Erythropoiesis stimulating agents

Indicated when hemoglobin levels followed below 10-11 g/dL in patients receiving palliative cancer chemotherapy.

The lowest ESA dose that avoids or minimizes transfusion risk is recommended.

Response to therapy ranges from 50-70% of patients and requires 4-6 weeks of therapy.

In chronic kidney disease ESAs may increase hemoglobin levels and induce functional iron deficiency.

Partial correction of anemia with ESA’s is the cornerstone of management for patients undergoing dialysis, as these agents increase hemoglobin levels, and reduce blood transfusion rates.

Partial correction of anemia in patients undergoing dialysis enhances the quality of life.

Intensive treatment with ESA’s in dialysis patient, targeting near-normal hemoglobin levels in the Normal Hematocrit Study (NHS), and in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study, and the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) further reduced the need for blood transfusions but with increased composite of death and nonfatal myocardial infarctions, stroke and cardiovascular events.

When intravenous iron is administered in combination with erythropoiesis stimulating agents in patients with end-stage kidney disease, their hemoglobin levels are increased compared to those patients who receive erythropoiesis stimulating agents alone, and required erythropoiesis stimulating agents dose to maintain hemoglobin levels is decreased.

Increasing response to treatment may be achieved by dose titration or iron supplemention.

Use associated with a higher mortality rate and increased rate of tumor growth in advanced head and neck cancer treated with radiotherapy, an in patients with metastastic breast cancer receiving chemotherapy when such agents were given to maintain hemoglobin levels of more than 12 g/dL.

Analysis of 53 randomized trials with 13,933 enrolled patients found that ESAs was associated with greater mortality during the active study and shorter overall survival (Bohlius).

Use associated with higher chance of death in cancer patients not receiving chemotherapy.

Studies suggest the use of ESAs associated with increased mortality, venous thromboembolism, tumor progression, and stroke.

Not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

When used with small cell lung cancer, no greater mortality or tumor progression was noted (Pirker).

Overall evaluation in chemotherapy studies does not reveal greater tumor progression.

Meta-analyses assessing the overall survival of patients receiving ESA’s and chemotherapy have it estimated hazard ratio of around 1.02 or 1.03.

Use in cancer patients not receiving chemotherapy did not result in lowered use of transfusions.

These agents reduced need for red cell transfusion and improve quality of life for patients with end-stage renal disease that have severe anemia.

In patients with chronic kidney disease, but do not require dialysis and had moderate anemia the use of these agents as demonstrated little evidence of benefit and possible harm.

In chronic kidney disease patients with moderate anemia and not on dialysis, lowered hemoglobin targets with the use of ESAs is recommended.

Anemia is associated with increased rates of death and complications with chronic kidney disease in patients undergoing dialysis.

In patients undergoing dialysis the risk of death is inversely associated with good hematopoietic response to ESAs (Bradbury BD et al).

In a randomized double-blind trial assigning 2270 patients with systolic heart failure and mild to moderate anemia with hemoglobin levels 9-12 g/dL to receive either darbepoetin alfa or placebo: clinical outcomes were not improved (Swedberg K et al).

In the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) there was no reduction in the risk of cardiovascular or renal events are that in patients receiving darbepoetin alfa, as compared to those receiving placebo, but the risk of stroke was doubled (Pfeffer MA).

ESA accelerated erythropoiesis leads to iron-restricted erythrpoiesis despite initial adequate iron stores.

IV iron use with ESAs results in superior hemoglobin levels.

Most studies indicate intravenous iron replacement in cancer and/or chemotherapy-induced anemia are positive.

Use in patients with chronic renal failure associated with higher chance of thromboembolism, strokes, congestive heart failure, myocardial infarctions, when hemoglobin levels wee maintained at more than 12 g/dL.

In the Reduction of Events by Darbpoeitin Alfa in Heart Failure (RED-HF) trial: Treatment did not improve clinical outcomes in patients with systolic heart failure and mild to moderate anemia.

Utilization associated with higher rate of thromboembolism for those scheduled for major surgery.

2010 ASCO/ASH guidelines for use of ESAs: requires appropriate history, physical examination, and diagnostic tests to identify alternative causes of anemia aside from chemotherapy or an underlying hematopoetic malignancy and include a thorough drug history, review of the peripheral blood smear, serum iron, folate, vitamin B12 levels where indicated, particular site count, occult blood loss evaluation, and renal function studies, Coombs tests in patients with CLL, non-Hodgkin’s lymphoma, or history of autoimmune disease, EPO level analysis in patients with myelodysplastic syndrome, and consideration of the risks of thromboembolism.

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