LCD L39237: Erythropoiesis Stimulating Agents

Erythropoietin (EPO) is naturally produced by the kidneys and stimulates the proliferation of red blood cells (RBCs) in the bone marrow. An erythropoietin stimulating agent (ESA) is a biologically engineered analog of EPO. ESAs contain the identical (or very similar) amino acid sequence as naturally occurring EPO and have the same biological effect. Several chronic conditions, especially chronic renal failure, result in decreased production of or relative resistance to EPO, often causing anemia. Supplementation by synthetic drugs with structures identical or similar to naturally occurring EPO has been proven safe and effective in correcting anemia in certain groups of patients. By elevating or maintaining the RBC level (as demonstrated by the hematocrit (HCT) and/or hemoglobin (Hb) levels), these synthetic analogs can decrease anemia and the need for transfusions.

Since 2007, the Food and Drug Administration (FDA) has issued new warnings against target Hb levels above 12 g/dL (HCT of 36%) for “all patients.” The FDA has also issued specific warnings against off-label use in cancer patients whose anemia is not directly linked to chemotherapy. The FDA has consistently reminded physicians that the main endpoint in studies for on-label indications has been avoidance of or reduction in transfusions.

All ESAs covered in this LCD per FDA indications must be administered per FDA-approved label guidance. Please see the FDA drug label for the FDA-approved indications and dosages. This can be accessed at: https://labels.fda.gov/ .

Centers for Medicare and Medicaid Services (CMS) has issued a National Coverage Determination (NCD) 110.21 for the use of ESAs in cancer and related neoplastic conditions.

Please refer to CMS Internet-Only Manual Publication 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1, Part 2, §110.21 for nationally covered indications related to ESA treatment for anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma, and lymphocytic leukemia. This national determination includes dosing information which is not superseded by this LCD. Nationally non-covered indications for which ESA treatment is not reasonable and necessary for beneficiaries with certain clinical conditions is also detailed. The Decision Memo for ESAs for non-renal disease indications (CAG-00383N) provides insight related to the evidence analysis use in promulgating the NCD.

This LCD does not supersede but does incorporate information from the NCD and covers some additional limited non-cancer related indications per the discretion afforded to Medicare Administrative Contractors (MACs). For specificity as to billing and coding advice that will support the reasonable and necessary nature of ESA administration for various conditions, it is critical that the related billing and coding article to this LCD be reviewed.

This A/B MAC does recognize the widely variable use of ESAs for a broad spectrum of conditions. The strength and quantity of evidence supporting such uses is also widely variable in terms of quality and volume. As such, this LCD has specified only limited coverage outside of FDA-approved indications. Denials of claims related to this limited coverage may be appealed on a case-by-case basis.

Covered Indications for ESAs:

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

• Treatment of symptomatic anemia related to end-stage renal disease (ESRD) and stages IIIb, IV and V chronic kidney disease (CKD);

• Treatment of anemia induced by AZT (Zidovudine) used in HIV/AIDS therapy;

• Treatment of selected patients with anemia related to low prognostic risk myelodysplastic syndrome (MDS) and some myeloproliferative neoplasms;

• Peri-surgical adjuvant therapy for purposes of allogenic RBC transfusion reduction

The following causes of anemia should be considered, documented, and corrected before starting or continuing ESA therapy for any of the above covered indications:

• Iron deficiency;

• Underlying infection, inflammatory or malignant processes;

• Underlying hematological disease;

• Hemolysis;

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

• Blood loss-overt or occult;

• Aluminum intoxication;

• Osteitis fibrosis cystica; or

• Pure RBC aplasia

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 (chronic myeloid leukemia (CML), acute myeloid leukemia (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 EPO-type resistance due to neutralizing antibodies; and

• Anemia due to cancer treatment if patients have uncontrolled hypertension.

Non-ESRD ESA services are not considered reasonable and necessary within the context of other medical conditions for which resolution would be reasonably expected prior to starting or continuing ESA administration. Such conditions would include, but not be limited to iron/vitamin B12/folate deficiencies, G6PD deficiency, pyridoxine deficiency, various forms of hemolysis, hereditary spherocytosis, and pure red cell aplasias. The presence of any of these conditions would reduce the therapeutic impact and effectiveness of the ESA. Additionally, the presence of unspecified anemia suggests appropriate evaluation, to determine the nature of the treated anemia, has not been completed.

There are very rare patients whose cardiac, pulmonary or other medical conditions warrant the use of ESAs to maintain a Hb/HCT higher than the FDA target levels discussed in this LCD. Documentation to support this practice must be available upon request. (This instruction does not apply to ESA therapy for anemia related to cancer chemotherapy, which follows the rules mandated by the NCD 110.21.)

During therapy with an ESA, many patients will require supplemental iron. For these patients, stores of iron should be regularly monitored. Reference the related billing and coding article for further detail.

For patients receiving chemotherapy for non-myeloid malignancies, the goal of therapy is to avoid transfusions. ESA therapy will be reimbursed only when the Hb 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 Hb 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 Hb and/or HCT. However, judicious, appropriately timed dose adjustments are expected to prevent inappropriate increases in Hb and HCT levels.

The likelihood of anemia associated with EPO deficiency increases as renal failure progresses and the diseased kidneys are unable to produce sufficient amounts of EPO. The anemia of CKD should not be confused with the anemia of chronic disease. In the latter, inflammatory cytokines suppress the endogenous production of EPO and erythropoiesis directly. Measurable levels of circulating cytokines may be found in stable dialysis patients, but, in the absence of inflammation, do not adversely affect the action of ESAs. In patients with impaired renal function and a normochromic, normocytic anemia, it is rare for the serum EPO level to be elevated. Therefore, measurement of EPO levels in such patients is not likely to guide clinical decision making or ESA therapy.

ESAs may be administered by intravenous or subcutaneous routes. An intravenous route is generally recommended for an ESRD indication. Please see the related billing and coding article for details related to required modifier use on claims for ESA administration reporting.

Coverage Criteria: (Review the related billing and coding article for further detail regarding documentation)

• For ESRD patients on dialysis

• Diagnosis of ESRD

• Anemia of ESRD with a Hb

• Most recent creatinine within the past month prior to initiation or next dosing of ESA

• Use of an ESA that is FDA-approved for this indication

• For CKD patients NOT on dialysis

• Anemia of CKD with a Hb

• Most recent creatinine within the past month prior to initiation or next dosing of ESA

• Glomerular filtration rate (GFR) less than 45 mL/min/1.73 m 2

• Use of an ESA that is FDA-approved for this indication

For patients with non-myeloid malignancies with anemia due to chemotherapy

This LCD does not replace, modify or supersede existing Medicare applicable NCDs.

• Hb level immediately prior to initiation or maintenance of ESA treatment is

• Use of an ESA that is FDA-approved for this indication

• The starting dose for ESA treatment is the recommended FDA label starting dose.

• Maintenance of ESA therapy is the starting dose if the Hb level remains below 10 g/dL (or HCT is 1g/dL (HCT > 3%).

• For patients whose Hb rises

• Continued administration of the drug is not reasonable and necessary if there is a rapid rise in Hb > 1 g/dl (HCT >3%) over 2 weeks of treatment unless the Hb or HCT remains below or subsequently falls to

• ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.

• For patients with anemia related to AZT treatment for HIV/AIDS

• Anemia with Hb

• Use of an ESA that is FDA-approved for this indication

• An AZT dose 4200 mg/week

• An endogenous baseline pre-transfusion serum EPO (sEPO) level 500 mU/mL

• For Peri-surgical adjuvant therapy to reduce allogenic transfusion:

• Undergoing planned elective major hip or knee surgery

• Pre-surgical anemia with Hb between 10 and 13 g/dL at least 3 weeks prior to surgery

• Use of an ESA that is FDA-approved for this indication

• Not a candidate for autologous blood transfusion

• Expectation for peri-operative blood loss of 2 units or more

• Previous evaluation to ensure that the existing anemia is likely due to chronic disease rather than another reversible condition

In addition to the FDA-labeled indications above, ESAs are covered for the following off-label indications. At this time, there is no clearly established dosing regimen for off-label indications.

• For patients with symptomatic anemia related to very low, low or low score intermediate risk MDS

• Revised International Prognostic Scoring System (IPSS-R) score correlating to very low, low or a low score intermediate risk or IPSS score of low or intermediate-1 risk or WPSS of very low, low or intermediate risk*

• Pretreatment EPO levels of 500 or less

• Documented anemia-related symptoms such as fatigue, pallor, infection, bleeding or bruising or transfusion dependence

• Documentation of a reasonable expectancy of longer survival with a reduced need for transfusion support

• Diagnosis of MDS confirmed by bone marrow aspiration and/or biopsy report

• Anemia with Hb

Limitations Specified by CMS and/or This A/B MAC

See the related billing and coding article for further detail regarding necessary coding information.

* This A/B MAC will monitor new developing prognostic stratification systems, especially those anticipated to be based on mutational analysis and will adjust the billing and coding article as needed in this regard.

ESA Efficacy

The United States (U.S.) Normal HCT Trial by Besarab, et al. 1 was the first of a series of randomized controlled trials (RCTs) which cast serious doubt on the assumption that full anemia correction should be achieved in the majority of dialysis patients. A cohort of 1233 prevalent CKD5 HD patients with symptomatic heart failure or ischemic heart disease were allocated to either partial treatment of anemia or full anemia correction, using epoetin-alfa. The eventually achieved HCT values were 31% and 40%, respectively. In the normal HCT group treated with epoetin there were 183 deaths and 19 myocardial infarcts, producing 202 primary events, compared to 164 events (150 deaths, 14 myocardial infarcts) in the group in which anemia was partially corrected with epoetin. The risk ratio for the primary endpoint was 1.3 (95% confidence interval [CI] 0.9–1.9) which did not satisfy the pre-specified criterion for statistical significance (even though the nominal p value was 0.03) after adjusting for interim analyses. The trial was stopped early in a situation where the primary hypothesis was unlikely to be proven and the intervention being tested caused harm: 39% had vascular access clotting in the intervention arm and 29% in the control arm (P=0.001).

The double-blind Canada-Europe trial by Parfrey, et al. 2 of 596 incident CKD5 HD patients without symptomatic heart disease (18% with diabetic nephropathy) examined the question whether full anemia correction by epoetin-alfa in the group randomized to a Hb target of 13.5–14.5 g/dl, as compared to partial treatment of anemia in the group randomized to a Hb target of 9.5–11.5 g/dl, had a beneficial effect on left ventricular volume and mass index. The eventually achieved Hb values were 13.1 and 10.8 g/dl, respectively. There was no difference in left ventricular volume index or mass index between the 2 groups during this 96-week study. Of note, patients in the full anemia correction group had a significantly higher stroke incidence (secondary endpoint) than patients in the partial treatment correction group. However, the absolute numbers of patients with stroke were very small. As one might expect, the high Hb group received significantly fewer transfusions than the low Hb group, but extent of the benefit was modest: although 9% in the high Hb arm received at least 1 transfusion compared to 19% in the low Hb arm (P=0.004) during the 96-week study, the transfusions per patient per year was 0.3 in the high Hb arm and 0.7 in the low Hb arm (P

The U.S. CHOIR study by Singh, et al. 3 similarly aimed to show superiority of full anemia correction by ESA administration in terms of cardiovascular events and death, as compared to partial treatment of anemia, in patients with CKD not yet on dialysis. In this trial, 1432 CKD 3–4 patients (49% with diabetes) were randomized to Hb targets of 13.5 g/dl and 11.3 g/dl using epoetin alfa. Withdrawal rate was high: 17% due to renal replacement therapy and 21% for other reasons. The study was prematurely stopped after an interim analysis with a median study duration of 16 months. The achieved Hb values were 12.6 and 11.3 g/dl, respectively. At this time point, 125 patients in the complete anemia correction group but only 97 patients in the standard correction group had reached the primary combined cardiovascular endpoint (P=0.03). No differences in quality of life (QoL) were observed comparing the 2 groups; although, again, this finding must be interpreted cautiously because the study was open label.