The ESAs epoetin and darbepoetin were approved for treatment of chemotherapy-associated anemia in 1993 and 2002 and CKD-associated anemia in 1989 and 2001, respectively. In 2006, ESAs were the largest single pharmaceutical expenditure by the Center for Medicare and Medicaid Studies (CMS). Recently, a series of preclinical experiments, clinical trials, and meta-analyses of ESAs have been reported. The Food and Drug Administration (FDA), National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO), and Kidney Disease Outcomes Quality Improvement (KDOQI) have issued guideline statements for ESAs, and CMS has implemented an ESA Monitoring Policy (EMP) to help ensure appropriate ESA claims. Herein, we analyze these actions and usage trends of ESAs for anemic cancer and CKD patients. Data sources included basic science studies, clinical trials, meta-analyses, notifications from CMS, ESA manufacturers, and the FDA, guidelines from the NCCN, ASH/ASCO, and KDOQI, and published reports regarding ESA usage reported between 2006 and 2008. Search terms included erythropoietin, darbepoetin, anemia, neoplasm, and CKD. Results from eight recent clinical trials and one 2008 meta-analysis for anemic cancer patients identified tumor progression and mortality risks with ESA versus placebo/control use. Analyses from one clinical trial and one 2008 meta-analysis for CKD patients identified mortality and cardiovascular risks when high hemoglobin levels were targeted. Guidelines, manufacturer notifications, and reimbursement policies have become increasingly conservative. ESA administration to anemic cancer and CKD patients has decreased. Among anemic cancer patients, red blood cell transfusions are increasing and ESA use is decreasing. Among anemic CKD patients, target and achieved hemoglobin levels and ESA doses have decreased. Regulatory, clinical and professional communities now advocate for conservative use of ESAs for anemic patients with cancer or CKD.

Chemotherapy-associated anemiaCKD-associated anemia
Basic Science ESAs may be harmful: Erythropoietin receptors have been identified in tumor cells and have demonstrated downstream cellular effects including proliferation, anti-apoptosis, invasion, and chemotherapy resistance. ESAs may be beneficial: Studies have identified neurotrophic and neuroprotective effects of erythropoietin. Also, erythropoietin protects against hypoxia-induced apoptosis, ischemia-reperfusion injury, and promotes ventricular modeling. 
Clinical Trials and Meta-analyses Eight clinical trials and one meta-analysis have identified increased risk of mortality and/or tumor progression associated with ESA use. Two meta-analyses have identified significantly increased risk of VTE and seven trials reported four-fold or greater increased risk of VTE. One trial and one meta-analysis have identified mortality and cardiovascular risks when ESAs were targeted to higher versus lower hemoglobin levels. A second trial did not identify clinical benefits with ESA administration targeted to normal versus lower hemoglobin levels. 
Guidelines NCCN and ASH/ASCO guidelines support ESA administration targeted to between 10 and 12 g/dl and a trigger hemoglobin level to initiate ESA use at 10 g/dl. KDOQI supports hemoglobin levels targeted to between 11 and 12 g/dl and avoiding levels > 13 g/dl. 
Recent Manufacturer Notifications The FDA mandated that product labels state that ESAs are not indicated for patients receiving myelosuppressive therapy with curative intent, the trigger hemoglobin should be <10 g/dl, and ESAs should be withheld if the hemoglobin exceeds a level necessary to avoid transfusion. Revised labels indicated hemoglobin levels should be targeted to between 10 and 12 g/dl and that high ESA doses should be avoided. 
Reimbursement Policies Target and trigger hemoglobin levels of < 10 g/dl and a maximum duration of 8 weeks of treatment are supported by CMS. Target hemoglobin levels < 13 g/dl are supported by CMS. Reimbursement is reduced when hemoglobin levels > 13 g/dl are recorded for 3 or more consecutive billing cycles. 
Usage Trend Between November 2006 and October 2007, usage of ESAs declined from 42% to 15% per patient at risk while transfusions increased from 24% to 28% per patient at risk. ESA use among CKD patients not on hemodialysis decreased from 54% to 42% from 2007 to 2008. 
Chemotherapy-associated anemiaCKD-associated anemia
Basic Science ESAs may be harmful: Erythropoietin receptors have been identified in tumor cells and have demonstrated downstream cellular effects including proliferation, anti-apoptosis, invasion, and chemotherapy resistance. ESAs may be beneficial: Studies have identified neurotrophic and neuroprotective effects of erythropoietin. Also, erythropoietin protects against hypoxia-induced apoptosis, ischemia-reperfusion injury, and promotes ventricular modeling. 
Clinical Trials and Meta-analyses Eight clinical trials and one meta-analysis have identified increased risk of mortality and/or tumor progression associated with ESA use. Two meta-analyses have identified significantly increased risk of VTE and seven trials reported four-fold or greater increased risk of VTE. One trial and one meta-analysis have identified mortality and cardiovascular risks when ESAs were targeted to higher versus lower hemoglobin levels. A second trial did not identify clinical benefits with ESA administration targeted to normal versus lower hemoglobin levels. 
Guidelines NCCN and ASH/ASCO guidelines support ESA administration targeted to between 10 and 12 g/dl and a trigger hemoglobin level to initiate ESA use at 10 g/dl. KDOQI supports hemoglobin levels targeted to between 11 and 12 g/dl and avoiding levels > 13 g/dl. 
Recent Manufacturer Notifications The FDA mandated that product labels state that ESAs are not indicated for patients receiving myelosuppressive therapy with curative intent, the trigger hemoglobin should be <10 g/dl, and ESAs should be withheld if the hemoglobin exceeds a level necessary to avoid transfusion. Revised labels indicated hemoglobin levels should be targeted to between 10 and 12 g/dl and that high ESA doses should be avoided. 
Reimbursement Policies Target and trigger hemoglobin levels of < 10 g/dl and a maximum duration of 8 weeks of treatment are supported by CMS. Target hemoglobin levels < 13 g/dl are supported by CMS. Reimbursement is reduced when hemoglobin levels > 13 g/dl are recorded for 3 or more consecutive billing cycles. 
Usage Trend Between November 2006 and October 2007, usage of ESAs declined from 42% to 15% per patient at risk while transfusions increased from 24% to 28% per patient at risk. ESA use among CKD patients not on hemodialysis decreased from 54% to 42% from 2007 to 2008. 
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Topics:
anemia, cancer, erythropoiesis-stimulating agents, kidney failure, chronic, advocacy, edmonton symptom assessment scale, hemoglobin measurement, erythropoietin, chemotherapy regimen, hemoglobin

Disclosures: Spiegel:Amgen: Research Funding; Amgen: Serve on Amgen advisory board for non-anemia related drug.

Author notes

Corresponding author

2008, The American Society of Hematology
2008
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