Clinical and Economic Considerations for the Use of Erythropoiesis-Stimulating Agents

Michael Marlon Mohundro, PharmD; and Ann McMahon Wicker, PharmD, BCPS
Published: Friday, Mar 04, 2011
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.1,2The first recombinant human erythropoietin was introduced in the United States in 1989.3,4Currently, 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.2,4

COMPARISON OF ESAs

ESAs were a biotechnology medical innovation, initially marketed for the treatment of anemia in end-stage renal disease.2 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.5-7 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 Founda­tion’s Kidney Disease Out­come 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 Out­comes in Renal Insufficiency (CHOIR) study, revealed findings that led to changes for target Hb levels with ESA therapy.3,9,10In 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.1,3

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.1,5-7 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.3 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 Table.

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 thromboem­bolic 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.11


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