LCD L34356: Erythropoiesis Stimulating Agents (ESA)

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. Since 2007, the FDA issued new warnings against target Hgb levels above 11 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 https://urldefense.com/v3/__http://www.cms.gov/center/coverage.asp__;!!MfIcbwNr!qZ-cKua-vTCeMpYaDGiVFKyYdrfynBy1ay1aAaZFFIPARra1kHrZVz4snEQKZib-LS1G7s4pt7UGla_yFhYuX8faTQ$ . This local decision elaborates on the NCD and covers some additional indications.

ESAs are covered for the following indications:

• Treatment of significant anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy;

• Treatment of anemia induced by AZT and/or other Nucleoside Reverse Transcriptase Inhibitors (NRTI) used in treatment of HIV/AIDS;

• Treatment of selected patients with anemia related to myelodysplastic syndrome;

• Perisurgical adjuvant therapy (epoetin alfa only);

• 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:

• Iron deficiency;

• Underlying infection or inflammatory process;

• Underlying hematological disease;

• Hemolysis;

• Vitamin deficiencies (e.g. folic acid or B12);

• Blood loss;

• 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 periodically during treatment.

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 use of the lowest ESA dose sufficient to reduce the need for RBC transfusions. Hemoglobin levels should not intentionally exceed 11g/dL due to increased risk of adverse events. 1 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

• Diagnosis of end stage renal disease

• 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

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

• 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

• The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is 1g/dL (hematocrit > 3%).

• For patients whose hemoglobin rises 1 g/dl (hematocrit >3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to

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

• 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

• Myelodysplasia with less than 10% blasts

• Pretreatment erythropoietin levels of 500 or less

• 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

• Are undergoing hip or knee surgery

• Have an anemia with a Hgb between 10 and 13 g/dL

• Are not a candidate for autologous blood transfusion

• Are expected to lose more than two units of blood

• Have been evaluated to ensure that their anemia is due to chronic disease

G. For patients with anemia of chronic disease

• 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.

Guidelines such as NKF-K/DOQI Clinical Practice Guidelines 2 recommend an evaluation of anemia among patients with CKD when the Hb is 1