• ASH-ASCO Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin Now Available
• Ask the Hematologist and the Consult-a-Colleague Program

ASH-ASCO Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin Now Available

J. Douglas Rizzo, MD, MS

Dr. Rizzo is Associate Professor of Medicine at the Medical College of Wisconsin.

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.

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Ask the Hematologist and the Consult-a-Colleague Program

Kenneth A. Bauer, MD

Dr. Bauer is Professor of Medicine at Harvard Medical School, Director, Thrombosis Clinical Research, Beth Israel Deaconess Medical Center, and Chief, Hematology Section, VA Boston Healthcare System.

I recently received the following question from an ASH member through the Society’s new Consult-a-Colleague program. He asked:

How would you counsel a patient who is an asymptomatic heterozygote with the Factor V Leiden mutation who is planning her first pregnancy and wants to take enoxaparin thromboprohylaxis? No other thrombophilic factor is identified, but her mother, who is also heterozygous for Factor V Leiden, had her first deep venous thrombosis (DVT) with her first pregnancy and has suffered from recurrent venous thrombosis ever since. The patient is adamant on taking the medication.

The Response

I agreed with his assessment that the absolute risk of such a patient developing a first DVT during an uncomplicated pregnancy is sufficiently low (<1 percent) to forego the need for ante-partum and even postpartum thromboprophylaxis. The thromboembolic event in her mother along with the severe sequelae, however, can drive patients to do all that is possible to minimize the risk of thrombosis. Thus, it is not unreasonable to defer to patient preference after thoroughly counseling her of the potential risks (e.g., bleeding, low risk of heparin-induced thrombocytopenia) and discomfort of low-molecular-weight heparin injections (as well as the cost of the medication) for many months along with the benefit (albeit small).

In working through the issues with the patient, it could be useful to try to get as much information as possible regarding the occurrence of the first episode of DVT in the mother—were there other risk factors that she had that are not present in the daughter? These might include older age at the time of the first pregnancy, obesity, or prolonged immobilization due to preeclampsia, or if the thrombotic event occurred in the post-partum state or following a C-section. If the doctor was able to identify such a risk factor, he might use this in bolstering the case that other risk factors contributed to the thrombotic complication in addition to Factor V Leiden. If he was able to ascertain such information, it might strengthen the argument that she is at substantially lower thrombotic risk than was her mother at the time of her first pregnancy. Finally, by counseling the patient regarding symptoms of venous thromboembolism requiring prompt medical evaluation, she would hopefully be promptly diagnosed if she developed venous thromboembolism and managed appropriately, lessening the possibility of long-term complications. It is also important that the patient’s obstetrician and hematologist are in agreement with respect to this issue so that clear and coherent information is communicated to the patient.

About the Consult-a-Colleague Program

The Consult-a-Colleague program was launched in June of this year to facilitate the exchange of clinically focused information with ASH colleagues. The program is being piloted in the areas of hemostasis/thrombosis and lymphoproliferative disorders. ASH members submit their questions through the ASH Web site. The questions are routed to one of seven consultants who are expected to respond directly to the submitter within one to two business days. I have received seven requests to date. The types of questions are similar to those posed to presenters at ASH Educational and Meet-the-Expert Sessions in hemostasis and thrombosis. The questions are practical and have all been directly related to the diagnosis and management of individual patients. A common theme has been the benefits and risks of anticoagulation in high-risk patients.

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