For services on or after July 27, 2009, see policy I-110.

NOTE:

See Medicare Advantage Medical Policy Bulletin I-97 for information regarding Epoetin alfa use in home dialysis.

An erythropoietin stimulating agent (ESA) is an analog of erythropoietin. ESAs are biologically engineered hormones produced by recombinant DNA technology. Erythropoietin analogs contain the identical amino acid sequence as naturally occurring erythropoietin, and have the same biological effect. Primarily, the kidneys produce erythropoietin in response to hypoxia. Both erythropoietin and ESAs stimulate the bone marrow to form new red blood cells. They are used to treat anemia by elevating or maintaining the red blood cell level (as demonstrated by the hematocrit and/or hemoglobin levels), therefore decreasing anemia and the need for transfusions. Darbepoetin alfa (brand name Aranesp ®), an erythropoietin analog, differs from recombinant human erythropoietin alfa (brand name Epogen ® or Procrit ®) in having two additional N-glycosylation sites, which slows its clearance and makes its half-life two-three times longer, allowing less frequent injections. This policy will apply to new ESAs as they are approved.

Since darbepoetin alfa and epoetin alfa have a similar mode of action and their structures differ only by the number of N-linked oligosaccharides on the protein, this policy does not distinguish differences for on or off-label indications and contraindications, except for pre treatment of selective surgery where blood loss is anticipated. Several off-label uses are well-accepted clinically, as indicated by inclusion in various compendia. However, a contraindication for either ESA is binding on both. In March 2007, the FDA issued new warnings against target Hb levels above 12 g/dL (36% Hct) “for all patients.” The FDA also issued specific warnings against off-label use in cancer patients whose anemia is not directly linked to chemotherapy. The FDA also reminded physicians that the main endpoint in studies for on-label indications has been avoidance or reduction in transfusions. The policy contains descriptions of specific coverage guidelines and documentation that supports medical necessity for individual patients.

CMS has both a National Coverage Determination (NCD) and a National Benefit Policy regarding uses of ESAs. This policy (I) provides clarification and additional coding information for the National Benefit Policy, and (II) provides additional coverage information for uses of ESAs not specified in the NCD.

I. The ICD-9-CM codes listed in the coding section below are covered, when ESAs are used in keeping with the National Benefit Policy for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis.

II. Erythropoiesis Stimulating Agents (ESAs) may be considered reasonable and necessary for the treatment of anemia associated with any of the following conditions, which are not specified in the NCD:

1. Treatment of anemia induced by AZT used in treatment of HIV/AIDS;
2. Treatment of selected patients with anemia related to myelodysplastic syndrome;
3. Perisurgical adjuvant therapy (epoetin alfa only);
4. Treatment of anemia of selected chronic diseases: rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, and hepatitis C undergoing treatment.

The following causes of anemia should be considered, documented, and corrected (when possible) before starting erythropoietin analogue therapy for any of the covered indications:

1. Iron deficiency;
2. Underlying infection or inflammatory process;
3. Underlying hematological disease;
4. Hemolysis;
5. Vitamin deficiencies (e.g. folic acid or B12);
6. Blood loss;
7. Aluminum intoxication.

There are rare patients whose cardiac, pulmonary or other medical diseases warrant the use of ESAs to maintain a hemoglobin/hematocrit (Hb/HCT) higher than the levels discussed in this policy. Documentation to support this practice must be available upon request.

During therapy with an erythropoietin analog, many patients will eventually require supplemental iron. For these patients, stores of iron should be regularly monitored to ensure a transferrin saturation greater than 20% and/or serum ferritin levels greater than 100 ng/ml, in order to guide appropriate supplementation.

Coverage Criteria

A. For End Stage Renal Disease (ESRD) patients on dialysis:

1. Diagnosis of end stage renal disease;
2. Anemia of ESRD. Treatment with ESAs is given to achieve and maintain a Hb level of 10-12 gm/dl.

B. For chronic kidney disease patients NOT on dialysis:

1. Anemia. Treatment with ESAs is given to achieve and maintain a Hb level of 10-12 gm/dl.
2. Creatinine clearance less than 60 ml/min, or glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2.

C. For patients with anemia related to AZT therapy for HIV/AIDS:

1. Anemia with Hb/HCT less than 10 / 30% at initiation of therapy. Treatment with ESAs is given to achieve and maintain a Hb level of 10-12 gm/dl.

D. For patients with myelodysplastic syndrome (MDS):

1. MDS with bone marrow blast count of less than 10% blasts.
2. Pretreatment erythropoietin levels less than or equal to 500 IU/L, for ESA therapy initiated on or after the effective date of this policy.
3. Anemia associated with MDS, with Hb/HCT less than 10 / 30% at initiation of therapy. Treatment with ESAs is given to achieve and maintain a Hb level of 10-12 g/dl.

E. Perisurgical adjuvant therapy: epoetin alfa for patients who:

1. Are undergoing hip or knee surgery;
2. Have an anemia with a Hb between 10 and 13 gm/dL;
3. Are not candidates for autologous blood transfusion;
4. Are expected to lose more than two units of blood;
5. Have been evaluated to ensure that their anemia is due to chronic disease.

F. For patients with anemia of chronic disease:

1. Anemia with Hb/HCT less than 10 / 30% at initiation of therapy. Treatment with ESAs is given to achieve and maintain a Hb level of 10-12 gm/dl.

The literature covering use of ESAs for anemia of chronic disease is mixed, though developing. Most reported studies are small, and positive effects must be balanced with newer data that shows some patients given ESAs with anemia of cancer have shorter survival times. Currently there is evidence of patient benefit using ESA therapy to reduce transfusions for selected patients with significant refractory and symptomatic anemia who have inflammatory diseases (rheumatoid arthritis, Crohn’s disease, ulcerative colitis), and hepatitis C with anemia due to the medication therapy. Until further publications show clear benefit, ESAs for anemia of other chronic diseases other than those listed (rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, and hepatitis C undergoing treatment), will not be covered.

As per Change Request (CR) 5818, the following are Nationally Non-Covered Indications:

• Any anemia in cancer or cancer treatment patients due to bone marrow fibrosis;
• Anemia of cancer not related to cancer treatment;
• Prophylactic use to prevent chemotherapy-induced anemia;
• Prophylactic use to reduce tumor hypoxia;
• Patients with erythropoietin-type resistance due to neutralizing antibodies; and
• Anemia due to cancer treatment if patients have uncontrolled hypertension.

Because there are no specific ICD-9-CM codes for the indications above, they will be indicated on the claim with assigned ICD-9-CM code V49.89.

Payment for the drug and associated services (i.e., rescue agents, administration) will be denied as not medically necessary when reported with a diagnosis code not listed in the "Diagnosis Codes" section of this policy or diagnosis code V49.89 which indicates the patient has a non-covered condition. Effective January 26, 2009, a provider cannot bill the member for the denied service unless the provider has given advance written notice, informing the member that the service may be deemed not medically necessary and providing an estimate of the cost.  The member must agree in writing to assume financial responsibility, in advance of receiving the service.  The signed agreement, in the form of a Pre-Service Denial Notice, should be maintained in the provider's records.

Documentation Requirements

1. All documentation must be maintained in the patient’s medical record and available upon request.
2. Every page of the record must be legible and include appropriate patient identification information (e.g., complete name, dates of service(s)). The record must include the physician or non-physician practitioner responsible for and providing the care of the patient.
3. The submitted medical record should support the use of the selected ICD-9-CM code(s). The submitted CPT/HCPCS code should describe the service performed.

Listing of ICD-9-CM codes contained in this policy does not assure coverage of the specific service. Coverage criteria specified in this policy shall be applied to determine appropriate reimbursement.

Medical records such as physician’s (or non-physician practitioner's) order must be made available upon request. Documentation the provider is to maintain in the patient’s medical record include: patient’s weight; erythropoietin analogue units administered per kilogram of body weight; and medical justification for administration of erythropoietin analogues exceeding usual doses.

Documentation supporting the indication for erythropoietin analogues administration must be made available upon the request; for all patients, this includes Hb/HCT and documentation of adequate iron stores. Additional information is determined by indication. Regular reporting of Hb/HCT is needed to show monitoring of ESA dose.

Dialysis Patients: dialysis schedule, Hb/HCT immediately prior to billing period. For ESRD patients on home dialysis, the following additional information must be maintained in the medical record and available upon request: a care plan; evidence of home monitoring (including a record of the erythropoietin analogue supplied to the patient and a record of dose administration); patient instructions; and patient selection protocol.

Non-dialysis Patients / Chronic renal failure patients: creatinine clearance or GFR supporting a diagnosis of chronic renal failure.

Patients with myelodysplastic syndrome: date of initiation of erythropoietin analogue therapy, and response to erythropoietin analogue administration (change in Hb/HCT and/or transfusion requirements). Pretreatment erythropoietin levels, for ESA therapy initiated on or after the effective date of this policy. For patients on ESA therapy for MDS, initiated prior to the effective date of this policy, a physician’s statement that the patient has MDS must be included in the medical record. For ESA therapy initiated on or after the effective date of this policy, a copy of the actual bone marrow biopsy report, including the bone marrow blast count (%), must be included in the medical record.

NOTE:

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.

Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim.

Title XVIII of the Social Security Act (SSA), Section 1881(b)(1) allows payment for services furnished to individuals who have been determined to have end stage renal disease.

Title XVIII of the Social Security Act (SSA), Section 1881(11)(B)(I) allows payment for erythropoietin provided by a physician.

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 6:
30 Drugs and Biologicals

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 11:
30.1 Frequency of Dialysis Sessions
30.4 Drugs and Biologicals
30.5 New ESRD Composite Payment Rates Effective January 1, 2005
90 Epoetin (EPO)

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 15:
50 Drugs and Biologicals
50.1 Definition of Drug or Biological
50.2 Determining Self-Administration of Drug or Biological
50.3 Incident-to Requirements
50.4.1 Approved Use of Drug
50.4.3 Examples of Not Reasonable and Necessary
50.5.2 Erythropoietin (EPO)
50.5.2.1 Requirements for Medicare Coverage for EPO [home use]
50.5.2.2 Medicare Coverage of Epoetin Alfa (Procrit) for Preoperative Use

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 17:
20.5.8 Injections Furnished to ESRD Beneficiaries

CMS Publication 100-04, Medicare Claims Processing Manual, Transmittal No. 1212, Change Request #5480, March 30, 2007, Requirement for Providing Route of Administration Codes for Erythropoiesis Stimulating Agents (ESAs).

CMS Publication 100-04, Medicare Claims Processing Manual, Transmittal No. 737, Change Request #4108, October 31, 2005, provides updated HCPCS codes for epoetin alfa and darbepoetin alfa.

CMS Publication, Medicare Coverage of Erythropoietin Stimulating Agents. Includes link to Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N).

CMS Publication, IOM 100-03, Medicare National Coverage Determinations (NCD) Manual, Transmittal No. 80, Change Request #5818, January 14, 2008, describes the NCD for the use of ESAs in Cancer and Related Neoplastic Conditions.

CMS Publication, IOM 100-04, Medicare Claims Processing Manual, Transmittal No. 1413, Change Request #5818, January 14, 2008, describes the coding and claims processing rules for the use of ESAs in Cancer and Related Neoplastic Conditions.

CMS Publication, IOM 100-04, Medicare Claims Processing Manual, Transmittal No. 1412, Change Request #5699, January 11, 2008, describes the coding and claims processing rules for the Reporting of Hematocrit or Hemoglobin Levels on All Claims for the Administration of Erythropoiesis Stimulating Agents (ESAs), Implementation of New Modifiers for Non-ESRD Indications, and Reporting of Hematocrit/Hemoglobin Levels on all Non-ESRD, Non-ESA Claims Requesting Payment for Anti-Anemia Drugs.

CMS Publication, IOM 100-04, Medicare Claims Processing Manual, Transmittal No. 1503, Change Request #6047, May 16, 2008, describes the revisions to the billing requirements for ESRD-Related Epoetin Alfa (EPO) and Darbepoetin Alfa (Aranesp) administrations provided during unscheduled or emergency dialysis treatments in the outpatient hospital setting.

There is an updated NCD for use of Erythropoiesis Stimulating Agents, ESAs, in Cancer and Related Neoplastic Conditions. These uses are not addressed in this policy. Please see Change Request (CR) 5818 and MLN Matters article number MM5818 for specific instructions on these uses of ESAs. This CR is retroactive to July 30, 2007.

The CR 5699 and MLN Matters article number MM5699 give specific instructions on the reporting of hematocrit or hemoglobin levels with use of ESAs, as well as other anti-anemia drug use. They further describe the modifiers required. This CR is retroactive to January 1, 2008.

For patients on dialysis (Both diagnoses must be on claim.)

For patients with chronic kidney disease (not yet on dialysis) and anemia – must include 285.21 and one other listed diagnosis.

*Note: Patients with stage I and II do not meet the creatinine clearance or GFR requirements in coverage criteria B.

Patients with anemia related to treatment with zidovudine (AZT) for HIV disease. Must have 284.89 (aplastic anemia due to drugs) and either 042 or 079.53 on claim.

Patients with anemia related to Myelodysplastic Syndrome.

Preoperative use in specified patients. Must have an anemia diagnosis (Note: 285.29 or 285.9) and other specified prophylactic measure diagnosis. (Anemia must be primary diagnosis).

* Do not use this code to identify uses of ESAs associated with cancer and related neoplastic conditions. Specifically do not use this code to identify the following, which are non-covered under the NCD: prophylactic use to prevent chemotherapy-induced anemia, and / or prophylactic use to reduce tumor hypoxia.

For patients with hepatitis C and anemia of chronic inflammatory diseases must include 285.29 (anemia of other chronic disease) and one other listed diagnosis.