The "ASH-ASCO 2007 Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin" has recently been completed. In addition to updating recommendations made in 2002, new recommendations address the use of darbepoetin, thromboembolic risks of erythropoiesis-stimulating agents (ESAs), and comment on the risks of disease progression and survival.
Comprehensive systematic reviews support the equivalence of darbepoetin and epoetin with respect to safety and effectiveness. For patients with chemotherapy-associated anemia, the guideline recommends use of an ESA as a treatment option as hemoglobin approaches or falls below 10 g/dL to increase hemoglobin or decrease transfusions. ESAs continue to be recommended for patients with low-risk myelodysplasia. Conclusive evidence is lacking that, absent clinical circumstances necessitating earlier treatment, initiating ESA treatment at hemoglobin levels greater than 10 g/dL spares more patients from transfusion or substantially improves their quality of life. ESA therapy is associated with a statistically significant relative risk of thromboembolism that is 1.67 times that of patients not receiving an ESA. This finding suggests that clinicians should carefully weigh the risks of thromboembolism when prescribing an ESA in patients with anemia. The guideline panel recommends that clinicians follow recommendations in the U.S. Food and Drug Administration (FDA) package insert for starting dose and dose modification of ESAs. Alternative dose initiation or escalation schedules are not adequately supported by evidence. Assuming an appropriate dose increase has been attempted in non-responders, continuing ESAs beyond six to eight weeks in the absence of response does not appear to be beneficial. The guideline recommends monitoring iron stores and supplementing iron intake, though it also acknowledges that this remains an area where further clinical investigation is needed to guide recommendations for iron formulation and dosing. ESAs should not be used in patients with cancer who are not receiving chemotherapy, since recent trials report increased thromboembolism and decreased survival in these patients.
The guidelines are based on evidence derived mainly from systematic reviews and meta-analysis of published clinical trials. Systematic reviews and evidence-based guidelines also provide valuable insight into important deficiencies in current knowledge that may affect practice. ESAs are no exception. Future research should include better assessment and reporting of adverse events graded by severity, such as thromboembolism, progression, and survival; better efforts to understand the impact of ESAs on tumor progression; more studies to understand appropriate dosing and formulation of iron supplementation; more trials to characterize benefits and harms in patients with MDS; additional evidence regarding quality of life; and studies comparing economic outcomes between alternative strategies to raise hemoglobin.
While it is anticipated that the 2007 guideline will provide important guidance to clinicians and inform regulatory agencies and payors, it should be acknowledged that closing the evidence gap described above is essential to establishing appropriate use of ESAs to maximize the benefits of therapy while reducing potential harm to patients.
