Erythropoiesis-Stimulating Agents - OpenPayer

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Erythropoiesis-Stimulating Agents - OpenPayer

Coverage Summary

This UnitedHealthcare medical necessity policy addresses coverage criteria for erythropoiesis-stimulating agents (ESAs) including Aranesp, Epogen, Procrit, Retacrit, and Mircera/CERA for multiple indications: anemia due to cancer chemotherapy, myelodysplastic syndromes (MDS), myelofibrosis (myeloproliferative neoplasms), zidovudine-related anemia in HIV-infected patients, hepatitis C therapy–related anemia, and perioperative use to reduce allogeneic transfusions. The policy is effective April 1, 2025 (Policy IEXD0028.08) and is Part 1 of 2.

Status note: mixed coverage stance (some indications proven/medically necessary when criteria are met; other uses are unproven or not medically necessary).

Medical-Necessity Criteria (by indication)

Anemia Due to Cancer Chemotherapy - Aranesp, Epogen, Procrit, Retacrit

Proven and medically necessary when ALL of the following are met (initial therapy):

Initial therapy

Hematocrit threshold: Hematocrit less than or equal to 30% at initiation of therapy<= 30%
Exclude other causes: Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency) and there is documentation of normal iron stores
Clinical contexts
- Patient has moderate to severe CKD
- Undergoing palliative treatment
- Receiving myelosuppressive chemotherapy not given with curative intent (i.e., adjuvant therapy or definitive therapy)
- ALL of the following
  - Receiving myelosuppressive chemotherapy with curative intent
  - Patient is refusing blood transfusion(s)

Anemia Associated with Myelodysplastic Syndromes (MDS) - Aranesp, Epogen, Procrit, Retacrit

Proven and medically necessary when ALL of the following are met (initial therapy):

Initial therapy

EPO level: Serum erythropoietin level less than or equal to 500 mUnits/mL<= 500 mUnits/mL
Hematocrit threshold: Hematocrit is less than or equal to 30% at the initiation of therapy<= 30%
Exclude other causes: Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency)

Anemia Associated with Myeloproliferative Neoplasms - Myelofibrosis

Proven and medically necessary when ALL of the following are met (initial therapy):

Initial therapy

EPO level: Serum erythropoietin level less than or equal to 500 mUnits/mL<= 500 mUnits/mL
Hematocrit threshold: Hematocrit is less than or equal to 30% at the initiation of therapy<= 30%
Exclude other causes: Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency)

Anemia Associated with Zidovudine Treatment in HIV-Infected Patients - Epogen, Procrit, Retacrit

Proven and medically necessary when ALL of the following are met (initial therapy):

Initial therapy

Zidovudine dose: Patient is receiving zidovudine administered at less than or equal to 4200 mg/week<= 4200 mg/week
EPO level: Endogenous serum erythropoietin level less than or equal to 500 mUnits/mL<= 500 mUnits/mL
Hematocrit threshold: Hematocrit is less than 30% at initiation of therapy< 30%

Anemia Associated with Hepatitis C with Ribavirin and Interferon Therapy - Epogen, Procrit, Retacrit

Proven and medically necessary when ALL of the following are met (initial therapy):

Initial therapy

Ribavirin/interferon: Patient is receiving ribavirin and interferon therapy
Hematocrit threshold: Hematocrit is less than or equal to 30% at initiation of therapy<= 30%
Exclude other causes: Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency)

Administration, Dosing, Monitoring & Hyporesponsiveness

ESA Hyporesponsiveness (Initial and Acquired)

Classification and dose escalation limits for hyporesponsive patients

Initial hyporesponsiveness: Classify as initial ESA hyporesponsiveness if no increase in Hb from baseline after first month of ESA on appropriate weight-based dosing.No Hb increase after 1 month

Not Graded

Initial hyporesponsiveness dose limit: In initial hyporesponsiveness, avoid repeated escalations beyond double the initial weight-based dose.Do not escalate beyond 2x initial dose

Suggestion (2D)

Provider Actions & Prior Authorization

Prior Authorization

Authorization durations and reauthorization limits

Initial authorizations are generally limited to no more than 12 months for most indications; perioperative (preoperative) authorizations are limited to no more than 3 months. Reauthorizations (continuation) are limited to no more than 12 months when continuation criteria are met.

Cancer chemotherapy (initial): up to 12 months; reauthorization up to 12 months (Hct ≤ 30% at initiation; continuation Hct ≤ 30%).
MDS (initial): up to 12 months; reauthorization up to 12 months (EPO ≤ 500 mUnits/mL; initiation Hct ≤ 30%; continuation Hct ≤ 36%).
Myelofibrosis (initial): up to 12 months; reauthorization up to 12 months (EPO ≤ 500 mUnits/mL; initiation Hct ≤ 30%; continuation Hct ≤ 36%).
Zidovudine-related anemia (initial): up to 12 months; reauthorization up to 12 months (zidovudine ≤ 4200 mg/week; EPO ≤ 500 mUnits/mL; initiation Hct < 30%; continuation Hct ≤ 36%).
HCV-related anemia (initial): up to 12 months; reauthorization up to 12 months (initiation Hct ≤ 30%; continuation Hct ≤ 36%).
Perioperative/preoperative use: authorization up to 3 months (perioperative Hct > 30% and ≤ 39%; elective noncardiac/nonvascular surgery; expected ≥2 units blood needed).

Coding & Claim Requirements

Clinical/billing requirementmixed

Claim form 1500 / 837P

ESA claims submitted on a 1500 form and/or 837P electronic claim form require the Hct level be submitted with the claim; Hct should be from within 30 days of the injection

No procedure/drug codes in this partmixed

No codes listed

Billing Rule

Claim-specific billing rule: Hct must be submitted on 1500/837P within 30 days of injection

For billing, include the hematocrit value on the 1500 form or 837P electronic claim; the Hct must be from within 30 days of the injection. Failure to submit the Hct may result in denial or non-processing of the claim (see denial risk guidance on missing Hct).

Submit Hct on the 1500/837P claim from within 30 days of the injection to meet claim processing requirements.
Cross-reference denial risk: missing Hct on the claim can lead to denial (see 'Claim submission missing Hct').

Background & Evidence Summary

Background: The policy outlines medical necessity criteria for multiple ESAs (Aranesp, Epogen, Procrit, Retacrit, Mircera/CERA) across oncology (cancer chemotherapy–related anemia), myelodysplastic syndromes (MDS), myelofibrosis, zidovudine-related anemia in HIV, hepatitis C therapy–related anemia, and perioperative use. It references systematic reviews and randomized trials showing that ESAs reduce red blood cell transfusion requirements (e.g., Cochrane and AHRQ reviews) but are associated with increased thromboembolic events and signals for increased mortality in some oncology analyses; CKD trial data (TREAT) showed reduced transfusions and modest fatigue benefit but increased risk of stroke. The policy also documents perioperative and surgical trial evidence supporting reduced transfusion needs in certain elective surgery contexts, and it lists several unproven or not medically necessary uses.

Label	Key finding
Cochrane review (oncology)	ESAs reduced red blood cell transfusions (RR 0.65) but were associated with increased mortality (HR 1.17) and increased thromboembolic events (RR 1.52).
TREAT (CKD)	Darbepoetin alfa reduced transfusions and produced a modest improvement in FACT-Fatigue but increased risk of stroke (5.0% vs 2.6%).
Guideline strength examples	Work Group recommendations and suggestions vary in strength (examples range from 1A to 2D and Not Graded) for initiation, maintenance, dosing, monitoring, and hyporesponsiveness.

Revision History

2025-04-01revisedLatest

Supporting information/reference updates; archived prior version IEXD0028.07.