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dosing information which is not superseded by this LCD.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)

  1. For ESRD patients on dialysis
    * Diagnosis of ESRD
    * Anemia of ESRD with a Hb < 10 gm/dL or a HCT < 30% at initiation of therapy
    * 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
  2. For CKD patients NOT on dialysis
    * Anemia of CKD with a Hb < 10 g/dL or a HCT < 30% at initiation of therapy
    * 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 m2
    * Use of an ESA that is FDA-approved for this indication
  3. 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 < 10 g/dL (or HCT is < 30%)
    * 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 < 30%) 4 weeks after initiation of therapy and the rise in Hb is > 1g/dL (HCT > 3%).
    * For patients whose Hb rises < 1g/dL (HCT rise < 3%) compared to pretreatment baseline over 4 weeks of treatment and whose Hb remains < 10 g/dL afterwards (or HCT < 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 Hb rises < 1g/dL (HCT rise < 3%) compared to pretreatment baseline by 8 weeks of treatment.
    * 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 < 10 g/dL or 30% respectively. Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.
    * ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.
  4. For patients with anemia related to AZT treatment for HIV/AIDS
    * Anemia with Hb < 10 g/dL or a HCT < 30% at initiation of therapy
    * 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
  5. 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.

  6.  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 < 10 g/dL or a HCT of < 30% at initiation of therapy. If after 2 months of treatment, there is no significant increase in Hb/HCT and/or a significant decrease in transfusion requirements, EPO analog therapy should be stopped. 

**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<0.0001).

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.

Finally, the international trial of darbepoetin-alfa in type 2 diabetes and
CKD (TREAT) by Pfeffer, et al.4 examined cardiovascular and kidney outcomes in
4038 CKD 3-4 patients. Of note, this is by far the largest ESA trial, and has
the best research design, as it was placebo-controlled and double-blinded.
Patients received either darbepoetin-alfa to achieve a Hb target of 13.0 g/dl
or placebo with rescue darbepoetin-alfa when the Hb concentration was < 9.0
g/dl. The achieved Hb values were 12.5 and 10.6 g/dl, respectively. The median
follow-up duration of the study was 29 months. There were no differences in
the 2 primary endpoints, which were the composite outcomes of death or a
cardiovascular event (first primary endpoint) and death or ESRD (second
primary endpoint). The hazard ratio for death/composite cardiovascular event
was 1.05 (95% CI 0.94-1.17), and for death or ESRD it was 1.06 (95% CI
0.96-1.19). However, there was a substantial increased risk of stroke (HR
1.92; 95% CI 1.38-2.68), although the absolute risk of stroke overall was
modest: 5.0% of the high Hb group had a stroke compared to 2.6% in the placebo
group (P< 0.001). The relative increase in risk of stroke was similar in
patients with and without a past history of stroke. As a result, the absolute
risk of stroke was substantial in the 11% of subjects with a prior history of
stroke; 12% in the darbepoetin group compared to 4% in the placebo group.
Venous thrombo-embolic events occurred significantly more frequently in the
high Hb arm (2.0%) compared to the placebo arm (1.1%, P=0.02). A signal that
normalization of Hb with darbepoetin may be harmful in patients with a history
of malignancy was reported following a post-hoc analysis: 14/188 (7.4%) of
those with a history of malignancy at baseline died from cancer in the
darbepoetin arm compared to 1/160 (0.6%) (P=0.002) in the placebo arm. A
statistically significant improvement in Functional Assessment of Cancer
Therapy-Fatigue (FACT-fatigue) scores was reported at week 26 favoring the
darbepoetin group, but the clinical significance of this was modest as 55% of
the high Hb group had a clinically important improvement in fatigue score
compared to 50% of the placebo group. Transfusions were prescribed relatively
frequently and more often in the placebo arm (25%) compared to the high Hb arm
(15%). The harm:benefit trade-off in TREAT was 1 stroke for 5 transfusions
prevented by the high Hb target. In a large subset of the TREAT patients, QoL
was assessed using FACT-fatigue, 36-Item Short Form Survey Instrument (SF-36),
and EQ-5D through 97 weeks. Compared to placebo, darbepoetin conferred a
consistent, but small improvement over 97 weeks in fatigue and overall QoL,
but none in energy and physical function.

**Lab Analysis in Renal Patients Treated with ESAs**

****

The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Anemia Guidelines-
Chapter 3 (Use of ESAs and other agents to treat anemia in CKD) 5 regarding
frequency of monitoring was reviewed. Recommendations 3.12.1-3.12.3 noted Hb
measurement at least monthly during initiation of ESAs. For maintenance
therapy in CKD non-dialysis patients, measurement is recommended at least
every 3 months and for CKD 5 dialysis patients, at least monthly. Other key
recommendations for ESA treatment included the following:

  * Address all correctable causes of anemia (including iron deficiency and inflammatory states) prior to initiation of ESA therapy. (Not Graded)
  * In initiating and maintaining ESA therapy, potential benefits of reducing blood transfusions and anemia-related symptoms must be balanced against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension). (1B)
  * Use of ESA therapy with great caution, if at all, in CKD patients with active malignancy, in particular when cure is the anticipated outcome (1B), __ a history of stroke __ (1B), or a history of malignancy (2C) _._

Fishbane and Spinowitz in the Core Curriculum 2018: Update on Anemia in ESRD
and Earlier Stages of CKD6 extensively review both the considerable frequency
and complexity of iron metabolism in CKD. Certainly before starting ESA
treatment, iron status should be optimized. After initiating ESA treatment,
the recommendation is made for weekly Hb testing until Hb stability and goals
are achieved. A reasonable goal of an increase of 1 g/dL within the first
month of treatment is noted. As Hb concentration increases, a large amount of
iron is transferred from storage tissues to the developing red cells and iron
deficiency is frequently induced. Since this may limit the effectiveness of
ESA treatment, these authors of this nephrology fellowship core education
curriculum, recommend monthly iron status testing during the initial ESA
phase.

Hsu, et al. (2001)7 set out to better delineate relationships between level of
renal function and magnitude of reduction in HCT. This study was a cross-
sectional one examining 12,055 (8495 women, 3560 men) adult patients with
outpatient medical records at Brigham and Women's Hospital. Racial
categorization for this population was ~ 45% white, 25% black, and 30% other.
Age averaged 50. Instances of apparent AKI were excluded. Since the anemia of
CKD is characterized by normocytic/normochromic RBCs, the analysis was also
limited to subjects with RBC parameters falling within normal reference
ranges. In this study, renal function was assessed in 2 ways: the Cockcroft-
Gault equation for estimated creatinine clearance (CrCl) and Modification of
Diet in Renal Disease (MDRD) formula for GFR estimation normalized to body
surface area. Results showed that HCT decreased progressively below estimated
CrCl 60 mL/min in men and 40 mL/min in women. Compared with male subjects who
had a CrCl > 80 mL/min, men with CrCl 60 mL/min had a 1% lower mean HCT, in
those with a CrCl 50-40 mL/min the mean HCT was 2.4% lower, in those with a
CrCl 40-30 mL/min the mean HCT was 3.7% lower, in those with a CrCl 30-20
mL/min the mean HCT was 3.5% lower, and in those with a CrCl _<_ 20 mL/min the
mean HCT reduction was 10% lower. For women, the HCT significantly decreased
starting at a CrCl of less than 40 mL/min. With a CrCl of 40-30 mL/min the
mean HCT was 1.7% lower, with a CrCl of 30-20 mL/min the mean HCT was 2.9%
lower, and at a CrCl _<_ 20 mL/min the mean HCT was 6.3% lower. All these
values had a P value < 0.05. These results were similar with a slightly
diminished gender difference when indexed to body size. Men with GFRs of 50-40
mL/min/1.73m2, 40-30 mL/min/1.73m2, 30-20 mL/min/1.73m2, and _<_ 20
mL/min/1.73m2 had mean HCTs that were lower by 2.0, 4.4, 5.3, and 9.4%
respectively (P < 0.05). Corresponding reductions in women with GFR 50-40
mL/min/1.73m2, 40-30 mL/min/1.73m2, 30-20 mL/min/1.73m2, and _<_ 20
mL/min/1.73m2 were 0.6, 1.6, 3.8, and 5.3% (P < 0.05). For the entirety of
this study, the results were similar if Hb was used instead of HCT. Further
stratified analysis did not reveal effect modification by race or age. The
analyses were limited by smaller numbers of patients in the lowest categories
of CrCl and GFR.

Hsu, et al.8 published a separate study the following year which set out to
study and quantify the relationship between reduced renal function and Hb
level, to assess the iron status of CKD patients, and to estimate the burden
of anemia related to CKD. The nationally representative Third National Health
and Nutrition Examination Survey (NHANES III) (1988-1994) data of 15,971
patients (8506 women and 7465 men) was utilized with the measurements of
creatinine, Hb, and iron stores analyzed. Older people, Mexican Americans and
African Americans were oversampled. A statistically significant decrease in Hb
was seen in men at CrCl _<_ 70 mL/min and in women starting at _<_ 50 mL/min.
At any given level, men had a larger decrease in Hb than women. It was clear
that a substantial number of patients with CKD did not have sufficient iron
stores to support erythropoiesis. In those patients with CrCl 20-30 mL/min,
46% of women and 19% of men had transferrin saturation levels < 20%. 47% of
women and 44% of men had serum ferritin levels < 100 ng/mL. With specific
regard to Hb and renal function, the authors divided the subjects into 8
categories of renal function by their Cockcroft-Gault calculated CrCl: > 80
mL/min, >70 to _<_ 80 mL/min, > 60 to _<_ 70 mL/min, 50 to _<_ 60 mL/min, 40
to _<_ 50 mL/min, 30 to _<_ 40 mL/min, 20 to _<_ 30 mL/min, and _<_ 20 mL/min.
Hb was examined as the dependent variable in a general linear model. Three
different thresholds were used to define anemia: Hb < 10, < 11, and < 12 g/dL.
The likelihood of anemia at different levels of renal function was then
linearly modeled. The following CrCl characteristics were noted:

The following table notes the predicted change in mean Hb level by renal
function*

**CrCl** | **Women** | **Men**  
---|---|---  
Change in Hemoglobin (g/dl) | _P  _Value | Change in Hemoglobin (g/dl) | _P_
Value  
CrCl > 80 ml/min | Reference |   | Reference |  
80 > CrCl > 70 ml/min | -0.0 (-0.1, 0.1) | 0.68 | -0.1 (-0.2, 0.0) | 0.16  
70 > CrCl > 60 ml/min | -0.1 (-0.2, 0.0) | 0.08 | -0.2 (-0.3, -0.0) | 0.02  
60 > CrCl > 50 ml/min | -0.1 (-0.2, 0.1) | 0.36 | -0.3 (-0.5, -0.1) | 0.007  
50 > CrCl > 40 ml/min | -0.2 (-0.3, -0.0) | 0.01 | -0.4 (-0.6, -0.2) | 0.0005  
40 > CrCl > 30 ml/min | -0.4 (-0.6, -0.2) | <0.0001 | -0.8 (-1.1, -0.6) |
<0.0001  
30 > CrCl > 20 ml/min | -1.0 (-1.2, -0.7) | <0.0001 | -1.4 (-2.1, -0.6) |
0.0005  
CrCl < 20 ml/min | -2.3 (-2.8, -1.9) | <0.0001 | -2.7 (-3.8, -1.6) | <0.0001  
  
*Adjusted for age and race/ethnicity; values in parentheses are 95% confidence intervals for parameter estimates. CrCl, creatinine clearance.



And in Table 4 of the study:

_Table 4._ Predicted likelihood (%) of anemia by renal function in select
demographic subgroups (multivariate analysis)

**Demographic Subgroup** | **Women** | **Men**  
---|---|---  
Likelihood (5) of Hemoglobin Level: | Likelihood (5) of Hemoglobin Level:  
<10 g/dl | <11 g/dl | <12 g/dl | <10 g/dl | <11 g/dl | <12 g/dl  
**Non-Hispanic white**  
age 31-40 | CrCl > 80 ml/min | 2 | 4 | 11 | <1 | <1 | 1  
50 > CrCl > 40 ml/min | 3 | 6 | 15 | <1 | 1 | 2  
30 > CrCl > 20 ml/min | 10 | 18 | 34 | 2 | 3 | 6  
age 61-70 | CrCl > 80 ml/min | 1 | 2 | 7 | 1 | 1 | 3  
50 > CrCl > 40 ml/min | 1 | 3 | 10 | 1 | 2 | 4  
30 > CrCl > 20 ml/min | 6 | 12 | 25 | 4 | 7 | 12  
**Non-Hispanic black**  
age 31-40 | CrCl > 80 ml/min | 8 | 15 | 30 | 1 | 2 | 5  
50 > CrCl > 40 ml/min | 12 | 21 | 38 | 2 | 4 | 7  
30 > CrCl > 20 ml/min | 29 | 42 | 63 | 7 | 10 | 17  
age 61-70 | CrCl > 80 ml/min | 5 | 10 | 22 | 3 | 5 | 9  
50 > CrCl > 40 ml/min | 7 | 14 | 28 | 5 | 8 | 13  
30 > CrCl > 20 ml/min | 20 | 32 | 52 | 13 | 18 | 28  
**Mexican-American**  
age 31-40 | CrCl > 80 ml/min | 3 | 6 | 16 | <1 | <1 | 1  
50 > CrCl > 40 ml/min | 5 | 10 | 21 | <1 | 1 | 2  
30 > CrCl > 20 ml/min | 15 | 24 | 43 | 2 | 3 | 5  
age 61-70 | CrCl > 80 ml/min | 2 | 4 | 10 | 1 | 1 | 2  
50 > CrCl > 40 ml/min | 3 | 6 | 14 | 1 | 2 | 4  
30 > CrCl > 20 ml/min | 9 | 17 | 32 | 4 | 6 | 10  
  
* CrCl, creatinine clearance.



Compared with subjects with a CrCl > 80mL/min, the decrease in Hb for subjects
with CrCl of 20-30 mL/min was 1 g/dL in women and 1.4 g/dL in men.

NKF-K/DOQI Clinical Practice Guidelines5 recommend an evaluation of anemia
among patients with CKD when the Hb is < 11g/dL among premenopausal women and
< 12 g/dL among adult men and postmenopausal women. ESA treatment is
recommended, whether dialysis-dependent or not, to achieve a target Hb of
11-12 g/dL.

El-Achkar, et al.10 evaluated Kidney Early Evaluation Program (KEEP) data in a
cross-sectional, community-based study to determine the prevalence of anemia
by level of kidney function and by diabetes status. While the latter
connection was the focus, the stratified data in this study specific to
estimated GFR correlation with Hb levels was reviewed for purposes of this
LCD. GFR was calculated using serum creatinine values and categorized as _>_
90, 60-89, 30-59, and < 30 mL/min/1.73m2. Anemia was defined as Hb < 12 g/dL
in men and women older than 50, and < 11 g/dL in women _<_ 50\. 5380 subjects
were included with mean age of 52.5, race of 43% black/36% white/11%
Hispanic/11% other, and 33% male/67% female. 814 subjects were staged CKD 3.
Our attention was drawn to the data detail table demonstrating the
distribution of anemia prevalence by K/DOQI categories and 10 mL/min/1.73m2
increments of estimated GFR. 40.4% of diabetics in GFR category 31-40 had
anemia, 23.5% of diabetics in GFR 41-50 had anemia, and 16.2% in GFR 51-60 had
anemia. For non-diabetic subjects, 20.8% of GFR 31-40 were anemic, 10.1% of
GFR 41-50 were anemic and 4.8% of GFR 51-60 were anemic. The table detailing
mean Hb for the 10 mL/min/1.73m2 increments of estimated GRF showed the
following results for CKD stage 3:

**EGFR** | **Hb for Men w/ DM** | **Hb for Men w/o DM** | **Hb for Women w/
DM** | **Hb for Women w/o DM**  
---|---|---|---|---  
51-60 | 13.9 (P=0.006) | 14.7 | 13.1 | 13.5  
41-50 | 13.3 (P<0.001) | 14.3 | 12.9 | 13.2  
31-40 | 12.2 (P<0.001) | 14.2 | 12.4 | 13.0  
  
In a much older, but still relevant study, Radtke, et al.11 studied 117
patients not in need of dialysis. Five subgroups were created for CrCl between
2-9, 10-19, 20-29, and 30-39 and 40-90 mL/min/1.73m2. With CrCl plotted
against the corresponding HCT, renal anemia was clearly manifest in patients
with a CrCl below 40 mL/min/1.73m2. In the range between 2 and 40
mL/min/1.73m2, CrCl and HCT were highly significantly correlated (P < 0.0001)
whereas there was no significant correlation existing within the range between
41 and 90 mL/min/1.73m2.

**Myelodysplastic Syndrome (MDS) and ESA Use**

****

ESAs including EPO, recombinant human EPO and darbepoetin have been evaluated
in the treatment of symptomatic anemia in patients with MDS. Studies in mostly
lower risk MDS patients have demonstrated response rates of 40% and 60% in
initial trials. Clinical trial results have noted overall response rates to
darbepoetin similar to or possibly higher than epoetin. These improved
response rates may be related to dosage used (150-300 mcg SQ per week) or to
the fact that better-risk patients were enrolled. Predictive features for a
better ESA response rate have included low basal serum erythropoietin (sEpo)
levels, low percentages of marrow blasts, and fewer prior blood transfusions.

A study from the French myelodysplasia group12 analyzed ESA outcomes (epoetin
or darbepoetin), with or without growth colony stimulating factor (G-CSF), in
403 MDS patients with anemia. Based on the International Work Group (IWG) 2000
criteria, the hematologic response rate was 62% with a median duration of 20
months. Based on the IWG 2006 criteria, the hematologic response rate was 50%
for a median duration of 24 months. IPSS low- or intermediate-1 (int-1) risk
was associated with significantly higher response rates and longer response
durations. In comparing outcomes for low vs. int-1 risk subsets with anemia
between those treated (N=284) and a historical cohort of untreated patients
(N=225), multivariate analysis showed a significant association between
treatment with ESAs and survival outcomes.

A phase II study13 evaluated darbepoetin (given Q 2 weeks for 12 weeks), with
or without G-CSF (added at 12 weeks in non-responders). The lower risk IPSS
group with anemia and sEpo levels < 500 mU/mL had hematologic response rates
of 48% at 12 weeks and 56% at 24 weeks. This study also showed QoL
improvements among patients with responding disease.

The data is more limited regarding the effectiveness of ESAs in the treatment
of anemia in lower-risk patients with del(5q). Retrospective studies from the
French MDS group reported hematologic response rates between 46% and 64% with
median response duration of 11 months (mean duration, 13-14 months) in
patients with del(5q) treated with ESAs, with or without G-CSF.12 Duration of
response in these patients was significantly decreased compared to patients
without del(5q) (mean duration, 25-27 months). Multivariate analysis showed
del(5q) was a significant predictor of a shorter response duration with
treatment per the French group.

The 2021 NCCN guidelines14 call attention to the fact that the FDA alerts
issued in 2007 and 2008 related to observed increased mortality and possible
tumor promotion and thromboembolic events did not involve analysis of MDS
patients receiving ESAs. The guidelines note that ESAs have been used safely
in large numbers of adult MDS patients and have an important role in
improvement of anemia related symptoms related to MDS, often with a decrease
in blood transfusion requirements. Studies assessing the long-term use of EPO
with or without G-CSF in MDS patients have not shown a negative impact on
survival or AML evolution when compared to randomized controls or historical
controls.

Jadersten, et al.15 reported improved survival in low-risk MDS patients with
low transfusion need after treatment with ESAs. The French group study showed
improved survival and decreased AML progression of IPSS low or int-1 risk
patients after EPO treatment, with or without G-CSF, compared to the
historical control International Myelodysplasia Risk Analysis Workshop (IMRAW)
database patients. This is further evidence of lack of a negative impact of
ESAs in the treatment of MDS. The NCCN panel has thus recommended the use of
ESAs in the management of symptomatic anemia in MDS patients, with a target Hb
range of 10-12 g/dL. CMS, in constructing the NCD on the use of ESAs in non-
renal disease specifically narrowed the scope of the NCD to cancer and related
neoplastic conditions which excluded MDS as it is defined as a premalignant
condition rather than an oncologic disease. Thus, local Medicare contractors
may continue to make reasonable and necessary determinations on the use of
ESAs in MDS and MPN (myeloproliferative neoplasms).

The NCCN Guidelines Panel14 recommends lenalidomide be considered for patients
with symptomatically anemic non-del(5q) MDS with anemia that did not respond
to initial therapy.

The NCCN Guidelines Panel14 recommends therapeutic options for lower-risk
patients based on stratification centered on del(5q) status. Patients with
del(5q) abnormalities alone or with 1 other cytogenic abnormality, except
those involving chromosome 7, and symptomatic anemia should receive
lenalidomide. An alternative option to lenalidomide in these patients includes
an initial trial of ESAs only when sEpo levels are < 500 mU/mL. In patients
without del(5q) status, alone or with 1 other cytogenetic abnormality and with
symptomatic anemia, ESA treatment is recommended if the sEpo level is less
than or equal to 500 mU/mL, with or without G-CSF. Patients with normal
cytogenetics, < 15% ring sideroblasts and sEpo levels _<_ 500 mU/mL may
respond to ESAs if relatively high doses are administered. The EPO dose
required is 40,000 to 60,000 SC units 1-2 times per week. Darbepoetin should
be given SQ at a dose of 150-300 mcg every other week. Erythroid responses
generally are evident within 6-8 weeks.

The NCCN Guidelines14 are clear that iron repletion must be verified before
instituting ESA therapy.

**Prognostic Stratification in MDS**

****

While there are several risk-based stratifications available, the NCCN
Guidelines13 preference for IPSS-R has been noted. The IPSS-R system was
derived from analysis of a large dataset from multiple international
institutions. It refines the original IPSS by providing more detail for
cytogenetic subgroups, detailing subgroups within the "marrow blasts < 5%"
group and providing more precision regarding cutoffs for the cytopenias. Other
parameters including age, performance status, serum ferritin, LDH and beta-2
microglobulin provide additional prognostic information for survival outcomes.
The predictive value of the IPSS-R has been validated in several independent
studies based on registration data reviewed by the NCCN workgroup. Other
prognostic stratification systems may be used (e.g., IPSS or WPSS) but ESA
treatment is generally most effective for patients with very low, low or low
intermediate prognostic risk.

The NCCN Guidelines13 reference a multiregional study of MDS patient registry
data from Italy (N=646) Messa, et al. (2012) in which the predictive power of
the IPSS-R was found to be greater than the IPSS, WPSS and refined WPSS for
OS, AML evolution and progression free survival. The Guidelines also reference
the Spanish Group of MDS (2012) who performed a retrospective analysis of data
from lower-risk MDS (IPSS low or int-1) patients (N=2410) in Spain in which
the application of the IPSS-R system appeared to provide prognostic refinement
within the IPSS int-1 group with a large proportion of patients (511 of 1096)
identified as having poor prognosis (median survival of 21-30 months). IPSS-R
performed better in this regard than the refined WPSS (47% vs. 17%). Per the
Guidelines, data from the MDS Clinical Research Consortium also demonstrated
improved prognostic value of the IPSS-R in 370 AML transforming MDS patients
as compared to the IPPS, the global MD Anderson risk model or the transforming
MDS MD Anderson models.

The evidence reviewed and the stringent nature of FDA oversight over decades
certainly support the FDA label indications16,17,18 and warnings in place for
the various ESAs. The core of this policy regarding ESRD and CKD, presurgical,
and AZT treatment applications rests upon treatment in concordance with FDA
labeling.

NCD 110.21 is the source of detail for the use of ESAs in cancer and related
neoplastic conditions.

The literature covering the use of ESAs for anemia of chronic disease is
mixed. Most reported studies are small, and positive effects must be balanced
with newer data that shows the attendant potential thrombogenic and
hypertensive risk. Additionally, some patients given ESAs with anemia of
cancer have shorter survival times. Until further publications show clear
benefit, ESAs for anemia of chronic diseases will not be covered.

For the delineation of appropriate coverage criteria related to use of ESAs in
ESRD and CKD (specifically stages 3b or worse), the referenced 2002 Hsu study
was viewed as compelling. The limitations of this study were realized and
included use of calculated CrCl rather than actual measurements of CrCl or
GFR. It was understood that this was a cross-sectional study and thus not
viewing Hb changes over time. The oversampling of some patients at higher
risk, such as the elderly and minorities, was viewed as potentially very
representative of a Medicare demographic. A representative number of subjects
in the stage II and III range of CKD was felt to be present and provided solid
data for This A/B MAC evidence review. More than any other study we
identified, this one separated renal function into much smaller delineated
groups for purposes of gauging a reasonable cut-off value to support a
reasonable and necessary standard for ESA use in CKD that truly captures a
population who will most likely benefit while also being exposed to the least
potential harm. Our review of the stratified CrCl categorizations and the
positive correlating relationship of worsening renal function to worsening
anemia led to this A/B MAC's conclusion that coverage confined to CKD stages
3b and worse would amply and logically allow for coverage of reasonable and
necessary circumstances.

The El-Achkar, et al. study, while specifically designed to analyze the
influence of diabetes impact on anemia in CKD patients, also identified a
significant correlation between HCT and CrCl occurring below 40 mL/min/1.73m2
in Radtke, et al. and below eGFRs of 50 mL/min/1.73m2 in men and women in the
Hsu, et al. studies.

For the purposes of this LCD, this A/B MAC has considerable confidence in the
ESA coverage requirements with regard to stage of CKD and Hb/HCT parameters.
Iron storage monitoring information within specialty society guidelines (such
as NKF-K/DOQI) is confined to a monthly frequency during the initiation phase
of ESAs. This LCD establishes monitoring of iron stores during ESA maintenance
therapy at least every 3 months as a thoughtful reasonable standard.

Again, detailed coding and billing instructions can be found in the companion
local coverage article for this determination.

For the single off-label use of ESAs in the treatment of symptomatic anemia
related to very low, low and low scored intermediate risk MDS specified in
this LCD, per CMS-issued discretion provided to the MAC, the NCCN Guidelines
were used as the foundation to this LCD.

Since more accurate risk stratification by the IPSS-R compared to the IPSS and
WPSS has been demonstrated, the IPSS-R categorization is preferred as per NCCN
guidelines. Specifically, analysis of patients in the International Working
Group for the Prognosis of MDS database, which generated the IPSS-R, has
indicated that optimal prognostic separation of lower vs. higher risk patients
was obtained based on a dichotomization centered on 3.5 scoring points of the
IPSS-R raw score. However, as noted above other prognostic systems may be
utilized including those that are developed based on mutational analysis. The
evidence basis for use of ESAs in MDS currently best supports coverage when
risk is very low, low or low intermediate.