Erythropoiesis Stimulating Agents

Erythropoiesis stimulating agents (ESAs) are recombinant forms of erythropoietin that increase red cell production. They treat anaemia of chronic kidney disease and, selectively, chemotherapy-induced anaemia, and they reduce transfusion needs. Used to reach a normal haemoglobin they increase thrombosis, cardiovascular events and mortality, so treatment targets the lowest haemoglobin that avoids transfusion.

Mechanism. ESAs bind the erythropoietin receptor on erythroid progenitors, prevent apoptosis and drive proliferation and maturation. Response needs iron, folate, B12 and low inflammation.

Members.

• Epoetin alfa, beta and biosimilars (half-life 4 to 13 hours).
• Darbepoetin alfa (hyperglycosylated; half-life about 25 hours).
• Methoxy polyethylene glycol-epoetin beta (half-life about 130 hours).
• Oral hypoxia-inducible factor prolyl hydroxylase inhibitors (such as roxadustat) are licensed in some regions for kidney anaemia.

Titration.

• Aim to increase haemoglobin by 10 to 20 g/L each month. If the rise is more than 10 g/L in any 2 weeks, reduce the dose by 25%; if the rise is under 10 g/L after 4 weeks, increase by 25%.
• Hold or reduce the dose when haemoglobin nears 120 g/L (kidney disease) or exceeds the level needed to avoid transfusion.
• Ensure ferritin over 100 micrograms/L and transferrin saturation over 20% before and during therapy; give iron if either is lower.

• First-line. Symptomatic anaemia of chronic kidney disease (haemoglobin under 100 g/L), after iron repletion; target 100 to 120 g/L.
• Alternative. Chemotherapy-induced anaemia when treatment is palliative, haemoglobin is under 100 g/L and transfusion is otherwise needed; myelodysplastic syndrome with low-risk features and low erythropoietin level.
• Specialist. Perioperative use in patients who refuse transfusion; preterm infants (specialist); anaemia of zidovudine therapy.
• Emergency. None; transfusion for urgent need.

Selection. Choose long-acting agents for less frequent dosing in outpatients; use subcutaneous route in non-dialysis patients; do not start ESAs if iron deficiency, bleeding, haemolysis, infection or inflammation is untreated.

Causes of hyporesponse. Iron deficiency, infection or inflammation, hyperparathyroidism, aluminium, B12 or folate deficiency, haemolysis, bleeding, malignancy, pure red cell aplasia (rare, from anti-erythropoietin antibodies), ACE inhibitors and inadequate dialysis.

Contraindications. Uncontrolled hypertension; hypersensitivity; pure red cell aplasia after a previous ESA; ESAs in cancer treated with curative intent (avoid); active thromboembolic disease (relative).

Serious adverse effects. Hypertension, thrombosis (stroke, myocardial infarction, venous thromboembolism, vascular access thrombosis); increased mortality and tumour progression in cancer (boxed-warning-level risk); seizures with rapid haemoglobin rise; pure red cell aplasia; injection-site pain; flu-like symptoms.

Major interactions. ACE inhibitors and ARBs reduce response; androgens increase; immunosuppressants and myelosuppressive drugs reduce; iron deficiency and inflammation blunt response.

Common prescribing errors.

• Treating a normal or nearly normal haemoglobin.
• Starting without iron assessment.
• Increasing doses without reviewing the cause of hyporesponse.
• Targeting haemoglobin over 130 g/L.
• Giving ESAs to patients with cancer in curative treatment.

Special groups.

• Pregnancy: used when necessary in kidney disease; avoid initiating without indication.
• Breastfeeding: unlikely to pass in significant amounts.
• Children: used in kidney disease; specialist dosing with iron.
• Older adults: avoid high targets.
• Kidney: the main indication.
• Liver: no adjustment.
• East Africa: cost and cold-chain storage limit use; check blood pressure and treat iron deficiency and infection (malaria, HIV, tuberculosis) before starting; transfusion safety is a competing consideration.

Monitoring. Haemoglobin every 2 to 4 weeks when titrating, then monthly; blood pressure; ferritin and transferrin saturation every 3 months; reticulocyte haemoglobin when available.

Referral and escalation. No response to adequate dose with replete iron (look for bleeding, inflammation, marrow disease); sudden fall in haemoglobin with low reticulocytes (pure red cell aplasia); thrombosis; severe hypertension.

Comparison with alternative classes. ESAs reduce transfusions in kidney anaemia and avoid iron-related adverse effects, but carry cardiovascular and cancer risk and cost more than iron or transfusion. Hypoxia-inducible factor inhibitors are oral alternatives with different risk profiles.