Erythropoiesis Stimulating Agents (ESA)

Language quoted from Centers for Medicare and Medicaid Services (CMS), National Coverage Determinations (NCDs), and coverage provisions in interpretive manuals is italicized throughout the policy. NCDs and coverage provisions in interpretive manuals are not subject to the Local Coverage Determination (LCD) Review Process (42 CFR 405.860[b] and 42 CFR 426 [Subpart D]). In addition, an administrative law judge may not review an NCD. See Section 1869(f)(1)(A)(i) of the Social Security Act.

Unless otherwise specified, italicized text represents quotation from one or more of the following CMS sources:

Title XVIII of the Social Security Act (SSA):

Section 1833(e) prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

Section 1862(a)(1)(A) excludes expenses incurred for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Section 1881(b)(1) allows payment for services furnished to individuals who have been determined to have end stage renal disease.

Section 1881(11)(B)(I) allows payment for erythropoietin provided by a physician.

CMS Publications:

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 1
30 Drugs and Biologicals

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

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 7:
Administration of Medications

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 100-3, Medicare National Coverage Determinations Manual, Chapter 1, Part 2
110.21 - Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 6:
10.1 Consolidated Billing Requirement for SNFs
20.2 Services Excluded from Part A PPS Payment …
20.2.1.1 ESRD Services
20.2.1.4 Coding Applicable to EPO Services

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 8:
10.5 Hospital Services
60.4 Separately Billable ESRD Items and Services – Erythropoietin
60.4.1 Epoetin Alfa (EPO) Facility Billing Requirements
60.4.3 Payment Amount for Epoetin Alfa (EPO)
60.4.3.2 Epoetin Alfa (EPO) Provided in the Hospital Outpatient Department
60.7 Darbepoetin Alfa (Aranesp®) for ESRD Patients
60.7.1 Darbepoetin Alfa (Aranesp®) Facility Billing Requirements Using UB-04/Form CMS-1450
60.7.3 Payment Amount for Darbepoetin Alfa (Aranesp®)
60.7.3.2 Payment for Darbepoetin Alfa (Aranesp®) in the Hospital Outpatient Department
80.2.1 Required Billing Information for Method I Claims
90 Method II Billing
90.5 Method II Support Services Billed to the Intermediary by the Facility
90.5.1 Billable UB-04 Revenue Codes Under Method II
90.5.1.1 Unbillable UB-04 Revenue Codes Under Method II

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 17
80.8 Reporting of Hematocrit and/or Hemoglobin Levels
80.9 Required Modifiers for ESAs Administered to Non-ESRD Patients
80.10 Hospitals Billing for Epoetin Alfa (EPO) and Darbepoetin Alfa (Aranesp) for Non-ESRD Patients
80.11 Requirement for Providing Route of Administration Codes for Erythropoiesis Stimulating Agents (ESAs)
80.12 Claims Processing Rules for ESAs Administered to Cancer Patients for Anti-Anemia Therapy

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 25:
60 General Instructions for Completion of Form CMS-1450 for Billing

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 27:
80.8 ESRD Maintenance Transaction Error Codes.

CMS Publication, Medicare Coverage of Erythropoietin Stimulating Agents, http://www.cms.gov/center/coverage.asp.

CMS Publication 100.04, Medicare Claims Processing Manual, Transmittal No. 1307, Change Request # 5700, July 20, 2007, Modification to the National Monitoring Policy for Erythropoietic Stimulating Agents (ESAs) for End-Stage Renal Disease (ESRD) Patients Treated in Renal Dialysis Facilities.

An erythropoiesis stimulating agent (ESA) is an analog of erythropoietin. ESAs are biologically engineered hormones produced by recombinant DNA technology. ESAs 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 [Hct] and/or hemoglobin [Hgb] levels), therefore decreasing anemia and the need for transfusions. Darbepoetin alfa (brand name Aranesp ®), differs from epoetin (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.

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 certain specific pre-operative uses (see "Coverage Criteria" bullet F). However, a contraindication for either ESA is binding on both. In March 2007, the FDA issued new warnings against target Hgb 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.

Omontys ® represents the first new FDA-approved and marketed ESA for this condition since 2001. The approval of Omontys ® was based on 2 randomized, active-controlled, open-label, multi-center clinical trials, which showed the safety and effectiveness of Omontys in patients with CKD who were on dialysis. The trials randomly selected a total of 1,608 patients with Hb levels initially stabilized by ESA to receive either Omontys ® once-monthly or to continue their current ESA (epoetin) treatment. Results showed that Omontys ® was as safe and effective as epoetin in maintaining Hb levels within the studies’ pre-specified range of 10 to 12 g/dL. The most common side effects observed in 10 % or more of dialysis patients treated with Omontys ® were arthralgia, diarrhea, hypertension and vomiting.

According to the FDA-approved labeling, Omontys ® should not be used in patients with CKD who are not receiving dialysis or in patients with cancer-related anemia. Furthermore, it should not be used as a substitute for RBC transfusions in patients who require immediate correction of anemia. Omontys ® is administered as a once-monthly injection. (CGS will reimburse one injection per month.) The FDA approved Omontys with a Risk Evaluation and Mitigation Strategy (REMS) which added safety measures consisting of educational elements for health care professionals and a requirement to assess drug use data.

 

Effective February 23, 2013, Omontys ®  has been recalled by the FDA and will no longer be covered by CGS. The effective date of this non-coverage is February 23, 2013. More information regarding this recall is available on the FDA website.

CMS has issued a national coverage decision for non-renal uses of ESAs. The Decision Memo for ESAs for non-renal disease indications (CAG-00383N) is located at http://www.cms.gov/center/coverage.asp. This local decision elaborates on the NCD and covers some additional indications.
ESAs are covered for the following indications:

1. Treatment of significant anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy;
2. Treatment of anemia induced by AZT and/or other Nucleoside Reverse Transcriptase Inhibitors (NRTI) used in treatment of HIV/AIDS;
3. Treatment of selected patients with anemia related to myelodysplastic syndrome;
4. Perisurgical adjuvant therapy (epoetin alfa only);
5. 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 ESA 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.

The ESA treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include:

• any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis;
• the anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers;
• the anemia of cancer not related to cancer treatment;
• any anemia associated only with radiotherapy;
• 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.

There are rare patients whose cardiac, pulmonary or other medical conditions warrant the use of ESAs to maintain a Hgb/Hct higher than the target level discussed in this LCD. Documentation to support this practice must be available upon request. This does not apply to ESA therapy for anemia related to cancer chemotherapy, which follows the rules mandated by the National Coverage Decision.

During therapy with an ESA, 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. 

For patients receiving chemotherapy for non-myeloid malignancies, the goal of therapy is to avoid transfusions. ESA therapy will be reimbursed only when the Hgb is less than 10 g/dL or the Hct is less than 30%. For all other indications, the goal of therapy is to maintain a stable Hgb and Hct, with target ranges of 10-12 g/dL and 30-36% respectively. Doses must be titrated according to the patient’s response. ESA therapy need not be stopped completely simply due to the achievement of the target Hgb and/or Hct. However, judicious, appropriately timed dose adjustments are expected to prevent inappropriate increases in Hgb and Hct levels.

ESAs may be administered by intravenous or subcutaneous routes. The dosage may be dependent on several factors including the availability of iron stores, the baseline Hgb and/or Hct, and the presence of concurrent medical problems.


Coverage Criteria:

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

1. Diagnosis of end stage renal disease
2. Anemia of ESRD with a Hgb less than 10 gm/dL or a Hct of less than 30% at initiation of therapy

B. For chronic kidney disease patients NOT on dialysis

1. Anemia of ESRD with a Hgb less than 10 g/dL or a Hct of less than 30% at initiation of therapy
2. Serum creatinine equal to or greater than 3, creatinine clearance less than 60 ml/min, or glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2

C. For patients with non-myeloid malignancies where anemia is due to the effect of chemotherapy

1. The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is <10 g/dL (or the hematocrit is <30%).
2. The starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/3 times weekly for epoetin and 2.25 mcg/kg/1 time weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods.
3. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is <30%) 4 weeks after initiation of therapy and the rise in hemoglobin is > 1g/dL (hematocrit > 3%).
4. For patients whose hemoglobin rises < 1g/dl (hematocrit rise < 3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains < 10g/dL after the 4 weeks of treatment (or the hematocrit is < 30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if the hemoglobin rises < 1g/dl (hematocrit rise < 3%) compared to pretreatment baseline by 8 weeks of treatment.
5. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin > 1 g/dl (hematocrit >3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to < 10g/dL (or the hematocrit is < 30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.
6. ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.

D. For patients with anemia related to AZT and/or other Nucleoside Reverse Transcriptase Inhibitors (NRTI) therapy for HIV/AIDS:

1. Anemia with Hgb less than 10 g/dL or a Hct of less than 30% at initiation of therapy

E. For patients with myelodysplastic syndrome

1. Myelodysplasia with less than 10% blasts
2. Pretreatment erythropoietin levels of 500 or less
3. Anemia with Hgb less than 10 g/dL or a Hct of less than 30% at initiation of therapy. If after two months of treatment, there is no significant increase in Hgb/Hct and/or a significant decrease in transfusion requirements, erythropoietin analogs therapy should be stopped.

F. Perisurgical adjuvant therapy: (epoetin alfa only) for patients who

1. Are undergoing hip or knee surgery
2. Have an anemia with a Hgb between 10 and 13 g/dL
3. Are not a candidate 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

G. For patients with anemia of chronic disease

1. Anemia with Hgb less than 10 g/dL or a Hct of less than 30% at initiation of therapy

The literature covering the 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 regimen. Until further publications show clear benefit, ESAs for anemia of other chronic diseases other than those listed above will not be covered.
Use the lowest dose of an ESA that will gradually increase the Hgb concentration to the lowest level sufficient to avoid the need for red blood cell transfusion.

Limitations Specified by CMS

Effective for claims with dates of service on and after January 1, 2008, non-ESRD ESA services billed with modifier EC (ESA, anemia, non-chemo/radio) shall be denied when any one of the following diagnosis codes is present on the claim:

• any anemia in cancer or cancer treatment patients due to folate deficiency,
• B-12 deficiency,
  
  
• iron deficiency,
  
  
• hemolysis, or
  
  
• bleeding,
• anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML); or
• erythroid cancers.

Effective for claims with dates of service on and after January 1, 2008, contractors shall deny non-ESRD ESA services  billed with modifier EC (ESA, anemia, non-chemo/radio) for:

• 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.

Effective for claims with dates of service on and after January 1, 2008, non-ESRD ESA services billed with modifier EB (ESA, anemia, radio-induced), shall be denied.

Effective for claims with dates of service on and after January 1, 2008, contractors shall deny non-ESRD ESA services for HCPCS J0881 or J0885 billed with modifier EA (ESA, anemia, chemo-induced) for anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma, and lymphocytic leukemia when a hemoglobin 10.0g/dL or greater or hematocrit 30.0% or greater is reported.

N/A

N/A

The patient's medical record must contain documentation that fully supports the medical necessity for services included within this LCD. (See "Indications and Limitations of Coverage.") This documentation includes, but is not limited to, relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures.

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

Medical record documentation must be legible, maintained in the patient’s medical record, and meet the criteria contained in this LCD.

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

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

• Dialysis Patients
  Documentation must include dialysis schedule, Hgb/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 to CGS upon request: a care plan, evidence of home monitoring (including a record of the ESA supplied to the patient and a record of dose administered), patient instructions and patient selection protocol.
  
  
  
• Non-dialysis Patients
  For chronic kidney disease (CKD) patients: documentation must include serum creatinine, creatinine clearance, or GFR.
  Patients with myelodysplastic syndrome: bone marrow biopsy report*, date of initiation of ESA therapy, and response to ESA administration (change in Hgb/Hct and/or transfusion requirements).
  
  *For patients on ESA therapy for MDS, initiated prior to 12/01/2007, CGS Administrators, LLC requires that a physician’s statement that the patient does have MDS be included in the medical record. For ESA therapy initiated on or after 12/01/2007, a copy of the actual bone marrow report must be included in the medical record. MDS cannot be diagnosed definitively without a bone marrow biopsy.
  
  
  
  Not Applicable
  
  
  Literature describes a significant increase in risk associated with Hct greater than 36 %. Prompt and judicious dose adjustments are anticipated in response to reaching the target Hgb or Hct (delayed reductions or reductions of less than 25% must be justified in the medical record). The medical record must support the necessity of a target Hgb greater than 12 g/dL or Hct greater than 36 %.

This bibliography presents those sources that were obtained during the development of this policy. CGS Administrators, LLC is not responsible for the continuing viability of Web site addresses listed below.

AHA Coding Clinic Guidelines. 1st Qtr 2009.

Aranesp ® [package insert]. Thousand Oaks, CA: Amgen, Inc. 2007.

Arndt U, Kaltwasser JP, Gottschalk R, et al. Correction of iron-deficient erythropoiesis in the treatment of anemia of chronic disease with recombinant human erythropoietin. Ann Hematol. 2005;84(3):159-166.

Brunkhorst R. Darbepoetin alpha effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoetin in dialysis patients. Nephrology, Dialysis, Transplantation. 2004;19(5):1224-30.

Canon JL. Randomized, double-blind, active-controlled trial of every-3-week darbepoetin alfa for the treatment of chemotherapy-induced anemia, Journal of the National Cancer Institute. 2006;98(4):273-284.

Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. (CREATE Trial). The New England Journal of Medicine.2006;355(20):2071-2084.

Epogen ® [package insert]. Thousand Oaks, CA: Amgen, Inc., 2007.

Eschbach JW. Iron requirements in erythropoietin therapy. Best Pract Res Clin Haematol. 2005;18(2):347-361.

Gabrilove J, Paquette R, Lyons R, et al. Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anemia in patients with myelodysplastic syndrome. Br J Haematol . 2008;142:379-393.

Kotasek D. Darbepoetin alpha administered every 3 weeks alleviates anemia in patients with solid tumors receiving chemotherapy; results of a double-blind, placebo-controlled, randomized study.European Journal of Cancer 2003;39(14):2026-2034.

NKF. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2007.

Other Medicare contractors, specialty societies, and specialty consultants.

Parfrey P. Target Hemoglobin Level for EPO in CKD. American Journal of Kidney Diseases. 2006;47(1).

Park S, Grabar S, Kelaidi G, et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood. 2008;111:574-582.

Pujade-Lauraine E. Erythropoietic agents in anemic patients with cancer: a retrospective observational survey of epoetin alpha, epoetin beta and darbepoetin alpha use in routine clinical practice. Oncology Reports 2005;14(4): 1037-1044.

Schwartzberg LS. A randomized comparison of every 2-week Darbepoetin alpha and epoetin alpha for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecological cancer. Oncologist 2004;9(6): 696-707.

Singh AK, Szczeck L, Tang KL, et al. Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease CHOIR). The New England Journal of Medicine 2006;355(20):2085-2098.

Stasi R. “Management of cancer related anemia with erythropoietic agents: doubts, certainties, and concerns.” The Oncologist 2005;10(7):539-540.

Stein RS, Abels RI, Krantz SB et al. "Pharmacologic Doses of Recombinant Human Erythropoetin in the Treatment of Myelodysplastic Syndromes",Blood 1991;78:1658-1663.

The American Society of Hematology (ASH) Comments to The Center for Medicare and Medicaid Services on Coverage for Erythropoiesis Stimulating Agents (ESAs) filed electronically on April 12, 2007.

U.S. Food and Drug Administration Center for Drug Evaluation and Research, “Information on Erythropoiesis Stimulating Agents (ESA)”, (published 2/16/07).

Wintrobe's Clinical Hematology, 10th ed., © 1999 Lippincott Williams & Wilkins, pp. 184-187.

Macdougall IC, Wiecek A, Tucker B, et al. Dose-finding study of peginesatide for anemia correction in chronic kidney disease patients. Clin J Am Soc Nephrol. 2011;6(11):2579-2586.

U.S. Food and Drug Administration. FDA approves Omontys to treat anemia in adult patients on dialysis. March 27, 2012. FDA: Silver Spring, MD. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm297464.htm.

Omantys ® [package insert]. Palo Alto, CA: Affymax, Inc. 2012.

N/A