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._