UnitedHealthcare ESA Coverage Update & Prior Auth

Coverage Criteria for ESAs

Anemia Due to Chronic Kidney Disease - Patients Receiving Dialysis

ESAs are proven and medically necessary when ALL of the following are met

Initial therapy: Patient is on dialysis; Hematocrit is less than 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsHct <30%

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Continuation of therapy: Patient is on dialysis; Documentation of positive clinical response to ESA therapy; Hematocrit remains less than 33%; Reauthorization will be for no more than 12 monthsHct <33%

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Anemia Due to Chronic Kidney Disease - Patients Not Receiving Dialysis

ESAs are proven and medically necessary when ALL of the following are met

Initial therapy: Patient is not on dialysis; Hematocrit is less than 30% at initiation of therapy; Rate of hematocrit decline indicates likelihood of requiring RBC transfusion; Therapeutic goal is reducing risk of alloimmunization and/or other RBC transfusion-related risks; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsHct <30%

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Continuation of therapy: Patient is not on dialysis; Documentation of positive clinical response to ESA therapy; Therapeutic goal is reducing transfusion-related risks; Hematocrit remains less than 30% for continuation of therapy; Reauthorization will be for no more than 12 monthsHct <30%

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Anemia Due to Cancer Chemotherapy

Aranesp, Epogen, Procrit, and Retacrit are proven and medically necessary when ALL of the following are met

Initial therapy: Hematocrit less than or equal to 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency) with documentation of normal iron stores; One of: moderate to severe CKD OR undergoing palliative treatment OR receiving myelosuppressive chemotherapy not given with curative intent OR (receiving myelosuppressive chemotherapy with curative intent AND patient refuses blood transfusion(s)); Initial authorization will be for no more than 12 monthsHct ≤30%

Chunks 7-8

Continuation of therapy: Documentation of positive clinical response to ESA therapy; Hematocrit remains less than or equal to 30% for continuation of therapy; Reauthorization will be for no more than 12 monthsHct ≤30%

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Anemia Associated with Myelodysplastic Syndromes (MDS)

Aranesp, Epogen, Procrit, and Retacrit are proven and medically necessary when ALL of the following are met

Initial therapy: Serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit is less than or equal to 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Treatment of lower-risk (IPSS-R Very Low/Low/Intermediate) MDS with symptomatic anemia; AND one of: del(5q) chromosomal abnormality OR (no del(5q) AND ring sideroblasts <15% (or <5% with SF3B1 mutation)) OR (no del(5q) AND ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation) following no response to Reblozyl (luspatercept-aamt)); Initial authorization will be for no more than 12 monthsEPO ≤500 mU/mL; Hct ≤30%

Chunks 9-10

Continuation of therapy: Documentation of positive clinical response to ESA therapy; Serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit remains less than or equal to 36% for continuation of therapy; Reauthorization will be for no more than 12 monthsEPO ≤500 mU/mL; Hct ≤36%

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Anemia Associated with Myeloproliferative Neoplasms - Myelofibrosis

Aranesp, Epogen, Procrit, and Retacrit are proven and medically necessary when ALL of the following are met

Initial therapy: Serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit is less than or equal to 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsEPO ≤500 mU/mL; Hct ≤30%

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Anemia Associated With Zidovudine in HIV

Epogen, Procrit, and Retacrit are proven and medically necessary when ALL of the following are met

Initial therapy: Patient is receiving zidovudine administered at less than or equal to 4,200 mg/week; Endogenous serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit is less than 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsZidovudine ≤4,200 mg/week; EPO ≤500 mU/mL; Hct <30%

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Continuation of therapy: Documentation of positive clinical response to ESA therapy; Continued zidovudine administered at less than or equal to 4,200 mg/week; Endogenous serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit remains less than or equal to 36% for continuation of therapy; Reauthorization will be for no more than 12 monthsEPO ≤500 mU/mL; Hct ≤36%

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Anemia Associated With Hepatitis C on Ribavirin and Interferon

Epogen, Procrit, and Retacrit are proven and medically necessary when ALL of the following are met

Initial therapy: Patient is receiving ribavirin and interferon therapy; Hematocrit is less than or equal to 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsHct ≤30%

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Continuation of therapy: Documentation of positive clinical response to ESA therapy; Patient continues ribavirin and interferon therapy; Hematocrit remains less than or equal to 36% for continuation of therapy; Reauthorization will be for no more than 12 monthsHct ≤36%

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Preoperative Use to Reduce Allogeneic Transfusions

Epogen, Procrit, and Retacrit are proven and medically necessary perioperatively when ALL of the following are met

Perioperative use: Perioperative hematocrit is greater than 30% and less than or equal to 39%; Patient is expected to require at least 2 units of blood during the surgical procedure; Patient is at high risk for blood loss during surgery; Patient is unable or unwilling to donate autologous blood; Surgery is elective, noncardiac, and nonvascular; Authorization will be for no more than 3 monthsHct >30% and ≤39%

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General clinical criteria

Evidence-based considerations and coverage stance should balance transfusion-sparing benefits against increased risks observed in certain populations; covered when clinical criteria and risk assessment are documented

General coverage considerations: ESA therapy may be considered when anemia is documented and alternative measures are insufficient, AND provider documents individualized risk-benefit assessment considering increased mortality and thromboembolic risk observed in oncology trials and cardiovascular risks observed in some CKD trials; document prior therapies, transfusion risk, and monitoring plan.

Supported by meta-analyses and trials showing reduced transfusion needs but increased thromboembolic events and mortality signals in cancer and some CKD studies (chunks 19-22,24).

Oncology criteria / restrictions

Oncology-specific cautions

Contraindications / high-risk scenarios: Avoid ESA use in patients with non-myeloid malignancies not receiving chemotherapy or radiotherapy, or to target higher hemoglobin ranges (e.g., 12–14 g/dL) due to associations with decreased survival and increased thrombotic events; use only with strong justification and oncology specialist input when risks/benefits are documented.Hgb target ranges noted 12-14 g/dL

Randomized trials demonstrated worse survival and higher fatal thrombotic events with higher Hgb targets (chunk 21); meta-analyses show increased thromboembolism (chunks 19-20).

CKD criteria

CKD-related anemia evidence considerations

CKD therapy considerations: In CKD patients, ESA therapy reduces transfusion requirements but may increase stroke or other cardiovascular events (as in the TREAT trial); individual cardiovascular risk should be documented and lower hemoglobin targets considered per guideline recommendations.TREAT mean Hgb 12.5 g/dL vs 10.6 g/dL

TREAT found increased stroke with darbepoetin alfa and fewer transfusions (chunk 24); technology assessments show limited effects of CERA on patient-centered outcomes (chunk 37).

Neonatal criteria

Neonates / preterm infants

Neonatal ESA considerations: Early ESA administration in preterm or low birth weight infants reduces RBC transfusion use and some neonatal morbidities (IVH, PVL, NEC) though evidence on neurodevelopmental outcomes is mixed; use requires careful consideration and is not broadly recommended pending further data.Initiated before 8 days of age in studies

Cochrane reviews showed reduced transfusions and some reductions in IVH/PVL/NEC but variable neurodevelopmental findings (chunks 32-33).

Surgical criteria

Perioperative / surgical use

Surgical setting: Perioperative erythropoietin may reduce transfusion rates in orthopedic and spinal surgery but has been associated with increased thrombotic events in some trials and substantial cost; DVT prophylaxis and individual risk assessment should be documented.Preoperative Hgb 10-13 g/dL in arthroplasty trials

Spine and arthroplasty trials showed reduced transfusions but increased thrombotic risk in some studies and high cost-effectiveness ratios (chunks 25-27).

HCV therapy criteria

HCV and antiviral therapy context

HCV with RBV/IFN therapy: In patients receiving pegylated interferon and ribavirin, ESAs may be used for anemia (e.g., Hb < 10 g/dL) after ribavirin dose reduction to maintain ribavirin dosing; documentation should include timing of anemia (early vs late) because ESA benefit for SVR was seen in early-onset anemia.Hb <10 g/dL for ESA consideration in trials

IDEAL and randomized trials showed ESA use helped maintain RBV dosing and, in early-onset anemia, was associated with higher SVR (chunks 28-31).

Clinical coverage criteria

Covered when ALL of the following are met (examples drawn from KDIGO and NCCN recommendations):

KDIGO/NCCN-aligned coverage criteria: 1) Indication consistent with guideline recommendations (e.g., CKD patients meeting Hb/Hct thresholds; symptomatic anemia in MDS; anemia due to myelosuppressive chemotherapy when use aligns with NCCN/FDA indications). 2) Individualized risk-benefit assessment documented (include transfusion risk, prior iron response, cardiovascular and thrombotic risk). 3) Planned monitoring and dosing adjustments per guideline and product labeling (document Hb/Hct monitoring frequency and dose adjustments); Avoid intentional Hb >13 g/dL.see guidelines

Providers should follow ESA selection and monitoring guidance per KDIGO and NCCN (chunks 46-47,51).

ESA hyporesponsiveness, management, and PRCA

Guidance and criteria to manage ESA hyporesponsiveness and complication evaluation

Acquired ESA hyporesponsiveness definition: Classify as acquired ESA hyporesponsiveness if after treatment with stable doses of ESA the patient requires two increases in ESA doses up to 50% beyond the previously stable dose to maintain hemoglobin.2 dose increases up to 50%

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Limits on dose escalation: Avoid repeated escalations in ESA dose beyond double the dose at which the patient had been stable.<=2x stable dose

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Management of poor responsiveness: Evaluate and treat specific reversible causes of poor ESA response (iron deficiency, inflammation, infection, medication causes); if hyporesponsive despite correction, individualize therapy considering Hb decline, required ESA doses, and need for transfusion.

ESAs are considered unproven for several scenarios and should not be used routinely in those settings. Key exclusions include: patients receiving curative‑intent myelosuppressive chemotherapy (see NCCN guidance), patients receiving only hormonal agents, biologics, or radiotherapy (unless also receiving concomitant myelosuppressive chemotherapy), patients who need immediate correction as a substitute for red blood cell transfusion, patients undergoing cardiac or vascular surgery, patients scheduled to donate autologous blood preoperatively, and patients in whom anemia can be managed adequately with transfusion.

Randomized trials have shown harm when ESAs were used to achieve higher hemoglobin targets in oncology populations. In a study of women with metastatic breast cancer titrated to maintain hemoglobin between 12–14 g/dL, there were increased deaths attributed to disease progression and higher rates of fatal thrombotic events in the ESA arm. For cancer patients, requests to target higher hemoglobin ranges should be avoided or require strong oncology justification and documentation of individualized risk‑benefit assessment.

ESAs are not indicated for patients who are not receiving myelosuppressive therapy (or who are receiving non‑myelosuppressive therapy) or when an identifiable, treatable cause of anemia exists (for example, iron deficiency, B12 deficiency, or hemolysis) that should be corrected first. The policy also notes that ESAs are unproven when anemia can be managed by transfusion or when chemotherapy is given with curative intent.

Adjuvant and adjunctive agents to boost ESA response are generally not supported. The guideline work group recommends not using androgens as an adjuvant to ESA therapy and suggests against routine use of other adjuvants such as vitamins C, D, E, folic acid, L‑carnitine, and pentoxifylline.

The continuous erythropoietin receptor activator (CERA; Mircera) is considered unproven for the treatment of anemia due to cancer chemotherapy and is not an accepted substitute where ESAs are restricted. More broadly, use of ESAs in settings not supported by the evidence (for example, curative‑intent chemotherapy) is described as unproven.

ESA therapy intended solely to correct anemia in cancer patients who are not concurrently receiving myelosuppressive chemotherapy or radiotherapy, or to reach higher hemoglobin targets shown to be harmful in trials, is not supported. Evidence shows increased mortality and thromboembolic events when ESAs are used inappropriately in oncology populations; therefore ESA use to correct anemia without concurrent indicated anti‑cancer therapy or to target higher Hb should be avoided.

For chronic kidney disease, maintaining hemoglobin above recommended ranges is not medically necessary. The KDIGO work group recommends generally avoiding use of ESAs to maintain adult CKD hemoglobin above 11.5 g/dL and recommends not intentionally increasing Hb above 13 g/dL. These maintenance thresholds should guide clinical decisions and prior authorization determinations.

Procedure and Threshold Coding

Applicable procedure/HCPCS codesHCPCS

J0881	Injection, darbepoetin alfa, 1 mcg (non-ESRD use)
J0882	Injection, darbepoetin alfa, 1 mcg (for ESRD on dialysis)
J0885	Injection, epoetin alfa, (for non-ESRD use), 1000 units
J0887	Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)
J0888	Injection, epoetin beta, 1 microgram, (for non-ESRD use)
Q4081	Injection, epoetin alfa, 100 units (for ESRD on dialysis)
Q5105	Injection, epoetin alfa, biosimilar, (Retacrit) (for ESRD on dialysis), 100 units
Q5106	Injection, epoetin alfa, biosimilar, (Retacrit) (for non-ESRD use), 1000 units

Hematocrit initiation threshold

Hematocrit initiation thresholdHematocrit < 30% for initial therapy in most indications (CKD on dialysis, CKD not on dialysis, chemotherapy-associated anemia and others); some indications use Hct ≤ 30% wording

Perioperative exceptionPerioperative initiation criteria specify preoperative Hct > 30% and ≤ 39% for reduction of allogeneic transfusions (authorization ≤ 3 months)

MDS/Zidovudine/Chemotherapy specificsSeveral indications (MDS, myelofibrosis, zidovudine-associated anemia, chemotherapy-associated anemia) state initiation at Hct ≤ 30%

Hematocrit continuation threshold

Dialysis continuation thresholdHematocrit remains < 33% for continuation of ESA therapy in patients on dialysis

Non-dialysis continuation threshold

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for erythropoiesis-stimulating agents (ESAs). Initial authorizations are time-limited (generally up to 12 months) and reauthorizations are required for continued therapy (generally up to 12 months). Requests must meet the specific clinical criteria for the indicated condition per this policy and guideline-based recommendations.

Initial and reauthorization periods are generally limited to no more than 12 months.
Prior authorization must reference the specific indication (CKD on dialysis, CKD not on dialysis, cancer chemotherapy, MDS, myelofibrosis, zidovudine-associated anemia, etc.) and corresponding criteria.

Documentation Required

Required Clinical Documentation

Submit clinical documentation demonstrating the indication, baseline and recent hemoglobin/hematocrit values, prior therapies tried (including iron supplementation and transfusion history), and evidence that reversible causes of anemia have been evaluated and addressed. Include documentation of patient counseling on ESA risks and benefits when applicable.

Regimens and Line-of-Therapy Notes

Regimen	Coverage stance	Notes
Use of ESAs during curative‑intent myelosuppressive chemotherapy
ESAs are unproven for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure (except when the patient refuses blood transfusion). Requests in this situation may be denied.
Not applicable

Regimen	Coverage stance	Notes
Mircera (methoxy polyethylene glycol‑epoetin beta) for chemotherapy‑induced anemia
Mircera is specifically identified as unproven for the treatment of anemia due to cancer chemotherapy.
Initial authorization and continuation criteria for other ESAs do not apply to Mircera for this indication per policy statement.

Consideration	Guidance
Agent selection based on pharmacodynamics, safety, outcomes, cost, and availability
The work group recommends choosing an ESA based on the balance of pharmacodynamics, safety information, clinical outcome data, costs, and availability (1D).
Use of regulatory‑approved ESAs and true biosimilars for copy products
The work group suggests using only ESAs that have been approved by an independent regulatory agency; for 'copy' versions, true biosimilar products should be used (2D).

LINE OF THERAPY — first-line

Chemotherapy-associated anemia initial: Hct ≤30%; normal iron stores; not receiving curative-intent myelosuppressive chemotherapy (unless refusing transfusion); initial authorization ≤12 months

Chunks 7-8

LINE OF THERAPY — mixed

Use with concurrent anti-cancer therapy: Trials of ESAs during chemotherapy showed reduced transfusions but meta-analyses observed increased mortality signals; ESA use during active chemotherapy requires individualized assessment and documentation of intent and risks.

LINE OF THERAPY — second-line

Definitions and Key Terms

Pretreatment hematocrit

DefinitionPretreatment hematocrit: hematocrit values obtained prior to therapy (first 4–6 weeks) used for initiation decisions and baseline comparisons

Use in monitoringPretreatment Hct values are referenced to assess response and safety during ongoing titration

DocumentationProviders should document pretreatment Hct as part of authorization and baseline assessment

Hematocrit conversion

Conversion factorUse a conversion factor of 3 to approximate hematocrit from hemoglobin (e.g., Hb 10 g/dL ≈ Hct 30%)

ExamplesHb 11 g/dL ≈ Hct 33%; Hb 12 g/dL ≈ Hct 36% per policy guidance

Biomarker and Diagnostic Requirements

SF3B1

SF3B1 biomarker useSF3B1 mutation used in MDS branching criteria: ring sideroblasts <5% or ≥5% with SF3B1 mutation are part of eligibility determinations for ESA therapy

Ring sideroblast thresholdsCriteria reference ring sideroblasts thresholds of <15% or ≥15% overall, with special consideration of ≥5% when SF3B1 mutation present

Step therapy implicationFor ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation), ESA use may be allowed only after no response to luspatercept (Reblozyl)

Operational Line-of-Therapy and Thresholds

CKD criteria (operational)

CKD-related anemia evidence considerations and thresholds (operational)

CKD operational thresholds: Initiation and continuation thresholds should follow KDIGO and policy specifics: For CKD patients on dialysis, initiate when hematocrit <30% and continue while Hct remains <33%; for CKD patients not on dialysis, initiate when Hct <30% and continue while Hct remains <30%; avoid initiating ESA in CKD ND adults with Hb ≥10.0 g/dL unless individualized; document cardiovascular risk given TREAT findings.Hct initiation <30%; continuation Hct ≤33% (dialysis) or ≤30% (non-dialysis); Hb thresholds per KDIGO

Chunks 5-6,24,37

Background and Evidence Summary

Anemia arises from reduced red blood cell mass due to blood loss, decreased production, or increased destruction. Endogenous erythropoietin is the primary hormone regulating erythropoiesis; recombinant erythropoiesis‑stimulating agents (ESAs) such as epoetin alfa, darbepoetin alfa, and methoxy polyethylene glycol‑epoetin beta (CERA) act on erythropoietin receptors to stimulate red blood cell production. Darbepoetin and CERA are molecularly modified to prolong half‑life and receptor activity compared with epoetin products, which informs dosing intervals and agent selection.

OpenPayer

Erythropoiesis‑stimulating agents (ESAs) coverage

Coverage Criteria for ESAs

Procedure and Threshold Coding

Provider Actions, Prior Authorization, and Documentation

Regimens and Line-of-Therapy Notes

Definitions and Key Terms

Biomarker and Diagnostic Requirements

Operational Line-of-Therapy and Thresholds

Background and Evidence Summary