Response to Comments: Erythropoiesis Stimulating Agents

Submitting general comments from some of our physicians regarding the proposed policy DL39237, Erythropoiesis Stimulating Agents

1. Regarding the statement in the policy: "No ESA should be given within the context of uncontrolled hypertension," we acknowledge the need and purpose to monitor and manage but hypertension is relative and should be up to the physician's discretion. Hypertension is common and benefits of ESA in many cases outweigh the risk in this patient population. If hypertension is to be incorporated there should be more clear definition of uncontrolled with parameters.

2. Regarding the statement in the policy: "No ESA should be used to replace red blood cell transfusions in patient who need immediate urgent correction of anemia,” we acknowledge this is not the purpose but considerations should be made for physician discretion as ESA treatment could be making patient receive 2-4 less transfusions which is significant. Especially important with blood shortages.

3. MDS coverage currently excludes use of D46.9 Myelodysplastic syndrome, unspecified. We understand the need to be as specific as possible but for MDS an unspecified diagnosis is reasonable. For example, the high risk MDS patient with only anemia, frail, and elderly this patient is appropriate for ESA support without the ESA option, chemotherapy is next option which may be not best considering the overall patient.

1. ESA use within the context of uncontrolled hypertension

FDA prescribing information for all approved ESA products express contraindications to ESA use in the setting of uncontrolled hypertension as hypertensive encephalopathy and seizures have been reported in patients with CKD receiving such products. Per the FDA product labeling for all approved ESA products, reduction or withholding of ESAs when blood pressure control is difficult is the safest approach for patients. Intensified and improved blood pressure control is a reasonable expectation prior to initiating or continuing ESA therapy. The analysis of evidence in DL 39327 clearly states that ESA use should be accomplished in concordance with FDA labeling. We believe that position remains appropriate although your comments are certainly appreciated. Placing strict parameters on the definition of uncontrolled hypertension would be unduly limiting to providers wishing to exercise clinical judgment.

2. ESA use to replace red blood cell transfusion in patients needing urgent correction of anemia

FDA prescribing information for all approved ESA products note a limitation of use (non-indication) for ESAs as a substitute for red blood cells transfusions in patients who require immediate correction of anemia. Transfusions are the appropriate response to such clinical situations since increased hemoglobin levels are not generally observed for 2-6 weeks after treatment with any ESA. ESAs may obviate the need for maintenance transfusions but are not a substitute for emergent transfusion when clinically indicated. The analysis of evidence in DL 39327 clearly states that ESA use should be accomplished in concordance with FDA labeling. We believe that position remains appropriate although your comments are certainly appreciated. 

3. Myelodysplastic syndrome coverage excluding the use of ICD-10 code D46.9, Myelodysplastic syndrome, unspecified 

ICD-10 CM diagnosis codes provide multiple options to accurately record the nature of myelodysplastic syndrome (MDS) for a given patient. These codes provide for sufficient accuracy and specificity for the majority of patients based on bone marrow biopsy findings which led to the current diagnosis of MDS. In the event of a truly unusual circumstance in which no specificity is possible for a patient’s MDS, this proposed policy allows for appropriate appeal of any denial perceived to have not taken all clinical circumstances into account.

I participated in the 1000 call this morning regarding the ESA draft LCD and LCA. I am writing to share some questions and comments from my organization.

1) DL39237, Erythropoiesis Stimulating Agents Covered Indications for ESAs 2^nd bullet: Treatment of symptomatic anemia related to ESRD and Stages IIIb, IV and V CKD

• Will code N18.3 (CKD, unspecified) be accepted?
• If documentation does not specify IIIb, will PGBA accept labs that meet IIIb parameters with the N18.3 coded? If so, will this have to go to 2^nd level/reconsideration?

2) DL39237, Erythropoiesis Stimulating Agents Covered Indications for ESAs Chronic disease indications are not described/included:

• Rheumatoid Arthritis
• Lupus
• Ulcerative Colitis
• Crohn’s Disease

3) DL39237, Erythropoiesis Stimulating Agents Covered Indications for ESAs 4^th bullet: Treatment of selected patients with anemia related to low prognostic risk myelodysplastic syndrome & some myeloproliferative neoplasms

• Does this include myelodysplasia? If so, what codes?
• Does this include Myelofibrosis (D75.81)?

4) Coverage Criteria-DL39237, Erythropoiesis Stimulating Agents Covered Indications for ESAs for ESRD patient on dialysis 3^rd bullet: Most recent creatinine within the past month prior to initiation or next dosing of ESA

• Is there a parameter requirement for the creatinine value?

5) Coverage Criteria-DL39237, Erythropoiesis Stimulating Agents Covered Indications for ESAs for CKD patients NOT on dialysis 2^nd bullet: Most recent creatinine within the past month prior to initiation or next dosing of ESA

• Is there a parameter requirement for the creatinine value?

6) Coverage Criteria-DL39237, Erythropoiesis Stimulating Agents Covered Indications for ESAs for CKD patients NOT on dialysis 3^rd bullet GFR less than 45 mL/min/1.73m²

• Why 45? Other contractors use 60.

7) DA58982, Billing and Coding: Erythropoiesis Stimulating Agents

• Use of modifiers JA, JB, JE- I believe this a new requirement; will the absence of one of these cause a denial?

8) DA58982, Billing and Coding: Erythropoiesis Stimulating Agents

Group 5 Codes:

• D46.9 (MDS, unspecified) is not included
• Myelofibrosis codes are not included

9) DA58982, Billing and Coding: Erythropoiesis Stimulating Agents

• Codes for chronic disease indications are not included-rheumatoid arthritis, lupus, ulcerative colitis, Crohn’s disease

Thank you for your time and the opportunity to provide feedback.

1) Stage III CKD and unspecified CKD ICD-10 code use

“Unspecified” ICD-10 codes should be used in limited circumstances, when neither the diagnostic statement nor the actual documentation provides enough information to allow for more specific diagnosis coding. Unspecified codes that lead to coverage issues should be pre-emptively managed with appropriate clinical documentation clarification processes and/or practitioner education. Per the 2022 ICD-10-CM Official Guidelines for Coding and Reporting preamble, “A joint effort between the healthcare provider and the coder is essential to achieve complete and accurate documentation, code assignment, and reporting of diagnoses and procedures. The importance of consistent, complete documentation in the medical record cannot be overemphasized. Without such documentation accurate coding cannot be achieved.” Accurate codes are the responsibility of the provider submitting the claim. Palmetto GBA cannot be responsible for interpretation of lab results and the associated diagnosis coding.

2) Chronic disease indications

This proposed policy does not address the role of ESA treatment in anemia of chronic disease settings. The analysis of evidence in DL 39327 specifically addresses the substance of this comment insofar as our belief that the literature related to the use of ESAs for anemia of chronic disease is mixed in terms of results and overall quality of the available evidence. Most reported studies regarding ESA use in various chronic diseases is hampered by low subject number. Also, any demonstrated positive effects still have to be balanced by the potential for thrombogenic and/or hypertensive risk. We believe that anemia of chronic disease is multifactorial and too complex to allow for broad coverage of ESA therapy at the current time. Until further publications show clear benefit, ESAs solely for anemia of chronic disease will not be covered. Denials of claims related to limited coverage may be appealed on a case by case basis.

3) Treatment of selected patients with anemia related to low prognostic risk myelodysplastic syndrome & some myeloproliferative neoplasms

Please see the proposed companion billing and coding article, DA 58982 for details regarding ICD-10 codes for very low, low and low scored intermediate risk myelodysplastic syndrome which will now be considered for ESA treatment coverage if symptomatic anemia is present and documentation is present to support reasonable and necessary use. The commenter asked about inclusion of diagnosis code D75.81 Myelofibrosis for coverage as associated with secondary effects of disease. It was our intent to cover ESA therapy for symptomatic anemia associated with myeloproliferative neoplasms driven by secondary myelofibrosis. This circumstance would indeed involve coding of D75.81 and not D47.4 as originally noted. This change has been made to the billing and coding article within the descriptive narrative and the Group 5 codes. Thank you for this comment.

4) ESRD on dialysis- most recent creatinine within the past month prior to initiation or next dosing of ESA

For both CKD and ESRD patients, Palmetto GBA believes it is reasonable to have a reasonably up to date serum creatinine level to inform the payer as to the severity of potential renal failure issues. It is one element, but certainly an applicable one. Clinical circumstances can change, even in ESRD, and a creatinine measure within the prior one month is neither burdensome nor redundant. Lab values help establish a reasonable and necessary foundation for all treatment provided to the beneficiary. No specific serum creatinine value can be expected or predicted and no specific parameters are set.

5) CKD not on dialysis- most recent creatinine within the past month prior to initiation or next dosing of ESA

See response 4 above-same principle applies.

6) CKD patients not on dialysis-GFR coverage indication

At GFRs of 45 or greater, it is exceedingly unlikely that ESAs are needed due to symptomatic anemia solely driven by chronic renal disease. An exception might be a case of rapidly progressive glomerular issues in which the renal pathology is much more severe than biochemical indices might suggest. Should this scenario seem pertinent, and in the event of a denial that is felt by the provider to be unwarranted, the appeals process is always available. Otherwise, the decision to provide coverage for ESA use in symptomatic anemia with Hb < 10 for CKD patients with estimated GFRs < 45 is based upon the evidence review as outlined in the LCD and fully supported by various subject matter experts and Palmetto.

7) Billing and Coding Article-Use of modifiers for route of administration

The use of modifiers to demonstrate route of administration is not a new requirement. Since January 1, 2008, Medicare systems have been instructed to return to the provider all non-ESRD ESA claims containing ESA HCPCS codes without one of the following modifiers on the same line with the ESA HCPCS: EA, EB or EC. Per the Medicare Claims Processing Manual, Chapter 8, Section 60.4.2, after January 1, 2012, all facilities billing for injections of ESA for ESRD beneficiaries must include the modifier JA on the claim to indicate an intravenous administration or modifier JB to indicate a subcutaneous administration. Without these modifiers, the claims will be returned to the provider for correction. Also effective July 1, 2013 providers must identify when a drug is administered via the dialysate by appending the modifier JE.

8) Billing and Coding Article-Group 5 Codes

This comment has already been addressed. Please see Response 1, #3 above. Also please review #3 in this Response 2.

9) Billing and Coding Article-ICD-10 diagnosis codes for chronic disease indications

This comment has already been addressed. Please see this Response 2, #2 above.

We are writing to provide comments in response to Palmetto GBA’s Proposed Local Coverage Determination for Erythropoiesis Stimulating Agents (ESAs). While we are supportive of efforts to provide specificity with diagnosis codes associated with the appropriate utilization of ESAs, there is concern that coverage of ESA usage in Chronic Kidney Disease (CKD), End-Stage Renal Disease (ESRD), and Myelodysplastic Syndrome (MDS) may be particularly exclusionary given the existing evidence.

I. Include coverage of CKD Stage 3a and CKD Stage 3, Unspecified (ICD-10 Codes N18.31 and N18.30)

Anemia is common among non-dialysis CKD patients, as is the corresponding treatment with ESAs. Current practice guidelines consider ESA use when the hemoglobin (Hb) level is below 10 g/dL.¹ The prevalence of anemia increases with progressive CKD. The cited 2002 study by Hsu and colleagues demonstrates that the prevalence of anemia increases as creatinine clearance (CrCl) declines. Two limitations of the study were its cross-sectional design and the usage of a calculated CrCl, rather than measured GFR.² We find this problematic in concluding that a GFR cutoff point of 45 mL/min/1.73 m² is definitive criteria for the indication of ESAs. Further stated by the authors, the study does not examine the benefits and cost-effectiveness of treating anemia with ESAs in subjects with mild-to-moderate Chronic Renal Insufficiency.² Given the presented concerns, we emphasize that treatment of anemia with ESAs among non- dialysis patients with CKD should be individualized, and coverage be expanded to include CKD Stage 3a (ICD-10 Code N18.31) and thus CKD Stage 3, Unspecified (ICD-10 Code N18.30) as well.

For patients with CKD who have a Hb <10 g/dL, a transferrin saturation (TSAT) greater than 20 percent and ferritin greater than 200 ng/mL, the administration of ESAs has substantially reduced the need for red cell transfusions with an associated decrease in risk for transfusion- related complications.¹ Provided that all other root-causes of anemia have been investigated, we believe a population of patients with CKD Stage 3 is present that will not be covered and would benefit from ESA use. Ultimately, restriction of use in this population may lead to suffered quality of life and/or need for blood transfusion.

II. Remove requirement for serum creatinine within the prior month for dosing of ESAs in CKD and ESRD

Aside from staging of CKD or ESRD, additional monthly serum creatinine labs provide little utility for justification of ESA use. Requiring more creatinine measurements than clinically necessary merely to satisfy an LCD requirement for creatinine values, subjects already anemic patients to greater phlebotomy-related blood loss and unnecessary needle sticks. Further, serum creatinine labs in ESRD should never be required as creatinine is not reflective of kidney function in patients who have been diagnosed with ESRD. Thus, we find the criteria, “most recent creatinine within the past month prior to initiation or next dosing of ESA”, to be unnecessarily restrictive in respect to ESAs, which are dosed on a weekly-to-monthly basis. The requisite stage of CKD is already required by the LCD and is a reasonable and sufficient program integrity safeguard. Unnecessary monthly creatinine measurements harm the beneficiary and create administrative burden without improving program integrity. 

III. Include coverage of MDS, Unspecified (ICD-10 Code D46.9)

The current World Health Organization (WHO) classification of MDS includes unclassifiable MDS (MDS-U), as some MDS has always been unclassifiable by any classification system.³ MDS-U does not have an alphabetical index mapping to a specific ICD-10-CM diagnosis code. Depending on whether the coder feels “unclassifiable” should be considered “specified” or “unspecified,” either D46.Z or D46.9 will be used. In reality, practitioners who are not hematologists will refer to this as “MDS” or “MDS NOS” and it will be coded as D46.9. D46.9 should be an allowable MDS diagnosis code as it actually is the most specific diagnosis available in ICD-10-CM for some MDS patients. 

IV. Remove requirement for IPSS-R

The Revised International Prognostic Scoring System (IPSS-R) should not be required for patients with MDS, as it is not universally used. The International Prognosis Scoring System (IPSS) is still in use and according to Garcia-Manero and colleagues, remains an accepted scoring system.⁴ In addition, both IPSS-R and IPSS are most useful at the time of initial diagnosis and are not well-validated as dynamic predictors of prognosis in the same patient over time.

Of equal concern is that the WHO working group and the MDS field are moving toward mutational analysis based prognostic tools rather than cytogenetic and clinically based models like IPSS and IPSS-R. Prognostic models that incorporate mutational analysis are likely to supplant IPSS and IPSS-R in the near future.

While ESA effectiveness data is most robust in low to intermediate risk MDS, the three other Medicare Administrative Contractors (MACs) with ESA LCDs do not require MDS documentation of low to intermediate risk. While language that ESAs are most commonly utilized for low to intermediate risk MDS may be appropriate context to include in the LCD, we feel that blanket noncoverage for higher risk MDS is unnecessarily restrictive and hinders personalized care. Further, for the reasons mentioned above, if coverage is decided to be contingent on a determination of risk, it should be based on a clinician’s assessment of the MDS prognostic risk and not solely on the IPSS-R given the lack of universal usage and likelihood to be supplanted in the near future.

Lastly, patients with MDS in underserved communities are not always cared for by hematologists, especially if the goals of care are primarily supportive and chemotherapy is not desired. LCD language that links ESA coverage to very specific documentation of MDS subtype or a highly technical prognostic model may have the unintended consequence of limiting access to ESAs in patients who can benefit from them. 

V. Remove documentation requirements for reasonable expectancy of longer survival with a reduced need for transfusion support

The documentation requirement for “reasonable expectancy of longer survival with a reduced need for transfusion support” for patients with MDS should be removed because the former is not proven with ESAs and the latter is implicit and such narrow documentation should not be used as a condition of payment. The two survival studies cited were both retrospective cohort studies of limited size and confounded by co-administration of G-CSF.^5,6

VI. Include coverage of antineoplastic chemotherapy induced pancytopenia (ICD-10 Code D61.810) or antineoplastic chemotherapy induced anemia (ICD-10 Code D64.81) for covered malignancies in conjunction with a malignancy code.

The current proposal only includes antineoplastic chemotherapy induced anemia (D64.81) and there exist clinically appropriate situations where antineoplastic chemotherapy induced pancytopenia (D61.810) would instead be coded alongside one of the listed malignancies, and still be appropriate for ESA usage.

Thank you for the opportunity to provide comments. We applaud the efforts undertaken to define the appropriate diagnosis codes and documentation that should be recorded in association with ESA provision, but urge Palmetto GBA to provide consideration to the patients described above who can benefit from ESAs but fall outside of the currently proposed coverage policy, so that individualized and equitable care may still be provided.

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¹ Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825-830.

² Hsu CY, McCulloch CE, Curhan GC. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol. 2002;13(2):504-510.

³ Hong M, He G. The 2016 Revision to the World Health Organization Classification of Myelodysplastic Syndromes. J Transl Int Med. 2017;5(3):139-143.

⁴ Garcia-Manero G, Chien KS, Montalban-Bravo G. Myelodysplastic syndromes: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2020;95(11):1399-1420.

⁵ Park S, Grabar S, Kelaidi C, et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood. 2008;111(2):574- 582.

⁶ Jadersten M, Malcovati L, Dybedal I, et al. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. 2008;26(21):3607-3613.

I. Coverage of CKD Stage 3a and CKD Stage 3, Unspecified (ICD-10 Codes 31 and N18.30)

Thank you for your comment. Please see Response 2, #6 above. As with all coverage issues, evidence is reviewed to help define any limitations on coverage. There really is no possibility that estimated GFR “cut-offs” can be precise particularly within any heterogenous patient demographic with varying co-morbid conditions. We are unaware of any study that has demonstrated a health benefit and cost effectiveness analysis precisely weighed against the known adverse health outcomes associated with ESAs in a CKD population. We believe the evidence presented within the LCD provides an well reasoned support for the proposed limitation on coverage. No evidence has been submitted to support clear benefit to the use of ESAs in milder stages of CKD. Your opinion that a population of patients with CKD Stage 3 is present that will not be covered and would benefit from ESA use is certainly appreciated. Please recall the statement within the General Information of DA58982 noting our understanding of beneficiary unique clinical circumstances and history. We stated that in the event of a denial that the provider feels is unwarranted, an appeals process will allow the opportunity for the provider to substantiate a reasonable and necessary basis for the ESA treatment based on medical literature, specialty organization best practice alignment, and the unique clinical circumstances for the beneficiary. Explanatory documentation within the medical record is crucial. 

II. Remove requirement for serum creatinine within the prior month for dosing of ESAs in CKD and ESRD

This comment has already been addressed. Please see Response 2, #4-5 above.

III. Include coverage of MDS, Unspecified (ICD-10 Code D46.9) 

This comment has already been addressed. Please see Response 1, #3 above. 

Additionally, it is noted that MDS-Unclassifiable is a complex, problematic diagnosis in general. In one large series of patients with MDS, the overall incidence of MDS-U was 6%. For this relatively small number of Medicare beneficiaries, we reiterate our understanding of unique beneficiary histories and clinical circumstances. We do not believe that allowing the use of an unspecified MDS code such as D46.9 effectively addresses the concerns related to this small population without creating opportunity for erroneous coding on a much broader, unintended scale. In the event of a denial that the provider feels is unwarranted, an appeals process will allow the opportunity for the provider to substantiate a reasonable and necessary basis for the ESA treatment based on medical literature, specialty organization best practice alignment, and the unique clinical circumstances for the beneficiary. Explanatory documentation within the medical record is crucial.

IV. Remove requirement for IPSS-R 

Thank you for your comments; your concerns are appreciated.

This LCD, at least in part, has made an effort to assure that ESA use can be covered for certain Medicare beneficiaries with MDS. This is a significant improvement as compared to the previous “silence” on the topic which made it difficult for providers to understand under what circumstances ESA use in MDS would in fact be considered reasonable and necessary for coverage purposes. We believe it important and consistent with the statutory mandate for a reasonable and necessary standard, that ESA use be limited to those beneficiaries for whom will most likely benefit. The NCCN Guidelines Version 3.2021 was carefully reviewed and NCCN guidelines have always served as a reliable compendium from a Medicare standpoint. This involves the concept of limiting coverage based on prognostic category. As consistently noted above in other responses, for the low volume of cases in which clinical circumstances unique to the beneficiary require further review, the appeals process may be utilized. 

Indeed, there are multiple prognostic categorization options. NCCN has opined a preference for the IPSS-R categorization due to more accurate risk stratification. IPSS-R is quite widely used though some may utilize IPSS due to its simplicity. There is no clear superior prognostic model for MDS and all models have advantages and limitations as the commenter has noted. We agree that that these models are primarily useful at the time of diagnosis and that is not inconsistent with this policy insofar as understanding a reasonable starting point for ESA use. The WHO prognostic scoring system (WPSS) is applicable at diagnosis and later time points and can be used for de novo and therapy-related MDS, however it has not broadly adopted and we felt that fact made any suggestion of its use somewhat unreasonable. Likewise the MD Anderson Cancer Center MDS model is complicated and also not widely adopted in a clinical practice setting. We do appreciate these comments and we are open to more expansive narrative regarding the use of other prognostic models outside of IPSS-R. We will make these changes in the LCD and billing/coding article. 

Lastly the absence of hematologic consulting care does not allow for coverage criteria to be abrogated. Presumably Medicare beneficiaries with MDS are generally under the care of a hematologist, even if infrequently. High quality continuity of care requires hematology recommendations and data to be conveyed to and utilized by other practitioners providing primary care to the patient.

V. Remove documentation requirements for reasonable expectancy of longer survival with a reduced need for transfusion support

Thank you for your comments. We agree that the documentation requirement for an expectation of longer survival with a reduced need for transfusion support is indeed implicit for patients with MDS and should be removed from the billing and coding article.

VI. Include coverage of antineoplastic chemotherapy induced pancytopenia (ICD-10 Code D61.810) or antineoplastic chemotherapy induced anemia (ICD-10 Code D64.81) for covered malignancies in conjunction with a malignancy code.

Thank you for your comments. We agree that there are clinically appropriate situations where antineoplastic chemotherapy induced pancytopenia (D61.810) may be the more accurate diagnosis and that it would also be acceptable as a potential reason for reasonable and necessary use of ESA treatment. This change will be made within the billing and coding article.