0 mg/dL were included in the analysis, but patients receiving erythropoiesis-stimulating agents (ESAs, such as epoetin alfa and darbepoetin alfa) or iron therapy were excluded. The mean age was 68 years, and 50% of patients had diabetes and 33% of patients had hypertension. Most (98%) patients had a GFR less than 60 mL/min/1.73 m2 (i.e., stage 3, 4, or 5 CKD), with approximately 48% of these patients having anemia. If this percentage is extrapolated to the 8.3 million Americans with stage 3, 4, or 5 CKD (Table 11), roughly 4 million people in the United States have anemia and CKD. At the time patients with CKD initiate dialysis, approximately two thirds of patients have a hemoglobin concentration less than 11 g/dL and only about one third of patients have received ESAs.5 Thus, anemia often goes undetected and untreated in patients with CKD. Impact of anemia treatment Patients undergoing dialysis are frequently monitored for anemia. However, anemia is a significant problem in the predialysis population, where patients are often lost to follow-up because of non-compliance with clinic appointments or failure to seek medical care. Treatment of anemia in the predialysis population has been shown to improve energy and work capacity, improve health-related quality of life (QOL) and cardiac indices, slow renal disease progression, and decrease mortality.13,–18 In an open-label study of 101 patients with CKD, the 40 patients who also had anemia received a mean weekly dosage of epoetin alfa 4100 units subcutaneously (s.c.) for six months.16 The other 61 patients without anemia served as a control group. Epoetin alfa therapy resulted in a significant 2-g/dL increase in hemoglobin concentration and a significant reduction in left ventricular mass index (LVMI, a measure of cardiac hypertrophy) over a six-month period.16 There were no significant changes from baseline in the hemoglobin concentration or LVMI in the control group. These findings suggest that anemia correction can improve left ventricular function in patients with CKD. Health-related QOL was assessed using the Linear Analog Scale Assessment (LASA) in an open-label, non-randomized study of 1338 predialysis patients with CKD and anemia (hemoglobin ≤10 g/dL).14 Epoetin alfa 10,000 units was administered s.c. once weekly for 16 weeks, with an increase in dosage to 20,000 units once weekly permitted at week five if an increase in hemoglobin concentration of at least 1 g/dL had not occurred. A significant increase in the mean hemoglobin concentration from 9.1 g/dL at baseline to 11.6 g/dL at the end of the study was observed. This increase was accompanied by significant increases from baseline in the mean LASA scores for energy, activity, and overall QOL. A post-hoc analysis of data from a prospective open-label study of the use of epoetin alfa to treat anemia in 1183 predialysis patients with CKD found a correlation between increases in hemoglobin concentration and improvements in LASA scores for energy, activity, and overall QOL.15 The greatest improvement in QOL occurred in the hemoglobin concentration range between 10 g/dL and 12 g/dL, with smaller improvements in QOL at hemoglobin concentrations exceeding 12 g/dL. Few studies have examined the impact of treating anemia on mortality in predialysis patients with CKD, in part due to relatively low mortality in this population compared with the dialysis population. In a retrospective, observational cohort study of 4866 patients with CKD who began dialysis, a 20% reduction in mortality was associated with the predialysis use of epoetin alfa compared with those who did not receive epoetin alfa during the predialysis period.18 Here, the greatest survival benefit was observed in patients with the highest hematocrit values at the start of dialysis. These findings suggest that optimizing the hemoglobin or hematocrit value before initiating dialysis can improve health outcomes, including mortality. Healthcare resource utilization in CKD Although patients with ESRD account for only 0.1% of the Medicare population (~400,000 patients), they are responsible for 6.4% of its total expenditures.4 By 2010, this population is expected to grow to 660,000, with annual Medicare costs exceeding $35 billion. The annual costs of predialysis CKD are approximately $33,000 to $42,000, depending on the stage.19 These costs are approximately $14,000–$23,000 higher than costs for age-matched patients without CKD.19 Anemia is a CKD-specific complication that contributes to the cost of CKD.4 Several factors need to be considered for economic analyses related to the treatment of anemia in patients with CKD. These considerations include the drug acquisition cost, drug administration cost, hospital costs, inpatient physician fees, cost of blood transfusions (and associated labor), costs of laboratory tests, and indirect costs, such as reduced work productivity and premature death. Drug acquisition costs and hospitalization costs are the two largest components of direct healthcare costs for patients with CKD. A primary component of drug administration costs in CKD patients is the route of administration. For example, the efficacy and cost-effectiveness of epoetin alfa are greater when this drug is administered subcutaneously compared with the intravenous route.20 Here, the lower bioavailability is offset by the prolonged elimination half-life, resulting in a more physiologic plasma concentration profile.20 This results in a relatively constant degree of exposure, which is needed for continuous stimulation of erythropoiesis. Unfortunately, most dialysis patients receive epoetin alfa by the intravenous route because of ease of administration. However, it is estimated that conversion of these patients to the subcutaneous route could lead to a reduction in epoetin alfa dosage requirements by 30% (48 units/kg/week), at an annual cost savings of $681–2841 per patient.21 Other models suggest that conversion of 25–75% of dialysis patients to subcutaneous administration, with a 32% reduction in epoetin alfa dosage requirements, would result in annual cost savings of $47 million to $142 million for Medicare. 22 Further reductions to 50% of dosage requirements in all dialysis patients would save Medicare $295 million annually.22 Heart failure is an expensive disease, with direct costs amounting to $30.2 billion in 2007.23 Hospitalizations account for the largest component of the direct costs of heart failure ($17.8 billion).23 The impact of CKD and anemia on hospitalization rate in heart failure patients was evaluated in a retrospective study of 59,772 patients with heart failure, some of whom also had CKD.24 Significantly higher hospitalization rates were observed in patients with estimated GFR below 60 mL/min/1.73 m2, with the highest rates in those with further decreases in GFR (i.e., as the disease progressed from stage 2 to stage 3 and stage 4). In heart failure patients with and without CKD, hospitalization rates increase progressively with decreases in hemoglobin concentration below 12 g/dL.24 Here, hemoglobin concentration was shown to be an independent predictor of hospitalization at all levels of kidney function. Because anemia is correctable, these hospitalizations may have been preventable. Thus, it could be expected that efforts to slow the progression of CKD and treat anemia in heart failure patients could have a substantial impact on hospitalizations and healthcare costs. Conclusion Anemia in predialysis patients often goes undetected and untreated, despite the potentially serious and costly consequences. The benefits of anemia treatment and correction include improved health-related QOL and cardiac function and reduced mortality and healthcare resource utilization and costs. Early treatment of anemia in patients with CKD can delay the progression of renal disease and help prevent costly consequences. Footnotes Based on the proceedings of a symposium held December 4 and 6, 2006, during the ASHP Midyear Clinical Meeting, Anaheim, CA, and supported by an educational grant from Roche Pharmaceuticals. Dr. Dowling received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Dowling reports that he has no affiliation with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 Erslev AJ. Erythropoietin. N Engl J Med . 1991 ; 324 : 1339 –44. Crossref Search ADS PubMed 2 Hakim RM, Lazarus JM. Biochemical parameters in chronic renal failure. Am J Kidney Dis . 1988 ; 11 : 238 –47. Crossref Search ADS PubMed 3 National Kidney Foundation. Kidney/Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis . 2002 ; 39 (2 suppl 1): S1 –266. PubMed 4 Thorp ML, Eastman L, Smith DH et al. Managing the burden of chronic kidney disease. Dis Manag . 2006 ; 9 : 115 –21. Crossref Search ADS PubMed 5 United States Renal Data System. USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006. www.usrds.org/adr.htm. (accessed 2007 Feb 7). 6 National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis . 2006 ; 47 (5 suppl 3): S11 –145. Crossref Search ADS PubMed 7 Adamson JW. Iron deficiency and other hypoproliferative anemias. In: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005 :586–92. 8 Campbell D. How acute renal failure puts the brakes on kidney function. Nursing. 2003 . 33 : 59 –63. 9 Venkatesan J, Henrich WL. Anemia, hypertension, and myocardial dysfunction in end-stage renal disease. Semin Nephrol . 1997 ; 17 : 257 –69. PubMed 10 Levin A, Singer J, Thompson CR et al. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis . 1996 ; 27 : 347 –54. Crossref Search ADS PubMed 11 Muzzarelli S, Pfisterer M, TIME investigators. Anemia as independent predictor of major events in elderly patients with chronic angina. Am Heart J . 2006 ; 152 : 991 –6. Crossref Search ADS PubMed 12 McClellan W, Aronoff SL, Bolton WK et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin . 2004 ; 20 : 1501 –10. Crossref Search ADS PubMed 13 Anon. Double-blind, placebo-controlled study of the therapeutic use of recombinant human erythropoietin for anemia associated with chronic renal failure in predialysis patients. The US Recombinant Human Erythropoietin Predialysis Study Group. Am J Kidney Dis . 1991 ; 18 : 50 –9. Crossref Search ADS PubMed 14 Provenzano R, Garcia-Mayol L, Suchinda P et al. Once-weekly epoetin alfa for treating the anemia of chronic kidney disease. Clin Nephrol . 2004 ; 61 : 392 –405. Crossref Search ADS PubMed 15 Lefebvre P, Vekeman F, Sarokhan B et al. Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa. Curr Med Res Opin . 2006 ; 22 : 1929 –37. Crossref Search ADS PubMed 16 Ayus JC, Go AS, Valderrabano F et al. Effects of erythropoietin on left ventricular hypertrophy in adults with severe chronic renal failure and hemoglobin <10 g/dL. Kidney Int . 2005 ; 68 : 788 –95. Crossref Search ADS PubMed 17 Jungers P, Choukroun G, Oualim Z et al. Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients. Nephrol Dial Transplant . 2001 ; 16 : 307 –12. Crossref Search ADS PubMed 18 Fink J, Blahut S, Reddy M et al. Use of erythropoietin before the initiation of dialysis and its impact on mortality. Am J Kidney Dis . 2001 ; 37 : 348 –55. Crossref Search ADS PubMed 19 Smith DH, Gullion CM, Nichols G et al. Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population. J Am Soc Nephrol . 2004 ; 15 : 1300 –6. Crossref Search ADS PubMed 20 Besarab A. Optimizing anaemia management with subcutaneous administration of epoetin. Nephrol Dial Transplant. 2005 ; 20 (suppl 6): vi10 –5. Crossref Search ADS PubMed 21 Besarab A, Reyes CM, Hornberger J. Metaanalysis of subcutaneous versus intravenous epoetin in maintenance treatment of anemia in hemodialysis patients. Am J Kidney Dis . 2002 ; 40 : 439 –46. Crossref Search ADS PubMed 22 Hynes DM, Stroupe KT, Greer JW et al. Potential cost savings of erythropoietin administration in end-stage renal disease. Am J Med . 2002 ; 112 : 169 –75. Crossref Search ADS PubMed 23 American Heart Association. Heart disease and stroke statistics: 2007 update at-a-glance. www.americanheart.org/downloadable/heart/1166711577754HS_StatsInsideText.pdf (accessed 2007 Feb 8). 24 Go AS, Yang J, Ackerson LM et al. Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation . 2006 ; 113 : 2713 –23. Crossref Search ADS PubMed Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Gilmartin,, Cheryl

doi: 10.2146/ajhp070183pmid: 17591991

Abstract Purpose. Barriers to the treatment of anemia in patients with chronic kidney disease (CKD), the role of pharmacists in screening patients for anemia and developing guidelines for the use of anemia therapies in patients with CKD, the goals of and considerations in developing pharmacist-managed anemia management clinics, and the potential benefits of these clinics are described. Summary. The complexity of patients with CKD, patient nonadherence to the treatment regimen, a shortage of nephrologists, and a lack of familiarity with clinical practice guidelines and recommendations for treating anemia in these patients are possible barriers to the treatment of anemia. Pharmacists can play a role in improving the treatment of anemia in patients with CKD by screening for anemia, developing guidelines for the use of anemia therapies, and providing patient education to promote adherence to the treatment regimen. The optimal upper limit for hemoglobin concentration during treatment with erythropoietin-stimulating agents (ESA) in patients with CKD remains to be determined, but it should not routinely exceed 13.0 g/dL. Extended dosing of darbepoetin alfa and the new agent continuous erythropoiesis receptor activator appears effective. Iron status often is not assessed in patients with CKD because of difficulty interpreting iron laboratory values and identifying iron deficiency. The usefulness of iron supplementation is not limited to patients with iron deficiency. The intravenous (i.v.) or oral route of administration may be used for iron supplementation in predialysis patients and peritoneal dialysis patients, but the i.v. route is recommended for hemodialysis patients. Adverse effects and drug interactions limit the use of oral iron supplements. Administration of parenteral iron is time consuming and accompanied by concerns about iron accumulation and uncertainty about the optimal maximum serum ferritin concentration. Improved access to care and clinical outcomes and reduced costs have been documented in pharmacist-managed anemia management clinics. Conclusion. Pharmacists can help overcome barriers to treating anemia in patients with CKD. Clinical and economic benefits are associated with pharmacist-managed anemia management clinics. Anemia, Compliance, Continuous erythropoiesis receptor activator, Darbepoetin alfa, Diagnosis, Dialysis, Dosage schedules, Drug administration routes, Drug interactions, Economics, Hematopoietic agents, Iron, Iron preparations, Kidney diseases, Patient information, Patients, Pharmaceutical services, Pharmacists, Protocols, Toxicity Screening for and detection and treatment of anemia in patients with chronic kidney disease (CKD) are inadequate (see the overview article by Dowling in this supplement) for several reasons.1 Patients with CKD are complex, often presenting with hypertension, diabetes mellitus, or other comorbid conditions (e.g., secondary hyper-parathyroidism).2 Many primary care physicians are overwhelmed by the complexity of patients with CKD and the practice guidelines for management of CKD. Obtaining reimbursement from the Centers for Medicare and Medicaid Services (CMS) for anemia therapies also has become complex because of changes in CMS rules and regulations. Physician time constraints, inefficient coordination and inconsistent delivery of patient care, and knowledge deficits present barriers to the management of anemia in patients with CKD. Patient nonadherence to complex treatment regimens also interferes with the management of anemia. Patients with CKD often receive numerous medications. Advice about proper medication use from various healthcare professionals sometimes differs, resulting in patient confusion. Failure to properly manage anemia in patients with CKD may be explained in part by a shortage of nephrologists and the delayed referral of patients by primary care physicians to nephrologists until the late stages of CKD when patients have complex problems that are difficult to manage.3 The prevalence of patients with end-stage renal disease (ESRD) is increasing (see the overview article by Dowling in this supplement).4 Each 10% increase in patients with CKD requires the services of 33 nephrologists.3 A lack of familiarity with clinical practice guidelines for the treatment of anemia in patients with CKD is another possible barrier to the treatment of anemia in these patients. In a survey of 388 ambulatory care pharmacists who routinely provide care to predialysis patients or patients with risk factors for CKD (e.g., diabetes, hypertension, decreased creatinine clearance), only 24% of pharmacists routinely monitored hemoglobin or hematocrit levels in these patients.5 Only 7% of pharmacists were very familiar and 45% were somewhat familiar with the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative clinical practice guidelines and recommendations for treating anemia in CKD.6 Another 34% were not very familiar and 13% were not at all familiar with the NKF guidelines and recommendations. Pharmacist involvement Pharmacist participation in the management of anemia in patients with CKD who do not yet require dialysis (i.e., stages 2, 3, and 4) is a logical extension of pharmacist involvement in the management of hypertension and diabetes because of the prominent role that these diseases play in CKD (see the overview article by Dowling in this supplement). A favorable impact on clinical and economic outcomes has been demonstrated in pharmacist-managed hypertension and diabetes clinics.7,–11 Predialysis (i.e., stage 2–4) CKD can be thought of as a separate disease state from ESRD requiring dialysis (i.e., stage 5 CKD). The impact of pharmacy services as part of multidisciplinary efforts to improve outcomes in dialysis patients has been described, and these multidisciplinary approaches could be applied to predialysis patients.12,–15 Screening for and detecting anemia in patients at risk for CKD (i.e., patients with diabetes, hypertension, or a glomerular filtration rate < 90 mL/min), generating interest among key institutional opinion leaders in clinical and economic outcomes in patients with anemia and CKD, and spearheading or assisting in the development of guidelines for the use of anemia therapies in predialysis patients with CKD are among the roles that pharmacists can play in treating anemia in patients with CKD. Pharmacists also can promote patient adherence to the anemia treatment regimen by providing patient education about the proper use of therapy. Erythropoietin-stimulating agents (ESAs) are among the most costly drug therapies in the pharmacy budget at healthcare institutions. Efforts by pharmacists to develop and implement institutional protocols or guidelines for ESA use can have economic benefits as well as improve clinical outcomes.13 ESA use Hemoglobin levels should be monitored at least monthly after the initiation of an ESA.6 The target hemoglobin concentration should be 11.0 g/dL or greater, but there is insufficient evidence to recommend routinely maintaining hemoglobin levels of 13.0 g/dL or greater in ESA-treated patients.6 At the University of Illinois Medical Center, hemoglobin levels are monitored quarterly after the therapeutic goal (11–12 g/dL) is reached in predialysis patients. There is evidence of harm from higher hemoglobin concentrations.16,–19 The Correction of Hemoglobin and Outcomes in Renal Insufficiency trial, an open-label study known as CHOIR, compared a target hemoglobin of 13.5 g/dL with a lower target of 11.3 g/dL using epoetin alfa therapy in 1432 patients with CKD.19 The study was terminated early because a significantly higher risk of a composite of death, myocardial infarction, hospitalization for congestive heart failure, and stroke was associated with the higher hemoglobin target compared with the lower target.19 However, in a three-year study of subcutaneous (s.c.) epoetin beta therapy (a formulation not available in the United States) in 603 patients with CKD, there was no significant difference in cardiovascular events between patients treated to a target hemoglobin concentration of 11.0–12.5 g/dL and patients treated to a target hemoglobin of 13.0–15.0 g/dL.20 In light of the boxed warnings, several studies are under way to clarify the optimal upper limit for hemoglobin concentration during ESA therapy in patients with CKD.21 Reimbursement rules and regulations of CMS provide incentive to limit hemoglobin concentrations during ESA therapy. Medicare requires a 25% reduction in ESA dosage for reimbursement if the hemoglobin concentration reaches or exceeds 13 g/dL. The reimbursement rate for ESA is only 75% of the previous month’s dose used to attain a hemoglobin of 13 g/dL or greater if the hemoglobin is 13 g/dL or higher. Extended ESA dosing In a retrospective review of the charts of 243 predialysis patients who received subcutaneous (s.c.) epoetin alfa for a mean of 10.3 months to treat anemia associated with CKD, 185 patients used extended dosing intervals of two or more weeks.22 Most (79%) of the 124 patients who used a two-week dosing interval maintained the target hemoglobin of at least 11 g/dL for at least three months. The number of patients using a three-week, four-week, or longer dosing interval was 22, 30, and 9, respectively, and the percentage of these patients who maintained the target hemoglobin of at least 11 g/dL for at least three months was 96%, 90%, and 100%, respectively. In a prospective, open-label study, 519 predialysis patients with CKD and stable hemoglobin values of at least 11 g/dL who had been receiving epoetin alfa were randomly assigned to receive s.c. epoetin alfa 10,000 units once weekly, 20,000 units every two weeks, 30,000 units every three weeks, or 40,000 units every four weeks for 16 weeks.23 Dosage reductions were permitted, but dosage increases were not allowed. The target hemoglobin (≥11 g/dL) was maintained throughout the study in 94%, 90%, 77%, and 76% of patients receiving epoetin alfa once weekly, every two weeks, every three weeks, and every four weeks, respectively. Thus, biweekly dosing of epoetin alfa appears feasible, but longer dosing intervals may be less effective. Extended dosing of epoetin alfa was similarly tolerated for all dosing intervals. Prior to the initiation of epoetin alfa, 37.6% of patients were hypertensive (i.e., blood pressure > 140/90), while hypertension occurred in 41.6% of the patients maintaining a mean hemoglobin of 11.6 ± 0.9 g/dL. However no statistically significant differences occurred among patients for each of the dosing regimens in either mean systolic or diastolic pressure. Likewise, the occurrence of hospitalizations was similar between groups. Studies have demonstrated the efficacy of extended dosing of darbepoetin alfa for up to 78 weeks in predialysis patients with CKD.24,–27 These studies included CKD patients who were being treated for anemia of CKD successfully and unsuccessfully who had been switched to extended dosing (i.e., they were not naïve to ESAs). In a 29-week study, the target hemoglobin (10–12 g/dL) was achieved and maintained when the biweekly dose of darbepoetin alfa was doubled and administered once monthly in 73 (85%) of 86 patients.24 Adverse events were similar between each of the four treatment groups (n = 513). Thrombotic events and death occurred in 2.5% and 1.4% of the patients, respectively. Another study evaluated the effectiveness and safety of extended darbepoetin dosing in patients with CKD who did not require dialysis.25 Patients who were already stable on biweekly dosing were switched to monthly dosing. Patients in the study had stage 3–4 CKD and Hb > 11 g/dL (i.e., adequate iron stores). The goal Hb was 11–13 g/dL. The group attained a mean final Hb of 11 g/dL. Additionally quality of life scores were maintained or improved within each dosing regimen. Two studies of once-monthly administration of darbepoetin alfa for 20 weeks with eight weeks of follow up were conducted in a total of 319 predialysis patients with CKD who had received at least eight weeks of epoetin alfa treatment once weekly or every two weeks.26 The target hemoglobin concentration (10–12 g/dL) was maintained throughout the study by monthly darbepoetin alfa therapy, and 305 (96%) of the 319 patients preferred monthly darbepoetin alfa treatment over more frequent epoetin alfa treatment. In a 52-week study of monthly darbepoetin alfa, 70% (n = 48) of 108 predialysis patients with CKD achieved the target hemoglobin (11–12 g/dL).27 The other 30% (n = 21) of patients who did not achieve this target had significantly lower serum albumin concentrations and transferrin saturation values, reflecting malnutrition and iron deficiency. Malnutrition is associated with ESA resistance, and iron is required for erythropoiesis and a hematopoietic response to ESA.28 These factors should be considered in patients who fail to exhibit a response to an ESA before attributing therapeutic failure to an extended dosing regimen. Continuous erythropoiesis receptor activator Continuous erythropoiesis receptor activator (CERA), a new agent with a long elimination half-life created by integrating polyethylene glycol into recombinant human erythropoietin, has been used once monthly in dialysis patients with CKD (see the preceding article by Grabe in this supplement).29,–31 Data from clinical studies in predialysis patients recently became available. In a phase II study, 65 ESA-naïve predialysis patients with CKD were randomly assigned to receive CERA at various s.c. doses (0.15–0.60 μg/kg/week) and dosing intervals (once every one to three weeks).32 The mean increase from baseline in hemoglobin concentration after six weeks of therapy ranged from 0.30 g/dL at lower doses to 1.76 g/dL at higher doses. In 51 patients who entered an extension trial, the mean hemoglobin concentration was maintained at the target (>11 g/dL) for more than 54 weeks. The efficacy of extended dosing of CERA was compared with that of darbepoetin alfa in a Phase 3 open-label, randomized, multicenter, parallel group study of 324 predialysis patients who were ESA naïve.33 The mean baseline hemoglobin in both treatment groups was 10.2 g/dL. In the initial phase of the study, patients received either CERA 0.6 μg/kg/week s.c. biweekly or darbepoetin alfa 0.45 μg/kg/week with dose adjustments to achieve an increase from baseline in hemoglobin of at least 1 g/dL and a target hemoglobin of 11–13 g/dL. Patients with a hemoglobin response after 28 weeks of CERA treatment were randomized to receive an additional 24 weeks of CERA treatment once every two weeks or once every four weeks during an extension phase of the trial. The hemoglobin response rates after 28 weeks of treatment were high in both treatment groups (98% with CERA and 96% with darbepoetin alfa). Patients in both groups had a significant change in Hb from baseline to end of study at week 28 (12.3 g/dL in the CERA group and 12.2 g/dL in the darbepoetin group). The mean change in baseline Hb was 0.16 g/dL (−0.05–0.35, p < 0.001). The hemoglobin was maintained in the target range with CERA administration every two weeks and every four weeks during the 24-week extension phase of the study. Adverse events were similar in both groups and included hypertension, nasopharyngitis, diarrhea, and peripheral edema. At weeks 1–28, 67.7% of CERA patients and 80.6% of darbepoetin patients had Hb > 13 g/dL (p < 0.0082). Thus, extended dosing of CERA appears effective in predialysis patients with CKD as well as in dialysis patients. Iron therapy The assessment of iron status in patients with CKD usually involves measurement of the serum iron concentration (which reflects iron available for hemoglobin synthesis), the serum ferritin concentration (an indirect measure of total body iron stores), and the total iron binding capacity (TIBC). The transferrin saturation (TSAT) is calculated by dividing the serum iron concentration by the TIBC and multiplying the result by 100. It is a measure of the iron that is immediately available for hemoglobin synthesis. The content of hemoglobin in reticulocytes is a new measure that also reflects the adequacy of iron for erythropoiesis.6 Interpreting iron laboratory values and identifying iron deficiency in patients with CKD can present a challenge. In a study conducted at the Nephrology Clinics at the University of North Carolina (UNC) at Chapel Hill, iron status was not evaluated in 43% of patients with CKD, and 22% of those patients had a serum ferritin value <100 ng/mL and 55% of the patients had a TSAT < 20% (i.e., laboratory values suggesting the presence of iron deficiency).34 Sixty percent of patients did not receive iron therapy. In a retrospective study of a cohort of 602 patients with CKD (serum creatinine ≥2.0 mg/dL in men and ≥1.5 mg/dL in women) and a mean predicted glomerular filtration rate of 22 mL/min, screening laboratory iron tests were performed in 18% of patients.35 A hematocrit less than 30% (i.e., anemia) was present in 38% of patients. Thus, failure to assess iron status is not uncommon in patients with CKD. This failure can have consequences if iron deficiency goes undetected. Iron status should be measured in conjunction with hemoglobin in patients with CKD and anemia to ensure that patients have adequate iron stores when initiating ESA therapy. Iron supplementation should be initiated simultaneously with ESA treatment. Parenteral iron therapy may be needed to replenish diminished iron stores (i.e., serum ferritin <100 ng/mL or TSAT <20%), but the usefulness of iron supplementation is not limited to patients with iron deficiency.6 Iron supplementation can help prevent depletion of iron stores during erythropoiesis and achieve and maintain target hemoglobin levels.6 Iron status should be monitored monthly in patients with iron deficiency until stores are replenished. Quarterly monitoring of iron status suffices in patients with adequate iron stores. The intravenous (i.v.) or oral route of administration may be used for iron supplementation in predialysis patients and peritoneal dialysis patients, but the i.v. route is specifically recommended by NKF for hemodialysis patients.6 Oral iron supplements include ferrous sulfate, ferrous gluconate, and ferrous fumarate, and the elemental calcium content of these products is 300 mg/g, 120 mg/g, and 330 mg/g, respectively.36 A daily dosage of at least 200 mg of elemental iron (i.e., three 325-mg ferrous sulfate tablets or two 325-mg ferrous fumarate tablets) is recommended for patients with CKD who receive an ESA because of the increased iron demands associated with erythropoiesis.37 However, oral iron absorption may be impaired in patients with CKD, and the recommended amount of oral iron usually is inadequate in dialysis patients because of blood losses.36,38 Parenteral iron circumvents problems with low oral bioavailability. Adverse effects from oral iron (e.g., constipation, abdominal pain, gastrointestinal [GI] upset) often limit patient adherence.36 The supplements are preferably taken on an empty stomach two hours before or one hour after a meal, but tolerability may be a problem. Taking iron at bedtime or in divided doses may ameliorate adverse effects. Combination products that contain the stool softener docusate sodium may be used to minimize constipation. Extended-release and enteric-coated iron products have been purported to reduce adverse GI effects, but iron absorption from these products is diminished compared with immediate-release products.36 Oral iron supplements may interact with aluminum-containing phosphate binders and certain other drugs.36 Doses of iron supplements and drugs that interact with them should be taken as far apart as possible to minimize the risk of interaction. Parenteral iron supplements include iron sucrose and sodium ferric gluconate. The recommended dosage of iron sucrose, which contains 20 mg/mL elemental iron, in hemodialysis patients with iron deficiency is 100 mg one to three times weekly.39 Doses may be administered by slow i.v. injection (preferably at a rate not to exceed 20 mg/min) or by i.v. infusion (100 mg diluted in 100 mL of 0.9% sodium chloride over at least 15 min).39 Total cumulative doses of 1000 mg in divided doses have been used for predialysis and peritoneal dialysis patients with iron deficiency.40 Five 200-mg doses over 2–5 minutes were used over a 14-day period in predialysis patients.40 Two 300-mg infusions over 1.5 hours 14 days apart followed 14 days later by 400 mg over 2.5 hours were used in peritoneal dialysis patients.40 Sodium ferric gluconate contains 12.5 mg/mL elemental iron. Most hemodialysis patients with iron deficiency require a cumulative dose of 1000 mg of elemental iron in eight divided doses.41 Each 125-mg dose may be given undiluted by slow i.v. injection at a rate of 12.5 mg/min or the dose may be diluted in 100 mL 0.9% sodium chloride and given by i.v. infusion over one hour.42 The safe serum ferritin concentration in hemodialysis patients receiving i.v. iron is controversial because of concerns about accumulation of iron in the liver and other organs (see the preceding article in this supplement by Grabe). The Dialysis Patients’ Response to Intravenous Iron With Elevated Ferritin (DRIVE) trial was conducted to explore the safety and efficacy of i.v. iron therapy in anemic hemodialysis patients treated with epoetin alfa who had high serum ferritin levels and low or normal iron saturation values.43 These results were recently published. Anemia management clinics The goals of anemia management clinics for patients with CKD include increasing awareness of the problem of anemia in patients with CKD and providing proactive screening for anemia in all patients with or at risk for CKD. Monitoring anemia therapy to improve the continuity and consistency of care provided to patients, and ensuring that care is consistent with NKF guidelines and recommendations and that billing is adequate to obtain reimbursement from CMS and other insurers also are goals. Therapy should be streamlined and patients and healthcare providers should be educated to promote the use of treatment plans consistent with NKF guidelines and patient adherence to the treatment plan. Considerations in developing an anemia management clinic include current use of anemia therapies and clinical and financial outcomes in patients with CKD who develop anemia. Potential clinical and economic benefits from proposed changes in the use of anemia therapies and patient monitoring associated with an anemia management clinic should be quantified to the extent possible. Such an analysis requires an assessment of current prescribing and monitoring practices and the potential impact of an anemia management clinic on these practices. A plan for implementing an anemia management clinic that establishes an organizational structure for the clinic and takes into consideration the institutional organization can then be developed based on these analyses. Failure to consider institutional organizational relationships could compromise the success of the clinic. In 2002, a pharmacist-managed clinic for the management of anemia in patients with CKD was established at the Nephrology Clinics at UNC after conducting a retrospective analysis of the clinical and financial management of anemia in this patient population at the institution.34 A multidisciplinary approach, including staff from the billing department as well as physicians (the chief of nephrology and several fellows), pharmacists (a nephrology clinical pharmacist and pharmacy fellow), and nurses (clinic and clinical research nursing staff), was used to ensure that reimbursement for services and pharmaceuticals was obtained. Clinicians at UNC were educated about the findings of the retrospective clinical and financial analysis, which included a loss of substantial revenue due to improper billing. Failure to achieve NKF goals (i.e., hematocrit values below the target range, failure to provide iron therapy despite iron laboratory values suggesting iron deficiency) also was documented. The goals of the clinic and an action plan for its operation were presented to and feedback was elicited from the UNC clinical staff. One day each week was designated for patient clinic visits. The nephrology clinical pharmacist obtained clinical privileges to manage anemia (i.e., prescribe drug therapies and order laboratory tests) under a protocol approved by the medical staff. A billing code was established for the clinic, and a template was developed for scheduling clinic visits and billing for clinic services provided to patients with CKD. Patients with CKD were screened for anemia at the clinic, and it soon became apparent that two days per week would be required to meet patient needs. To forestall and resolve billing and reimbursement issues, health insurance status was verified and documented for all patients, and prior approval was obtained for the use of ESAs and other drug therapies as necessary. Patients lacking health insurance were enrolled in manufacturer patient assistance programs. Analysis of ESA and iron use in patients with CKD and anemia led to the decision to convert patients receiving epoetin alfa once weekly to darbepoetin alfa every other week and then once monthly. Patients initiating ESA treatment received darbepoetin alfa 0.75 μg/kg s.c. once every two weeks initially, with eventual lengthening of the dosing interval. Initially, iron therapy was administered orally to most clinic patients, with titration of the dosage to 200 mg/day of elemental iron over several weeks. However, the need for an i.v. iron protocol soon became apparent because of problems with tolerability and a low response rate to oral iron therapy (20%). The target hemoglobin was achieved and maintained with a darbepoetin alfa dosing interval of four to six weeks in approximately 40% of clinic patients and an interval of two or three weeks in 58% of patients (total of 98% receiving extended dosing). In the first three months of clinic operations, a cost savings was realized that was equivalent to the financial losses experienced in the preceding year. Benefits of the clinic for established patients included reduced transportation time and costs due to a reduced frequency of visits. Access to care was improved for new patients, who experienced shorter waits to be seen by a nephrologist after referral from a primary care provider. Clinical and financial outcomes in patients receiving epoetin alfa at another pharmacist-managed protocol-driven outpatient clinic were compared with outcomes in patients receiving conventional care provided by primary care physicians.44 The baseline hemoglobin concentrations in the two groups were similar, but the time to achieve the target hemoglobin (11.0–12.9 g/dL) was substantially shorter in clinic patients (56 days) than in conventional care patients (103 days). The percentage of time with the hemoglobin concentration in the target range was higher in the clinic group (70%) than in the conventional care group (44%). The amount of epoetin alfa used in the clinic group (8449 units/week) was lower than that in the conventional care group (20,148 units/week), resulting in considerable cost savings. At the University of Illinois Medical Center, where a clinic for the management of anemia in patients with CKD was established not long ago, a retrospective analysis of the management of anemia in CKD patients revealed that no particular ESA was used consistently, and ESA administration was performed weekly or biweekly for most patients (i.e., extended dosing was seldom used). Scheduling of patient visits for ESA injections was not coordinated with physician visits. Laboratory tests for hemoglobin concentration and iron status were ordered haphazardly. Iron therapy often was improperly prescribed, if it was ordered at all, and ESA doses were not routinely adjusted based on hemoglobin values. The clinic had four nephrology attending physicians, four to six physician fellows, a pharmacist, and a nurse. Prescribing and laboratory monitoring practices were inconsistent among the attending physicians and physician fellows. A patient might be seen by any of the 10 physicians at any one visit, resulting in a lack of continuity of care. The nurse monitored blood pressure before ESA injections, but she did not order laboratory tests or modify ESA doses because of inexperience and time doing so. Problems were identified with improper billing and failure to obtain reimbursement from CMS and private insurers for clinic services and medications. Failure to obtain patient referrals at an early stage when treatment could prevent disease progression also was a source of concern. The clinic staff convened and decided to designate one individual, the pharmacist, to coordinate clinic operations and improve the consistency and continuity of care. The staff networked with personnel at clinics regarding patients at high risk for CKD and anemia (e.g., a diabetes clinic), and patient referrals to the anemia clinic were solicited for proactive screening for anemia. Certain days were set aside at the anemia clinic for visits by newly referred patients. A computer-based anemia management system was developed for use in the clinic. This computer system addresses billing and reimbursement problems (e.g., patient eligibility for coverage by Medicare Part B, Medicaid, or another health insurer is verified and documented). It also facilitates coordination of patient visits for evaluation by a physician or pharmacist, ESA injections by the nurse, and laboratory monitoring. The decision was made to use monthly darbepoetin alfa therapy for all clinic patients. In patients who had been receiving epoetin alfa, the dosage was titrated until the target hemoglobin was achieved before switching to biweekly darbepoetin alfa administration and then monthly darbepoetin alfa therapy. In most cases, the target hemoglobin was maintained by increasing the biweekly darbepoetin alfa dose by 25% to 50% and giving it monthly. Assessment of iron status and the use of oral or i.v. iron therapy as appropriate became routine when the computer system was implemented. The pharmacist evaluates the most recent laboratory hemoglobin and iron values and makes ESA and iron dosing recommendations to the physician before each patient visit, and the nurse is informed about these recommendations. The pharmacist also orders follow-up laboratory tests. The use of computer templates (i.e., standardized screens) for laboratory tests and drug therapy ensures the continuity and consistency of care. Reimbursement for anemia therapies Obtaining reimbursement for ESAs and iron therapy requires a knowledge of the requirements of CMS and private insurers. Medicaid requirements may vary locally. Two International Classification of Diseases, 9th revision (ICD-9) codes (one for the anemia of CKD and the other for the CKD stage) are required to obtain Medicare reimbursement for ESAs. Medicare Part B covers ESA injections administered in the clinic setting. In Illinois, Medicaid covers ESA administration on an outpatient basis, which allows self administration. Medicare Part D and some private insurance plans cover outpatient ESA prescriptions with prior approval. Letters requesting approval must include information about the ESA dose, CKD stage, and laboratory values for hemoglobin, iron, TIBC, TSAT, and ferritin. Coverage for ESAs by private insurers varies and is consistent with coverage under Medicare or Medicaid in some but not all private insurance plans. Medicare Part B provides coverage for i.v. iron therapy administered in a clinic setting. Two ICD-9 codes are required (one for iron deficiency anemia and the other for the CKD stage). In Illinois, reimbursement is provided by Medicaid for i.v. but not oral iron therapy if prior approval is obtained. The iron product and dosage, ESA dosage, CKD stage, and laboratory values for hemoglobin, iron, TIBC, TSAT, and ferritin are required in the request for approval. Private insurers may follow Medicare or Medicaid reimbursement policies for iron therapy. Conclusion Pharmacists can use various strategies to overcome barriers to the management of anemia in patients with CKD, including spearheading a multidisciplinary approach to improve patient screening and the continuity and consistency of care for anemic patients. The use of extended dosing regimens for anemia therapies has the potential to simplify therapy, promote adherence to the treatment regimen, and improve clinical and financial outcomes. Footnotes Based on the proceedings of a symposium held December 4 and 5, 2006, during the ASHP Midyear Clinical Meeting in Anaheim, CA, and supported by an educational grant from Roche Pharmaceuticals. 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Presented at the American Society of Nephrology Annual Meeting and Scientific Exposition; San Diego, CA: November 14–19, 2006 . Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Dowling, Thomas, C.

doi: 10.2146/ajhp070180pmid: N/A

Chronic kidney disease (CKD) affects nearly 20 million Americans, and it is estimated that 2–4 million of these patients with CKD have anemia.1,2 Anemia often goes undetected and untreated despite the availability of effective anemia therapies.3 High healthcare costs are associated with CKD, and anemia contributes to these costs.4 Healthcare costs are projected to increase because of anticipated increases in the number of Americans with CKD.5 The first article in this supplement provides an overview of the prevalence of CKD and anemia in the United States, classification scheme for CKD, definition of anemia, etiology and consequences of anemia in patients with CKD, and the clinical and economic benefits of correcting anemia. In the second article, recently released clinical practice guidelines and recommendations from the National Kidney Foundation for treating anemia in patients with CKD are summarized. The dosing, frequency, and route of administration, efficacy, and safety of established and emerging therapeutic modalities for treating anemia associated with CKD also are described. The third article discusses barriers to the treatment of anemia in patients with CKD, the role of pharmacists in screening patients for anemia and developing guidelines for the use of anemia therapies in patients with CKD, the goals of and considerations in developing pharmacist-managed anemia management clinics, and the potential benefits of these clinics. Footnotes Based on the proceedings of a symposium held December 4 and 6, 2006, during the ASHP Midyear Clinical Meeting, Anaheim, CA, and supported by an educational grant from Roche Pharmaceuticals. Dr. Dowling received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Dowling reports that he has no affiliation with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 National Kidney Foundation. Kidney/Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis . 2002 ; 39 (2 suppl 1): S1 –266. PubMed 2 McClellan W, Aronoff SL, Bolton WK et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin . 2004 ; 20 : 1501 –10. Crossref Search ADS PubMed 3 United States Renal Data System. USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006. http://www.usrds.org/adr.htm. (accessed 2007 Feb 7). 4 Smith DH, Gullion CM, Nichols G et al. Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population. J Am Soc Nephrol . 2004 ; 15 : 1300 –6. Crossref Search ADS PubMed 5 Thorp ML, Eastman L, Smith DH et al. Managing the burden of chronic kidney disease. Dis Manag . 2006 ; 9 : 115 –21. Crossref Search ADS PubMed Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.