	Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that stimulate erythropoiesis through direct or indirect action on the erythropoietin receptor producing an increase in reticulocyte count, hemoglobin (Hb), and hematocrit levels.

The first recombinant human erythropoietin was introduced in the United States in 1989.

Currently, there are 3 available ESAs—epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). The use of ESAs has been associated with a reduced need for blood transfusion, reduction in the frequency and severity of anemia-associated morbidity, and improvement in quality of life.

	ESAs were a biotechnology medical innovation, initially marketed for the treatment of anemia in end-stage renal disease.

 Today, labeled indications for the use of these agents include the treatment of anemia associated with chronic renal failure in dialysis and nondialysis patients and the treatment of anemia in metastatic cancer patients (nonmyeloid malignancies) due to concurrent chemotherapy. These agents are not indicated for use in cancer patients who are receiving lone hormonal therapy, therapeutic biologic therapy, or radiation therapy, and patients receiving myelosuppressive therapy when the expected outcome is cure. Additional US Food and Drug Administration (FDA)-approved indications for epoetin alfa include the treatment of anemia (1) associated with HIV therapy and (2) in those undergoing selective, noncardiac, and nonvascular surgeries, to reduce the need for allogeneic blood transfusions.

 However, these indications lack extensive study and will not be covered in detail in this review.

 ESAs for the Treatment of Anemia Associated with Chronic Kidney Disease

	The 2006 National Kidney Founda&shy;tion’s Kidney Disease Out&shy;come Quality Initiative (KDOQI)guidelines define anemia of chronic kidney disease as an Hb level <13.5 g/dLin men or <12.0 g/dLin women.8Two clinical trials, the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) study and the Correction of Hb and Out&shy;comes in Renal Insufficiency (CHOIR) study, revealed findings that led to changes for target Hb levels with ESA therapy.

In September 2007, the 2006 KDOQI clinical practice guidelines on anemia and chronic kidney disease were updated to reflect the new evidence that supports a target Hb level in the range of 11.0 to 12.0 g/dLin dialysis and nondialysis patients receiving ESA therapy. This target range was selected to maintain flexibility in medical decision making and supports a patient-centered treatment approach. The guidelines were also updated to reflect the importance of not targeting Hb levels >13 g/dL due to an increased risk of serious cardiovascular events and death associated with ESAadministration.

	Full prescribing information outlines a weight-based calculation for dosing ESAs. In chronic renal failure patients, the recommended starting dose for epoetin alfa is 50 to 100 units/kg administered either subcutaneouslyor intravenously 3 times per week. The approved starting dose for darbepoetin alfa is 0.45 mcg/kg once weekly or an alternate dosing of 0.75 mcg/kg every 2 weeks for nondialysis patients, administered either by the subcutaneous or intravenous route. The intravenous dosing route is the preferred method of administration for hemodialysis patients. Maintenance therapy should be individualized to maintain target hemoglobin levels. Increases in dosages should be limited to once every 4 weeks to allow sufficient time for changes in Hb levels. Doses should be titrated by 25%, and if a rapid rise in Hb (>1 g/dL per 2-week time period) occurs, therapy should be discontinued until the Hb level decreases. Therapy should be resumed at a dose that is 25% less than the previous dose.

 When adjusting doses, clinical judgment plays an important role because therapy is individualized. Retrospective cohort studies focusing on dosing regimens of epoetin alfa show similar results in achieving Hb levels to those reported in clinical trials.

 In practice, extending dosing of darbepoetin alfa from once every 2 weeks to once monthly while maintaining Hb levels may be possible in hemodialysis or nondialysis patients. An advantage to the use of darbepoetin alfa compared with epoetin alfa is its longer serum half-life, which allows for dosing of the medication once weekly or every 2 weeks. Estimated dosing conversion from one agent to the other is outlined in the 

 ESAs for the Treatment of Chemotherapy-Related Anemia

	The American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) updated their guidelines in 2007 to address the thromboem&shy;bolic risks associated with ESAs and the use of darbepoetin alfa, which was not included in the original ASCO/ASH guidelines published in 2002. Initiation of ESA therapy is recommended in patients with an Hb level that is approaching or falling below 10 g/dL.

	The FDA-approved starting dose of epoetin alfa is 150 units/kg 3 times per week or 40,000 units weekly via subcutaneous administration. Subcutaneous administration of darbepoetin alfa is recommended at an initial dose of 2.25 mcg/kg once weekly or an alternative dosing of 500 mcg once every 3 weeks. Adjustment of doses should be aimed at maintaining the lowest Hb level to avoid red blood cell transfusion. Dose escalation of epoetin alfa 3 times per week by an increase of 300 units/kg 3 times per week is suggested if there is no reduction in transfusion requirements or no increase in Hb levels after 8 weeks of therapy. The recommended weekly dose of epoetin alfa should be increased to 60,000 units if Hb levels do not increase by 1 g/dL or more after 4 weeks of therapy. If after 6 weeks of therapy with weekly dosing of darbepoetin alfa there is a greater than 1-g/dL rise in Hb level, then it is recommended to increase the dose to 4.5 mcg/kg. The epoetin alfa dose should be reduced by 25% when the Hb level approaches 12 g/dL or increases >1 g/dL in 2 weeks. The darbepoetin alfa dose should be reduced by 40% when the Hb level exceeds 11 g/dLor rises >1 g/dL in 2 weeks. Doses of ESAs should be withheld when the Hb level exceeds12 g/dL.5-7,

 Two randomized controlled trials comparing ESA use in cancer patients with anemia dueto chemotherapy were inconclusive with respect to superiority of one agent over another.

	In recent clinical studies, the use of ESAs has been associated with an increased risk of serious cardiovascular events, thromboembolic events, tumor progression, and death.4These risks were associated with a rapid rise in Hb (>1 g/dL over 2 weeks) and maintenance of higher Hb levels. Disease-related concerns associated with ESAs for cancer patients and chronic renal failure patients have led the FDA to mandate a black box warning on ESA product labeling. It is advised to individualize dosing in patients with renal failure so the Hb level is achieved and maintained within target range. Higher Hb levels were associated with increased risk of death and serious cardiovascular events.5-7 These data are further supported by recent findings in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), which linked a target Hb level of approximately 13g/dL in patients given darbepoetin alfa with an increased incidence of stroke.

The FDA has warned that ESA use in patients with breast, non—small-cell lung, head and neck, lymphoid, and cervical cancers can shorten overall survival and/or increase the risk of tumor progression. Additionally, ESAs are not indicated for cancer patients when the anticipated outcome is cure. Discontinuation of ESA therapy is recommended when chemotherapy is complete. In all patient populations, the appropriate use of ESAs is defined as Hb levels not surpassing the target range of 10 to 12g/dL and not exceeding an increase in Hb levels >1 g/dL per 2-week period during therapy.

	Since the arrival of the first ESA, the financial impact on institutions and payers has been significant. ESAs account for the single largest expenditure for Medicare ($1.8 billion).

 In 2007, the Centers for Medicare & Medicaid Services (CMS) issued a statement regarding reimbursement, which closely followed the black box warning from the FDA, suggesting that reimbursement is becoming more closely tied to drug safety. CMS further issued changes to the Medicare claims-processing policy for ESAs administered to patients receiving dialysis, capping the maximum cumulative dose per billing cycle at 400,000 units for epoetin alfa and 1200 mcg for darbepoetin alfa. Furthermore, as of January 2008, CMS requires a 50% dose reduction in patients whose Hb level persists at >13 g/dLfor 3 consecutive months.16While CMS stops short of denying claims in this circumstance, the claim will be paid at a reduced rate. In addition, Medicare will only reimburse costs for ESAs in chronic kidney disease and cancer-induced anemia when ESAs are initiated at an Hb level of >10 g/dL. Implementation of bundled payments by Medicare promotes an additional incentive to reduce the expense of these medications by removing financial incentives and encouraging providers to operate in a more cost-conscious manner.

Much of the literature to date has focused on claims data and cost-minimization strategies with few studies examining cost-effective utilization. Studies have been criticized for using average wholesale price or wholesale acquisition cost to conduct the cost comparisons, which tends to favor epoetin alfa over darbepoetin alfa. Manufacturer rebates and discount programs have led to poor price transparency in the US market, making it difficult for direct comparisons of these 2 products. Some studies in Canada and Europe suggest that using either of these agents may be cost-effective, but this has not been demonstrated in the United States.

 In addition, most studies fail to account for baseline Hb levels, which can bias the results.18 In a few randomized trials and observational studies that controlled for cost, the advantage typically favored epoetin alfa.

	The setting in which a patient receives ESA therapy can play an important role in determining the choice of agent. When choosing between agents, both the direct and indirect acquisition costs should be weighed along with clinical efficacy and reimbursement. According to marketing information from the manufacturer, darbepoetin alfa offers the advantage of extended interval dosing relative to epoetin alfa. Evidence, however, suggests that extended interval dosing with epoetin alfa can be successful in some patients. Research has also shown that patients receiving epoetin alfa achieved goal more rapidly than patients administered darbepoetin alfa, with lower overall indirect costs despite more frequent administration. These results, however, may not translate for all patient populations or disease states associated with the use of ESAs.

	In the inpatient setting, a strategy of cost minimization should be used when diagnosis-related groups are used for reimbursement. With the flexible dosing schedule of epoetin alfa, patients could be treated in a cost-effective manner by using divided dosing via a hospital-approved protocol. This has the potential to reduce the number of units that are administered in the inpatient setting, thus minimizing cost. Establishing patient-specific doses is another methodology that can reduce waste and should be a standard, as it is consistent with the Joint Commission Medication Management Standards as well as cost-effective. The 340b program can also be used to maximize savings to an organization that qualifies as a disproportionate share under the Medicare Cost Report. Financial savings from this program could drive the use of one agent versus another in the outpatient setting, especially if the patient is seen in a health system clinic. Because the subcutaneous route of administration requires approximately 30% of the intravenous dose to maintain comparable Hb levels, the route of administration should also be further examined.

	After more than 20 years in the market, a review of literature shows a rapidly changing landscape with ESAs, with the need for additional research being the most repetitive theme. It is no wonder that ESAs continue to be a high-profile topic given the evolving information and complex array of factors that play a role in the cost-effective use of these molecules. Key factors that will influence stakeholders include patients’ quality of life, efficacy, safety, cost of ESAs, and outcomes. Certainly, when ESAs first appeared on the market, they were hailed as wonder drugs due to their ability to reduce the number of blood transfusions, while benefiting patients by reducing fatigue. While these agents are effective in raising Hb levels, recent studies have raised concerns that ESAs may increase the risk of complications such as thromboembolic events, stroke, and lead to rapid tumor progression in some types of cancer. Entry of “biosimilar” agents into the market will likely further complicate and compound these issues, but may lead to price reductions due to competition. As healthcare reform takes shape in the United States, cost-effective medication management will continue to be an integral part of a cost-avoidance strategy. The large expenditure of healthcare dollars on ESAs will likely continue to receive scrutiny, especially in the presence of an ever-increasing diabetic population and the aging baby boom generation that will see an increased prevalence of cancer.

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Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that stimulate erythropoiesis through direct or indirect action on the erythropoietin receptor producing an increase

Michael Marlon Mohundro, PharmD

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