ModifiedUnitedHealthcarePolicy CS2025D0028Q

Erythropoiesis-Stimulating Agents

Medical benefit drug policy governing outpatient use of ESAs (darbepoetin alfa, epoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilars) for specified anemia indications under UnitedHealthcare Community Plan; affects providers prescribing or requesting authorization for these agents.

Policy Summary

PayerUnitedHealthcare

PolicyErythropoiesis-Stimulating Agents

Policy CodePolicy CS2025D0028Q

Change TypeReferences updated

Effective DateApr 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and document hematocrit/hemoglobin values, indication, iron status, and clinical rationale when requesting ESA therapy.

SourceLink

POLICY UPDATE CHANGES

Updated References section to reflect the most current information and archived the previous policy version CS2024D0028P.

12 monthsMax initial auth (most indications)

Hct <30%Common Hct initiation threshold

HR 1.17Increased mortality (cancer)

RR 1.52Thromboembolic risk (cancer)

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Coverage Criteria

Patients Receiving Dialysis

Covered when ALL of the following are met for dialysis patients

Dialysis 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%

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

Patients Not Receiving Dialysis

Covered when ALL of the following are met for non-dialysis CKD patients

Non-dialysis initial therapy: Patient is not on dialysis; Hematocrit is less than 30% at initiation of therapy; The rate of hematocrit decline indicates likelihood of requiring an 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%

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

Anemia Due to Cancer Chemotherapy

Covered when ALL of the following are met for cancer chemotherapy-associated anemia (Aranesp, Epogen, Procrit, Retacrit)

Chemo initial therapy: Hematocrit less than or equal to 30% at initiation of therapy; 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; One of the following: patient has moderate to severe CKD; or undergoing palliative treatment; or receiving myelosuppressive chemotherapy not given with curative intent; or both receiving myelosuppressive chemotherapy with curative intent AND patient is refusing blood transfusion(s); Initial authorization will be for no more than 12 monthsHct <=30%

Mircera is unproven for this indication

Chemo continuation 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%

ESAs are unproven when anticipated outcome is cure (except transfusion refusal) or when anemia can be managed by transfusion

Anemia Associated with Myelodysplastic Syndromes (MDS)

Covered when ALL of the following are met for MDS-associated anemia (Aranesp, Epogen, Procrit, Retacrit)

MDS 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; Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Treatment of lower risk disease (IPSS-R Very Low, Low, Intermediate) with symptomatic anemia; And one of the following: patient has del(5q) chromosomal abnormality; OR patient is without del(5q) and ring sideroblasts less than 15% (or <5% with SF3B1 mutation); OR patient is without del(5q) and ring sideroblasts greater than or equal to 15% (or >=5% with SF3B1 mutation) following no response to Reblozyl (luspatercept-aamt); Initial authorization will be for no more than 12 monthsEPO <=500 mUnits/mL; Hct <=30%

MDS continuation 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 mUnits/mL; Hct <=36%

Anemia Associated with Myeloproliferative Neoplasms - Myelofibrosis

Covered when ALL of the following are met for anemia associated with myelofibrosis

Myelofibrosis 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; Patient does not have 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 mUnits/mL; Hct <=30%

Myelofibrosis continuation 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 mUnits/mL; Hct <=36%

Anemia Associated with Zidovudine Treatment in HIV-Infected Patients

Covered when ALL of the following are met for zidovudine-associated anemia (Epogen, Procrit, Retacrit)

Zidovudine 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; Patient does not have 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 mUnits/mL; Hct <30%

Zidovudine continuation therapy: Documentation of positive clinical response to ESA 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 remains less than or equal to 36% for continuation of therapy; Reauthorization will be for no more than 12 monthsEPO <=500 mUnits/mL; Hct <=36%

Anemia Associated with Hepatitis C with Ribavirin and Interferon Therapy

Covered when ALL of the following are met for hepatitis C therapy-associated anemia (Epogen, Procrit, Retacrit)

Hep C initial therapy: Patient is receiving ribavirin and interferon therapy; Hematocrit is less than or equal to 30% at initiation of therapy; Patient does not have 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%

Hep C continuation therapy: Documentation of positive clinical response to ESA therapy; Patient remains on 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%

Preoperative Use for Reduction of Allogeneic Blood Transfusions in Surgery Patients

Covered when ALL of the following are met for perioperative use (Epogen, Procrit, Retacrit)

Perioperative criteria: 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 procedure is elective, noncardiac, and nonvascular; Authorization will be for no more than 3 monthsHct >30% and <=39%

ESAs are unproven for cardiac/vascular surgery or patients willing to donate autologous blood

Coverage considerations by clinical context

Consider ESA coverage when benefits (reduced transfusion needs, maintained therapy dosing, improvement in fatigue) outweigh documented harms (increased thromboembolism, potential increased mortality, stroke risk) for the specific population and indication.

Oncology-related considerations: Use of ESAs reduces RBC transfusion requirements (RR 0.65) and increases hematologic response; trials show increased thromboembolic events (RR ~1.5) and increased mortality during active treatment (HR up to 1.17); balance risks vs benefits and document patient-specific rationale.

Supported by Cochrane and meta-analyses.

CKD-related considerations: In CKD and dialysis populations, ESAs reduce transfusion needs but higher hemoglobin/hematocrit targets have been associated with increased mortality and increased stroke risk (TREAT); consider lower hemoglobin targets and individualized risk assessment.

TREAT and hemodialysis trial data.

Surgical patients: Preoperative ESA dosing can reduce transfusion rates in orthopedic/spinal surgery but may increase thrombotic events; consider DVT prophylaxis and cost-effectiveness.

Initial coverage criteria

Covered when ALL of the following are met

Oncology/hematology indication: Indication is symptomatic anemia due to myelosuppressive chemotherapy for lymphoid malignancy or solid tumor (non-curative intent) OR symptomatic myelodysplastic syndromes or myeloproliferative neoplasms.

Per NCCN guidance

Hemoglobin and prior therapy considerations: Documentation of hemoglobin level and prior iron therapy or iron status; for CKD, Hb <10.0 g/dL generally considered for initiation (individualize) and avoid maintaining Hb above 11.5 g/dL (do not intentionally exceed 13 g/dL).Hb thresholds per KDIGO

Per KDIGO guidance

Risk counseling and consent: Provider counseled patient on ESA risks and benefits and considered alternatives (e.g., transfusion); informed consent documented.

NCCN recommendation

Maintenance and monitoring

Covered when ALL of the following monitoring and dosing practices are followed

Monitoring frequency: Measure hemoglobin at least monthly during initiation; maintenance: CKD nondialysis at least every 3 months, CKD 5D at least monthly.

KDIGO monitoring recommendations

Dose adjustment: Adjust ESA dose based on hemoglobin, rate of change, current ESA dose and clinical circumstances; prefer dose reduction over withholding when lowering hemoglobin.

KDIGO dosing recommendations

Administration route and frequency: Select route (IV vs SC) and frequency based on CKD stage, setting, efficacy, tolerance and ESA type; individualize.

KDIGO suggests considering route/frequency by setting and ESA type

Hyporesponsiveness and poor response

Apply the following for hyporesponsiveness

Initial hyporesponsiveness: Classify as no hemoglobin increase after the first month of ESA treatment on appropriate weight-based dosing; avoid escalating beyond double the initial weight-based dose.1 month

KDIGO suggestion

Acquired hyporesponsiveness: Classify as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had been stable to maintain hemoglobin; avoid repeated escalations beyond double the stable dose.2 dose increases up to 50%

KDIGO suggestion

Management of persistent hyporesponsiveness: Evaluate and treat specific causes of poor ESA response; if remain hyporesponsive despite correction, individualize therapy considering continuing ESA vs transfusion and the doses required.

ESA hyporesponsiveness, management, and PRCA evaluation

Covered when clinicians follow recommended evaluation and management steps for ESA hyporesponsiveness and suspected PRCA

Evaluate and manage ESA hyporesponsiveness

Definition of acquired hyporesponsiveness: Requires two increases in ESA doses up to 50% beyond the dose at which the patient had been stable to maintain hemoglobin.2 dose increases up to 50%
(Not Graded)
Dose escalation guidance: Avoid repeated escalations in ESA dose beyond double the stable dose.
(2D)

Management when hyporesponsive despite corrections: Individualize therapy considering hemoglobin decline, continuing ESA with consideration of doses required, or blood transfusions.

ESAs are considered unproven for use in patients receiving curative chemotherapy. The policy also excludes use when patients are receiving only hormonal agents, biologic products, or radiotherapy unless they are concurrently receiving myelosuppressive chemotherapy. Additional exclusions include situations where immediate correction of anemia is needed as a substitute for an RBC transfusion, patients undergoing cardiac or vascular surgery, patients scheduled to donate autologous blood, and cancer patients whose anemia can be managed by transfusion.

The evidence does not support using ESAs to improve tumor response, progression-free survival, or overall survival. Multiple trials and systematic reviews have reported no tumor benefit and, in some settings, worse locoregional control or survival. Given these findings, ESA use with the intent of improving oncologic outcomes is not supported and should not be pursued as an objective of therapy.

ESAs are not indicated for patients with cancer who are not receiving anticancer therapy, who are receiving non-myelosuppressive therapy, or when an identified, treatable cause of anemia exists. Initiation in such contexts is inappropriate and may be denied; clinicians should address correctable causes (e.g., iron deficiency) or use transfusion when indicated.

The guideline work group recommends not using androgens as adjuvants to ESA treatment (1B) and suggests against routine use of other adjuvants — including vitamin C, vitamin D, vitamin E, folic acid, L-carnitine, and pentoxifylline — to augment ESA response (2D). These agents are not recommended as adjunctive therapy to ESAs.

Mircera (methoxy polyethylene glycol-epoetin beta / CERA) is stated as unproven for treatment of chemotherapy-induced anemia. More broadly, ESAs have limited or unproven utility in certain cancer-related contexts (for example, when cure is the anticipated outcome or when transfusion is an adequate management strategy), and the policy specifies that Mircera should not be considered equivalent to covered ESAs for chemotherapy-associated anemia.

Targeting higher hemoglobin ranges in oncology patients has been associated with harm. Trials that attempted to maintain hemoglobin in the range of approximately 12–14 g/dL showed increased mortality and higher rates of fatal thrombotic events. Because of these safety signals, clinicians should avoid aggressive correction to higher Hb targets and carefully weigh risks and benefits when considering ESA therapy in cancer patients.

KDIGO guidance advises caution when initiating ESA therapy in adult CKD non-dialysis patients. Specifically, the work group suggests that ESA therapy not be initiated for patients with Hb ≥ 10.0 g/dL (2D). Decisions to start ESAs for Hb < 10.0 g/dL should be individualized based on the rate of Hb decline, prior iron response, transfusion risk, symptoms, and other patient-specific factors.

Applicable HCPCS/J-codes referenced in the policy include: J0881, J0882, J0885, J0887, J0888, Q4081, Q5105, and Q5106. These codes are provided for reference and mirror the agents and billing units discussed in the coverage section.

Covered Regimens and Dosing Considerations

Regimen	Indication	Coverage status	Key criteria / notes
Aranesp (darbepoetin alfa)
Anemia due to cancer chemotherapy
Covered when criteria met
Hematocrit ≤ 30% at initiation; no other causes of anemia; patient has moderate–severe CKD, is undergoing palliative treatment, is receiving myelosuppressive chemotherapy not given with curative intent, or is receiving curative-intent myelosuppressive chemotherapy and refuses blood transfusion(s). Initial authorization ≤12 months. Mircera is unproven for this indication.

Guidance	Details / Rationale	Implications for dosing/titration	Supporting safety evidence
Trial-based dosing for epoetin alfa or darbepoetin alfa
Use epoetin alfa or darbepoetin alfa according to trial and prescribing regimens evaluated in cancer studies to reduce transfusion needs and maintain chemotherapy dosing.
Avoid aggressive titration to higher hemoglobin targets (e.g., attempting to maintain 12–14 g/dL); titrate conservatively and aim for the minimal effective Hb to reduce transfusions.
Meta-analyses and randomized trials show reduced transfusion need (RR ~0.65) but increased thromboembolic risk (RR ~1.5) and increased mortality during active treatment (HR ~1.17). Specific trials targeting higher Hb demonstrated worse outcomes.

Policy point	Content	Provider considerations	Alternatives / monitoring
FDA-approved dosing and REMS
Follow FDA-approved dosing and REMS requirements in the product labeling for epoetin alfa, darbepoetin alfa, and related agents (informational only; FDA approval alone is not a basis for coverage).
Prior authorization should document indication, hemoglobin/hematocrit, planned chemotherapy duration (≥2 additional months for oncology initiation per FDA), and clinician assessment of risks/benefits.
Assess iron status and correct treatable causes prior to or during ESA therapy; consider transfusion or non-ESA options when risks outweigh benefits; monitor for PRCA per prescribing information.

Agent	FDA oncology prescribing statement	Coverage implication	Initiation requirement
Epoetin alfa (Epogen, Procrit, Retacrit biosimilar)
Indicated for treatment of anemia in cancer patients on concomitant myelosuppressive chemotherapy when, upon initiation, there are at least two additional months of planned chemotherapy.
Covered for chemotherapy-associated anemia when policy clinical criteria are met and documentation includes planned chemotherapy duration and Hb/Hct values.
At initiation, require documentation of ≥2 additional months of planned chemotherapy and hematocrit ≤30% (or equivalent hemoglobin).

Provider Actions and Authorization Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for erythropoiesis-stimulating agents (ESAs) for all indications covered by this policy. Initial and continuation/reauthorization requests require documentation of medical necessity and indication consistent with the policy criteria. Initial authorizations and reauthorizations are generally limited in duration (commonly to no more than 12 months for CKD, MDS, myelofibrosis, HIV, and many other indications; perioperative authorization limited to no more than 3 months where applicable).

Prior authorization required for initial and continuation therapy
Typical maximum authorization length: ≤ 12 months (≤ 3 months for perioperative use)
Prior authorization applies to oncology, CKD (dialysis and non-dialysis), MDS, myelofibrosis, HIV, hepatitis C with ribavirin/interferon, and perioperative use

Documentation Required

Medical Necessity and Indication Confirmation

Prior authorization requests must confirm the medical necessity and that the indication meets policy criteria (see specific diagnosis sections). Approval should document the presenting indication, relevant baseline lab values, treatment intent, and that alternatives were considered or attempted when required by the indication.

Coding and Clinical Thresholds

Applicable HCPCS/J-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-epbx, biosimilar, (Retacrit) (for ESRD on dialysis), 100 units
Q5106	Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for non-ESRD use), 1000 units

Hematocrit initiation thresholds

Common initiation thresholdHematocrit <30% for initiating ESA therapy in both dialysis and non-dialysis CKD patients

Dialysis initiation criterionPatient is on dialysis and Hct <30% at initiation per dialysis-specific criteria

Non-dialysis initiation criterionPatient not on dialysis and Hct <30% at initiation with evidence rate of decline suggests likely need for RBC transfusion

Perioperative exceptionPerioperative use initiation may have different Hct range (>30% and ≤39%) for elective noncardiac/nonvascular surgery per perioperative criteria

MDS and oncology initiationFor certain oncology and MDS indications, hematocrit initiation threshold is specified as ≤30% (e.g., chemotherapy-associated anemia, MDS)

Line of Therapy

mixed

mixed: Used during myelosuppressive chemotherapy when goal is to reduce transfusions in non-curative settings or when patients refuse transfusion in curative settings; Hct <=30%; normal iron stores; initial authorization <=12 monthsHct <=30%

Mircera unproven

any

any: ESAs reduce transfusion requirements in patients receiving anticancer therapy but increase thromboembolic risk and may increase mortality; use requires individualized assessment.

Cochrane review and randomized trials.

second-line

Biomarker and Diagnostic Requirements

SF3B1 and ring sideroblast thresholds (MDS)

Ring sideroblast threshold optionsRing sideroblasts <15% or ≥15% are used in MDS criteria depending on context

SF3B1 mutation adjustmentWhen SF3B1 mutation present, thresholds may be <5% versus ≥5% to determine eligibility pathways

Reblozyl stepIf ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation) ESA use is considered following no response to Reblozyl (luspatercept-aamt)

Definitions

Hct–Hgb conversion approximations

Hct-to-Hb conversion factorUse conversion factor of 3: Hgb 10 g/dL ≈ Hct 30% (10→30%), Hgb 11 g/dL ≈ Hct 33% (11→33%), Hgb 12 g/dL ≈ Hct 36% (12→36%)

PurposeApplied when only hemoglobin measured to estimate hematocrit for initiation/continuation decisions

ExampleHemoglobin of 10 g/dL is approximately equal to hematocrit of 30% per policy guidance

Erythropoietin (Epoetin alfa) definition

Erythropoietin / Epoetin alfa definitionA recombinant form of endogenous erythropoietin produced by the kidney that stimulates differentiation of erythroid progenitors

MechanismStimulates diversion and differentiation of committed erythroid progenitors in bone marrow

Provider Notes and Supplemental Actions

Step Therapy

MDS: Reblozyl step required before ESA for specified ring sideroblasts

For MDS patients with ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation) reiteration: require documented nonresponse to Reblozyl (luspatercept‑aamt) prior to ESA coverage consideration.

Document prior Reblozyl trial and lack of response in the authorization record
Also include serum EPO ≤500 mUnits/mL and Hct ≤30% per MDS initiation criteria

Step Therapy

Document trials of alternatives and iron status before ESA

Document consideration of alternatives (iron/vitamin supplementation, transfusion, dose reduction of causative agents) before initiating ESA therapy and include any trials or corrections in the record.

Document iron status and any supplementation given
Record transfusion considerations and prior attempts

Revision History

2025-04-01revisionLatest

Updated supporting information and References section; archived previous policy version CS2024D0028P.

Policy Summary

PayerUnitedHealthcare

PolicyErythropoiesis-Stimulating Agents

Policy CodePolicy CS2025D0028Q

Change TypeReferences updated

Effective DateApr 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and document hematocrit/hemoglobin values, indication, iron status, and clinical rationale when requesting ESA therapy.

SourceLink

On This Page

Trials reported reduced transfusion rates but higher thrombotic events and high cost per avoided transfusion.

HCV infection: In HCV patients on ribavirin/interferon, ESAs increase hemoglobin and enable maintenance of ribavirin dosing; document anemia timing and effect on antiviral therapy.

Randomized trials show maintained RBV dosing and improved hemoglobin.

Neonates and preterm infants: Early ESAs reduce RBC transfusion use and some neonatal complications but evidence quality is low to moderate; benefits are small and use is not routinely recommended.

Technology assessment of 34 studies, 3,643 infants.

Critically ill patients (off-label): Low-quality evidence suggests possible mortality reduction with off-label ESA use in critically ill populations, but harms data are limited; weigh uncertain benefits against risks.

Technology assessment noted low-quality evidence.

Investigation for antibody-mediated PRCA: If patient on ESA >8 weeks develops sudden rapid hemoglobin decline (0.5–1.0 g/dl per week), requires approximately 1–2 transfusions per week, has normal platelets and white blood cell counts, and absolute reticulocyte count less than 10,000/µl, investigate for antibody-mediated PRCA and stop ESA therapy.Hb decline 0.5–1.0 g/dl/week; reticulocyte <10,000/µl

Recommend stopping ESA (1A) and consider peginesatide for treatment (1B).

Confirm indication consistent with guideline-referenced criteria (e.g., myelosuppressive chemotherapy, CKD with specified Hct/Hb thresholds, MDS criteria)
Document that ESA use is appropriate given risks and benefits for the individual patient
Assess and document alternatives (iron/vitamin supplementation, transfusion, dose-reduction of causative agents) before initiating ESA therapy when appropriate

Note

FDA Indications Noted (Informational)

FDA indications for listed ESAs are provided for informational purposes only and do not alone determine coverage. Coverage decisions require meeting the clinical criteria in this policy.

FDA approval noted for epoetin alfa, darbepoetin alfa, and MPG-epoetin beta for CKD (dialysis and non-dialysis) and select oncology, HIV, and perioperative indications
FDA approval alone is not a basis for coverage — medical necessity per policy criteria is required

Documentation Required

Dialysis Initiation Requirements

For patients receiving dialysis, initial ESA therapy requires documentation that the patient is on dialysis and that hematocrit (Hct) is <30% at initiation. For continuation therapy, documentation must show ongoing dialysis, clinical response to ESA, and Hct remaining below the continuation threshold (commonly <33%). Absent these criteria, therapy is not considered proven.

Initial dialysis criteria: patient on dialysis; Hct < 30% at initiation; no other identifiable causes of anemia; initial authorization ≤ 12 months
Continuation dialysis criteria: patient on dialysis; documented positive clinical response; Hct remains < 33%; reauthorization ≤ 12 months
ESAs are unproven for dialysis patients with Hct ≥ 33%

Documentation Required

Non-Dialysis CKD Initiation Requirements

For non-dialysis CKD patients, initial ESA therapy requires Hct <30% at initiation and evidence that the rate of Hct decline makes RBC transfusion likely; therapeutic goals should include reducing transfusion-related risks. Continuation requires documentation of response and that therapeutic goals remain valid. Absent these criteria, ESA use is unproven.

Initial non-dialysis criteria: patient not on dialysis; Hct < 30% at initiation; rate of Hct decline indicating likely need for RBC transfusion; goal to reduce alloimmunization/transfusion risks; no other causes of anemia; initial authorization ≤ 12 months
Continuation non-dialysis criteria: patient not on dialysis; documented positive clinical response; therapeutic goal persists; Hct remains < 30% for continuation; reauthorization ≤ 12 months
ESAs are unproven for non-dialysis CKD patients with Hct ≥ 30%

Denial Risk

Risks Associated with ESA Use

Use of ESAs is associated with increased risks that must be weighed against benefits. For oncology patients, ESAs have been associated with increased mortality, thromboembolic events, and adverse effects on progression-free or overall survival in certain settings. In CKD, targeting higher hemoglobin/hematocrit levels has been associated with increased mortality and cardiovascular events in trials.

Oncology risks: increased mortality and thromboembolic risk; possible decreased locoregional control/progression-free or overall survival in some cancers
CKD risks: higher hemoglobin/hematocrit targets linked to increased mortality and cardiovascular events (e.g., stroke)

Documentation Required

Required Clinical Documentation

Providers must include specific clinical documentation with authorization requests. Required items include baseline and on-therapy hematocrit/hemoglobin values, assessment and exclusion of other causes of anemia, current iron status and iron therapy history, treatment intent (e.g., curative vs non-curative in oncology), and prior transfusion history where applicable.

Baseline hemoglobin/hematocrit values and recent trend of values (pre-treatment and on-therapy when relevant)
Evidence ruling out other causes of anemia (iron deficiency, B12/folate deficiency, hemolysis) and documentation of iron studies if applicable
For oncology: cancer type, current anticancer therapy status (receiving myelosuppressive chemotherapy/radiation or not), treatment intent (curative vs non-curative), planned duration of chemotherapy (must have ≥ 2 additional months when required)
For CKD: eGFR, presence of cardiac disease, hemoglobin/hematocrit values, prior transfusion history, rationale for ESA over transfusion
Documentation of prior iron therapy and response, and discussion of risks/benefits with the patient

Step Therapy

MDS Step Requirement

For myelodysplastic syndromes (MDS), ESA use requires meeting specific step criteria: erythropoietin ≤ 500 mU/mL, Hct ≤ 30% at initiation, symptomatic anemia in lower-risk disease, and stratification by del(5q) and ring sideroblast percentages. For patients with ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation), ESA use is permitted only after no response to luspatercept (Reblozyl) where specified.

MDS initiation criteria: endogenous erythropoietin ≤ 500 mU/mL; Hct ≤ 30%; no other causes of anemia; symptomatic anemia in lower-risk IPSS-R categories
If ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation) treatment with luspatercept (Reblozyl) is required prior to ESA in the specified subgroup

Documentation Required

Assess Alternatives and Iron Status Prior to ESA Therapy

Before initiating ESA therapy, assess and document alternatives and iron status. Correctable causes (iron deficiency, B12/folate deficiency) should be treated and iron stores documented as adequate. Consider transfusion or dose modification of causative therapies where appropriate prior to or alongside ESA initiation.

Assess iron studies (ferritin, transferrin saturation) and provide iron supplementation when indicated before or during ESA therapy
Document consideration of alternatives: RBC transfusion, iron/vitamin supplementation, modification or delay of myelosuppressive therapy when feasible
For surgical and other settings, document why alternatives (e.g., autologous donation) are not feasible if ESA is requested

Denial Risk

Actions if Antibody-Mediated PRCA is Suspected

If antibody-mediated pure red cell aplasia (PRCA) is suspected (e.g., sudden rapid Hb decline, low reticulocyte count, normal WBC/platelets), ESA therapy should be stopped and the manufacturer contacted to perform assays for binding and neutralizing anti-erythropoietin antibodies per product labeling.

Suspect PRCA with rapid Hb fall (≈0.5–1.0 g/dL per week) or need for frequent transfusions and absolute reticulocyte count <10,000/µL
Stop ESA therapy immediately if antibody-mediated PRCA is suspected
Contact the manufacturer for assay testing and follow product-prescribing guidance; consider alternative management (e.g., peginesatide where recommended)

Continuation hematocrit thresholds

Common continuation thresholdsHematocrit generally limited for continuation: commonly ≤36% or ≤33% depending on indication and dialysis status

Dialysis continuationFor patients on dialysis, continuation requires Hct remains <33% for reauthorization

Non-dialysis continuationFor non-dialysis CKD continuation, hematocrit remains <30% for continuation of therapy

Hepatitis C / Zidovudine continuationFor hepatitis C and zidovudine-associated anemia, continuation requires hematocrit remains ≤36%

Hemoglobin initiation and maintenance thresholds

CKD non-dialysis initiation HbConsider initiation for adult CKD non-dialysis patients with hemoglobin <10.0 g/dL; individualize decision

Do not initiate at or aboveKDIGO suggests not initiating ESA therapy in adult CKD ND patients with Hb ≥ 10.0 g/dL

Maintenance upper limitAvoid using ESAs to maintain Hb >11.5 g/dL in adult CKD patients; do not intentionally increase Hb above 13 g/dL

CKD stage 5D guidanceFor CKD stage 5D, suggest starting ESA to avoid Hb falling below 9.0 g/dL, typically when Hb is between 9.0–10.0 g/dL

Oncology target hemoglobin

Oncology Hb ceilingAvoid correcting hemoglobin to targets >12 g/dL in patients with cancer due to increased risks

MDS targetUse ESAs for symptomatic anemia in MDS with target hemoglobin ≤12 g/dL per NCCN guidance

Chemotherapy-associated initiationChemotherapy-associated anemia initiation described using hematocrit ≤30% (equivalent Hb ≈10 g/dL) and aligned with avoiding high Hb targets

Absolute reticulocyte count (PRCA evaluation)

PRCA reticulocyte criterionAbsolute reticulocyte count <10,000/µl is part of diagnostic criteria for antibody-mediated PRCA

Context of useUsed when evaluating rapid Hb decline after >8 weeks of ESA therapy alongside other PRCA signs

Action implicationIf PRCA suspected, stop ESA therapy and pursue antibody testing per recommendations

Dose escalation for ESA hyporesponsiveness

Definition of acquired hyporesponsivenessAcquired ESA hyporesponsiveness: after stable ESA dosing, requirement for two dose increases up to 50% beyond the previously stable dose to maintain Hb

Escalation limitAvoid repeated escalations in ESA dose beyond double the dose at which the patient had been stable

Management implicationIf persistent hyporesponsiveness after correcting causes, individualize therapy considering continued ESA use versus transfusion

second-line: Use restricted to anemia due to myelosuppressive chemotherapy (non-curative intent) and symptomatic MDS/myeloproliferative neoplasms; not for curative-intent chemotherapy (except transfusion refusal).

Role in therapyUsed as an ESA formulation (epoetin alfa) for treatment of anemia from CKD and other indicated causes

Darbepoetin alfa (description)

Darbepoetin alfa descriptionA recombinant erythropoiesis‑stimulating protein with additional carbohydrate chains that prolong half‑life and stimulates erythropoiesis similar to endogenous erythropoietin

Pharmacologic differenceContains additional carbohydrate chains conferring longer half‑life compared to epoetin alfa

Clinical useUsed as an ESA alternative to epoetin formulations and considered based on pharmacodynamics, safety, and availability

Methoxy polyethylene glycol‑epoetin beta (CERA)

Methoxy polyethylene glycol‑epoetin beta (CERA)An ESA modified by conjugation with methoxy polyethylene glycol, increasing erythropoietin receptor activity and half‑life

Modification detailsConjugation between Lys 52 or Lys 45 and methoxy polyethylene glycol butanoic acid increases receptor activity and prolongs half‑life

Comparative studiesCERA has been compared with epoetin alfa/beta and darbepoetin alfa in CKD studies with no consistent large differences in clinical outcomes

CERA (continuous erythropoietin receptor activator) evidence

CERA in CKD studiesCERA (continuous erythropoietin receptor activator) has been evaluated in multiple CKD trials against epoetins and darbepoetin

Evidence summaryTwenty‑seven studies in adults with CKD compared CERA to epoetin alfa/beta or darbepoetin alfa with low‑certainty evidence of little or no effect on mortality or major CV events

Clinical implicationChoice of ESA should consider pharmacodynamics, safety, outcomes, costs, and availability

ESA indication in oncology

Oncology indication scopeESA use in oncology limited to anemia due to myelosuppressive chemotherapy (lymphoid malignancies and solid tumors) with non‑curative intent and symptomatic MDS/myeloproliferative neoplasms per NCCN guidance

Symptom requirementUse targeted for symptomatic anemia where benefit (reduce transfusion, maintain chemo dosing) outweighs risks

RestrictionsNot indicated for patients receiving curative‑intent chemotherapy except when patient refuses transfusion; Mircera is unproven for chemotherapy‑associated anemia

Acquired ESA hyporesponsiveness definition

Acquired ESA hyporesponsiveness definitionAfter treatment with stable ESA doses, requirement for two dose increases up to 50% beyond the previously stable dose to maintain hemoglobin

Avoid escalation beyond double doseWork group suggests avoiding repeated escalations beyond double the stable dose

Clinical actionEvaluate and treat specific causes of poor ESA response; individualize further therapy if hyporesponsive persists

Antibody‑mediated PRCA: recognition and actions

PRCA suspicion timelineSuspect antibody‑mediated PRCA when patient on ESA >8 weeks develops rapid Hb decline (0.5–1.0 g/dL per week)

Supportive diagnostic featuresConcurrent normal platelets and WBCs plus absolute reticulocyte count <10,000/µl and need for ~1–2 transfusions/week

Recommended actionStop ESA therapy and investigate for anti‑erythropoietin antibodies; consider peginesatide for treatment of antibody‑mediated PRCA per guidance

Anemia has multiple etiologies such as blood loss, decreased red cell production, or hemolysis. Endogenous erythropoietin produced by the kidney stimulates erythroid progenitor differentiation; recombinant erythropoietin and other erythropoiesis-stimulating agents (ESAs) act via the same mechanism to increase red cell production. Longer-acting agents (e.g., darbepoetin alfa, methoxy polyethylene glycol-epoetin beta) have structural modifications that extend their half-life compared with epoetin alfa.