Is it safe to combine desidustat with erythropoietin (EPO) injections in a patient with anemia, possibly due to chronic kidney disease (CKD)?

Combining Desidustat with Erythropoietin: Not Recommended

Desidustat should not be combined with erythropoietin (EPO) injections, as both agents stimulate erythropoiesis through different mechanisms and combining them creates unnecessary risk of excessive hemoglobin elevation, which increases cardiovascular events, stroke, and mortality. 1, 2, 3

Mechanistic Rationale Against Combination

• Desidustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that increases endogenous EPO production, making exogenous EPO administration redundant and potentially dangerous 4, 5

• HIF-PHIs like desidustat already stimulate the patient's own EPO production while simultaneously improving iron utilization and availability to erythroid cells, eliminating the need for injectable EPO 5, 6

• Combining two erythropoietic agents would create additive stimulation of red blood cell production, substantially increasing the risk of exceeding safe hemoglobin targets 1, 2

Critical Safety Concerns with Excessive Hemoglobin

• Target hemoglobin levels must remain between 10-12 g/dL for all anemia treatments in CKD, as multiple large trials demonstrate increased cardiovascular events, stroke, and mortality when hemoglobin exceeds 12 g/dL 1, 2, 3, 7

• Desidustat treatment should be temporarily discontinued if hemoglobin exceeds 12 or 13 g/dL, following protocols similar to other HIF-PHIs to prevent hyperviscosity and thrombotic complications 1

• ESAs (including EPO) are associated with increased risk for thromboembolic events, short-term mortality, and decreased overall survival across different patient groups, making combination therapy with another erythropoietic agent particularly hazardous 8

Clinical Context: When Each Agent Should Be Used

Desidustat Monotherapy

• Desidustat is indicated as monotherapy for anemia in CKD patients (both dialysis-dependent and non-dialysis-dependent) who have failed iron repletion and require erythropoietic stimulation 4, 1

• Desidustat demonstrated non-inferiority to darbepoetin alfa in achieving hemoglobin targets (1.95 g/dL vs 1.83 g/dL increase from baseline), with 77.78% responders versus 68.48% with darbepoetin 4

• Desidustat offers advantages over injectable ESAs including oral administration convenience, improved iron utilization (decreased hepcidin and increased ferroportin), and avoidance of high peak serum EPO concentrations 1, 4, 6

EPO Monotherapy

• EPO injections should be initiated only after iron stores have been corrected (TSAT ≤30%, ferritin ≤500 ng/mL addressed), other reversible causes treated, and hemoglobin remains below 10 g/dL 2, 3

• EPO is contraindicated in patients with active malignancy, history of stroke, and uncontrolled hypertension 2, 3

Switching Between Agents (Not Combining)

• If a patient is already on EPO and requires transition to desidustat, EPO should be discontinued before initiating desidustat, not continued concurrently 1

• Lower starting doses of desidustat should be considered for ESA-naïve patients compared to those transitioning from other ESAs, but this refers to sequential therapy, not combination 1

• Desidustat can overcome EPO hyporesponsiveness by improving iron utilization and decreasing inflammation, making it a potential alternative when EPO fails, not an addition to EPO 6

Special Consideration: Sickle Cell Disease Exception

• The only clinical context where combining an erythropoietic agent with another medication is conditionally recommended involves hydroxyurea (not desidustat) with EPO in sickle cell disease patients with CKD, and this is based on very low certainty evidence with specific hemoglobin thresholds not exceeding 10 g/dL 8

• This sickle cell disease recommendation does not apply to desidustat, as desidustat was not studied in this population and the rationale involves allowing higher hydroxyurea dosing, not combining two erythropoietic agents 8

Monitoring Requirements If Desidustat Is Used (Alone)

• Regular monitoring of hemoglobin levels is necessary to maintain target range of 10-12 g/dL 1

• Iron status (TSAT and ferritin) should be monitored at least every 3 months during treatment 2

• Consider discontinuation of desidustat if hemoglobin targets are not achieved despite dose escalation, at which point alternative strategies (not combination with EPO) should be pursued 1