DEPARTMENT OF HEALTH & HUMAN SERVICES 	 Office of Inspector General 

Washington, D.C. 20201 

NOV 5 2009 


TO: 	 Charlene Frizzera 

Acting Administrator 

Centers for Medicare & Medicaid Services 

Margaret A. Hamburg, M.D. 


Commissioner 


Food and Drug Administration 


FROM: Stuart Wright 

Deputy Inspector General 

for Evaluation and Inspections 

SUBJECT: 	 Memorandum Report: "Renal Dialysis Facilities' Dosage Protocols for 

Administering Erythropoiesis-Stimulating Agents," 0 EI -03 -09-000 10 

This memorandum report presents the results of our review to (1) determine the extent to which 

Medicare-certified dialysis facilities have protocols for administering erythropoiesis-stimulating 

agents (ESAs), (2) determine the extent to which facilities' protocols are consistent with the 

boxed warning and selected guidelines on ESAs' labels, and (3) determine the extent to which 

facilities' protocols conform with Medicare's benefit policy for ESAs and payment monitoring 

policy for ESA claims. 

While they are not required to do so, dialysis facilities may develop their own protocols for 

administering ESAs to patients with chronic kidney failure. The protocols may define target 

hemoglobin levels and dosage instructions for administering ESAs. When physicians approve 

the protocols for specific patients, the patients' target hemoglobin levels and ESA dosages are 

based on the protocols. 

According to the boxed warning on ESAs' labels, maintaining higher rather than lower 

hemoglobin levels in a patient with chronic kidney failure can adversely affect the patient's 

health and increase the risk of death. Specifically, the boxed warning states that providers 

should administer ESAs "to achieve and maintain hemoglobin levels within the range of 

10 to 12 grams per deciliter (g/dL)." The Medicare benefit policy for ESAs reflects the target 

hemoglobin range specified in the boxed warning. A separate Medicare policy for monitoring 

ESA payments states that the Centers for Medicare & Medicaid Services (CMS) will reduce 

reported dosages upon which ESA claims are paid when patients' hemoglobin levels exceed 

13g/dL. 

OEI-03-09-00010 Renal Dialysis Facilities' Dosage Protocols for Administering ESAs 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

 

We conducted this review in response to a request from Chairman Fortney Pete Stark of the 

Subcommittee on Health, Committee on Ways and Means, U.S. House of Representatives. 

Some members of Congress have raised concerns that dialysis facilities’ protocols for 

administering ESAs may not be consistent with the current boxed warning for these drugs. 

 

We found that most Medicare-certified dialysis facilities had protocols in place for administering 

ESAs, but only 56 percent of facilities’ protocols explicitly state a target hemoglobin range. We 

could not determine whether the remaining 44 percent of protocols were consistent with the 

boxed warning and Medicare’s benefit policy because they do not specify a target hemoglobin 

range. Of the protocols that state a target hemoglobin range, 94 percent are consistent with the 

boxed warning and the Medicare benefit policy for ESAs because the upper limit of the stated 

target range is equal to or less than 12 g/dL. 

In addition, our review of protocols to determine whether they are consistent with selected 

guidelines on ESAs’ labels revealed that some protocols contain information that differs from 

labeling guidelines regarding starting doses, dose adjustments, and withholding ESA doses. 

Finally, all of the protocols that include a target hemoglobin range or level at which to increase 

ESA doses conform with CMS’s monitoring policy for ESA claims. 

BACKGROUND 

End Stage Renal Disease 

Chronic kidney failure is the gradual loss of kidney function. When chronic kidney failure 

progresses, it may eventually lead to end stage renal disease (ESRD). ESRD is a permanent 

kidney impairment that requires either a regular course of dialysis or a kidney transplant. 

Generally, patients with ESRD are entitled to Medicare benefits regardless of their age.1

 CMS 

covers an estimated 400,000 beneficiaries with ESRD and spends about $8.1 billion annually for 

ESRD services, including dialysis and related supplies, equipment, and drugs.2

According to the National Kidney Foundation, dialysis is a treatment for ESRD patients that 

functions in place of healthy kidneys. Dialysis removes waste, salt, and extra water from the 

body; keeps a safe level of certain chemicals in the blood; and helps to control blood pressure.3

 

Dialysis facilities provide outpatient dialysis to ESRD patients. Dialysis facilities must be 

certified in order to receive Medicare reimbursement.4

 A dialysis facility may be a freestanding 

unit or be located in a hospital.5 As of October 2008, there were 5,113 Medicare-certified 

1

 Section 226A of the Social Security Act; 42 CFR § 406.13. 

2

 “Payment, Safety, and Quality Issues in Treatment of Patients With End-Stage Renal Disease: Hearing Before 

U.S. House Committee on Ways and Means Subcommittee on Health,” 109th Congress, 2007. Statement of Leslie 

Norwalk, Acting Administrator, CMS. 

3

 National Kidney Foundation, “Dialysis.” Available online at http://www.kidney.org/atoz/atozItem.cfm?id=39. 

Accessed on May 11, 2009. 

4

 42 CFR §§ 405.2102 and 488.60. 

5

 42 CFR § 405.2102; CMS, “Medicare Benefit Policy Manual,” Pub. No. 100-02, ch. 11, § 10.B. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

 

dialysis facilities in the United States. Eighty-one percent of these facilities (4,120) were 

for-profit entities, while 19 percent (993) were nonprofit entities. 

Anemia 

Nearly all patients with ESRD have anemia, which may begin to develop in the early stages of 

chronic kidney failure. Healthy kidneys produce a hormone that stimulates bone marrow to 

produce the proper number of red blood cells. Diseased kidneys often do not produce sufficient 

amounts of this hormone, which results in fewer red blood cells and the development of anemia. 

Tests that measure patients’ hemoglobin (a protein made by red blood cells) and hematocrit (the 

proportion of red blood cells in whole blood) can be used to monitor anemia. 

Erythropoeisis-Stimulating Agents 

ESAs are prescription drugs that increase the number of red blood cells in patients suffering from 

anemia. For ESRD patients, ESAs are typically administered during dialysis treatments by 

intravenous or subcutaneous injection. After an ESA dose is administered or a dose adjustment 

is made, it may take several weeks for a patient’s hemoglobin level to change significantly. 

Epoetin alfa (marketed under the names Epogen and Procrit) and darbepoetin alfa (marketed 

under the name Aranesp) are the two ESAs approved by FDA for the treatment of anemia 

associated with chronic kidney failure. 

ESAs are covered under the Medicare Part B benefit for ESRD patients.6

 CMS currently pays 

dialysis facilities a composite rate for most dialysis services, including labor costs, related 

supplies, and certain drugs.7 However, the composite rate does not include ESAs and other 

specific drugs. Dialysis facilities bill separately for these drugs.8 9 Payments for ESAs account 

for over 60 percent of separately billable drugs, and over 25 percent of total Medicare spending 

on ESRD services annually.10

Protocols for Administering ESAs 

While not required, dialysis facilities may develop their own protocols for administering ESAs to 

ESRD patients. The protocols may define target hemoglobin levels and dosage instructions for 

ESAs. For dialysis facilities with protocols in place for administering ESAs, physicians may 

approve the protocols as patients’ standing orders. 

When physicians approve the protocols for specific patients, the patients’ target hemoglobin 

levels and ESA dosages are based on the protocols. Anemia managers, frequently nurses 

6

 CMS, “Medicare Benefit Policy Manual,” § 90. 

7

 CMS, “Medicare Benefit Policy Manual,” § 30. 

8

 CMS, “Medicare Claims Processing Manual,” Pub. No. 100-04, ch. 8, § 60.4 (epoetin alfa) and § 60.7 (darbepoetin 

alfa). 

9

 Pursuant to section 153(b) of the Medicare Improvements for Patients and Providers Act of 2008 

(P.L. No. 110-275), CMS is required to implement a fully bundled payment system for ESRD services by January 1, 

2011. The new bundled payment will include reimbursement for both ESAs and services currently included in the 

composite rate. 

10 Norwalk, loc. cit. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

employed by dialysis facilities, oversee patients’ anemia management. These practitioners may 

make dosage changes based on the protocols without new orders from physicians. 

For facilities with protocols, physicians may still choose not to approve the protocols and instead 

may write individual ESA orders for their patients. For dialysis facilities that do not have 

protocols for administering ESAs, physicians must write individual orders for ESAs. 

FDA’s Requirements for Labeling of ESAs 

FDA determines whether new drugs are safe, effective, and should be approved for marketing in 

the United States. Once a drug is approved, FDA conducts postmarket surveillance and risk 

assessment to identify adverse reactions and safety risks that did not appear during clinical trials 

before drug approval. 

Clinical trials conducted after ESAs were approved have provided new safety information on the 

use of these drugs to treat anemia in patients with chronic kidney failure. Results of studies 

conducted in 1996 and 2006 showed that patients with chronic kidney failure were at increased 

risk for serious cardiovascular complications when ESAs were administered to target higher, 

rather than lower, hemoglobin levels. These complications included stroke, heart attack, heart 

failure, and death. 

FDA’s Cardiovascular and Renal Drugs Advisory Committee and Drug Safety and Risk 

Management Advisory Committee met in September 2007 to discuss the risks and benefits of 

ESAs when used to treat anemia due to chronic kidney failure.11 Although the committees did 

not reach consensus in recommending a specific target hemoglobin level, many members at the 

meeting recommended a target range of 10 to 12 g/dL or a specific target within that range. 

Boxed Warning. Based on the results of clinical trials and input from the FDA advisory 

committees, FDA required the manufacturer of ESAs to revise the labeling for ESAs and add a 

boxed warning. The warning information is placed prominently at the top of the labeling and is 

enclosed in a box. A boxed warning is the strongest warning for an FDA-approved product. It is 

used to highlight warning information that is especially important to the prescriber, including an 

adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, 

life-threatening, or permanently disabling adverse reaction) that it is essential that it be 

considered in assessing the risks and benefits of using a drug. It is also used to highlight a 

serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate 

use of the drug. 

The current boxed warning on ESA labels for patients with chronic kidney failure states: 

Patients experienced greater risks for death and serious cardiovascular events when 

administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower 

 

11 FDA establishes advisory committees to obtain independent, expert advice on products regulated by FDA, 

including drugs. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

 

hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. 

Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 

12 g/dL.12

The ESAs’ labels contain other information, including guidelines for selecting the starting dose 

and adjusting subsequent dosages for patients with chronic kidney failure. 

Medicare Policies for ESAs

According to Chapter 11 of the Medicare Benefit Policy Manual, ESAs are covered under Part B 

for ESRD patients suffering from anemia. The benefit policy states that “ESRD patients who 

have been receiving [ESA] therapy should have a hematocrit between 30 and 36.” This 

hematocrit range is equivalent to a hemoglobin between 10 and 12 g/dL. 

Effective January 1, 2008, CMS modified its policy for monitoring ESA claims and payments in 

response to emerging scientific data and the boxed warning on ESAs’ labels. Dialysis facilities 

are required to report patient hemoglobin or hematocrit levels on all ESA claims.13 CMS’s 

monitoring policy is based on these reported hemoglobin or hematocrit levels and establishes a 

threshold at which CMS reduces the reported ESA dosage upon which an ESA claim is paid.14 

For all patients whose hemoglobin levels exceed 13 g/dL for less than 3 months and for whom a 

reduction in the ESA dosage has not been reported, CMS will pay only for a dosage which 

represents a 25-percent reduction of the dosage reported on the claim.15 For ESA claims with 

reported hemoglobin levels that exceed 13 g/dL for 3 or more consecutive months, CMS will pay 

for a dosage that represents a 50-percent reduction from the dosage reported on a claim.16

METHODOLOGY 

Scope 

We reviewed current protocols for administering ESAs from a stratified random sample of 

Medicare-certified dialysis facilities. We compared information contained in these protocols to 

(1) the boxed warning and selected dosage guidelines on ESAs’ labels, and (2) Medicare’s 

benefit policy for ESAs and monitoring policy for ESA claims. We did not review Medicare 

claims for ESAs. We did not collect ESRD patients’ records to review documentation, such as 

physician orders, that may support ESA claims. 

12 FDA, “Information on Erythropoeisis-Stimulating Agents Epoetin alfa (marketed as Procrit, Epogen) and 

Darbepoetin alfa (marketed as Aranesp).” Available online at 

http://www.fda.gov/cder/drug/infopage/RHE/default.htm. Accessed on June 3, 2009. 13 CMS, “Medicare Claims Processing Manual,” §§ 60.4 (epoetin alfa) and 60.7 (darbepoetin alfa). 14 Although CMS’s monitoring policy refers to both hemoglobin and hematocrit levels, and each of these measures 

will be applied during the study as appropriate, hereinafter, we will refer only to hemoglobin levels. 

15 CMS, “Medicare Claims Processing Manual,” loc. cit. 

16 Ibid. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

Sample Design 

We selected a stratified random sample of 400 dialysis facilities from CMS’s October 2008 

Dialysis Facility Compare database, which contains all Medicare-certified dialysis facilities.17 

The total number of facilities in the sample was reduced from 400 to 399 because one facility 

responded that it is an inpatient hospital unit that does not provide outpatient dialysis services. 

As shown in Table 1, we stratified the population of dialysis facilities by profit status to ensure 

that our sample would contain a sufficient number of both for-profit and nonprofit facilities. 

Table 1: Sample of Dialysis Facilities

Stratum Description of Stratum Facilities in 

Population 

Facilities in 

Sample 

Responding 

Facilities 

1 For-profit dialysis facilities 4,120 200 190 

2 Nonprofit dialysis facilities 993 199 176 

Total 5,113 399 366 

Source: Office of Inspector General (OIG) sample design and CMS Dialysis Facility Compare Database, October 2008. 

Data Collection

We obtained business name and address information for each dialysis facility in the sample from 

the Dialysis Facility Compare database. In January 2009, we requested by mail the sample 

facilities’ protocols for administering ESAs. We asked all facilities to complete a one-page 

request form indicating whether they have a protocol in place and providing general information 

about the characteristics of the facility. We received responses to our request from 366 of 399 

sample dialysis facilities—a 92-percent response rate. 

Some facilities did not have protocols in place. Fourteen facilities in our sample had more than 

one ESA protocol in place at the time of our request. These 14 facilities submitted multiple 

protocols for administering ESAs. For example, a facility may have a protocol in place for the 

administration of epoetin alfa, in addition to a separate protocol for the administration of 

darbepoetin alfa. 

We received a total of 357 protocols from the 366 responding facilities. Eighty-four percent of 

protocols were specific to epoetin alfa and 16 percent were specific to darbepoetin alfa. 

We created a structured data collection instrument to guide our review of each ESA protocol we 

received from sample facilities. We collected information on the type of ESA protocol, target 

hemoglobin levels presented in the protocol, and starting dose and dose adjustment information 

presented in the protocol. 

 

17 “Medicare Dialysis Facility Compare Database.” Available online at 

http://www.medicare.gov/Download/DownloadDB.asp. Accessed on December 18, 2008. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

Data Analysis 

We determined the number of dialysis facilities that have ESA protocols in place. We analyzed 

the protocol review data to determine the percentage of protocols that are consistent with the 

boxed warning on ESA labels and the Medicare benefit policy for ESAs. The boxed warning 

and benefit policy specify that the target hemoglobin level for patients with chronic kidney 

failure should be in the range of 10 to 12 g/dL. We reviewed protocols to determine whether 

they specified an explicit target hemoglobin range. Of protocols that specified an explicit target 

range, we considered those in which the upper limit of the range was equal to or less than 

12 g/dL to be consistent with both the boxed warning and the benefit policy.18 We used the 

upper limit of the target range to determine consistency because the boxed warning on ESA 

labels states that health risks increase with higher hemoglobin levels. 

We analyzed the protocol review data regarding starting doses and dose adjustments.19 We 

compared this information to selected dosage and administration guidelines on the 

FDA-approved labeling for ESAs. The selected guidelines are presented in Table 2. 

Table 2: Selected ESA Dosage and Administration Guidelines for Patients With Chronic 

Kidney Failure

Starting Dose Guidelines 

Epoetin alfa starting dose for adults is 50 to 100 units per kilogram, 3 times per week. 

Darbepoetin alfa starting dose for adults is 0.45 micrograms per kilogram, weekly. 

Dose Adjustment Guidelines 

Increase epoetin alfa dose when hemoglobin level is less than 10 g/dL. 

Decrease epoetin alfa and darbepoetin alfa dose when hemoglobin approaches 12 g/dL. 

Withhold epoetin alfa and darbepoetin alfa dose when hemoglobin continues to rise after a dose decrease. 

Source: Epogen, Procrit, and Aranesp labels, approved by FDA on November 19, 2008. 

We also determined whether dialysis facilities’ protocols conform with the hemoglobin threshold 

specified in CMS’s monitoring policy for ESA claims. We considered protocols with target 

hemoglobin levels that do not exceed 13 g/dL to conform with the monitoring policy. In 

addition, we compared protocol review data regarding dose increases to the monitoring policy. 

Facilities that responded to our request for ESA protocols indicated their profit status, whether 

the facility is part of a chain, whether the facility is hospital-based or freestanding, and the size 

of the facility (number of dialysis stations). We examined whether the percentage of protocols 

 

18 Three protocols specified a single target hemoglobin level, rather than a target range. We considered the target 

hemoglobin level to be the upper limit of the target range for these protocols. 

19 Some ESA protocols include starting dose information that we cannot compare to the guidelines on the ESAs’ 

labels. Therefore, we did not include these protocols in our starting dose analysis. For example, some protocols 

include starting dose amounts, but do not specify how many times per week the dose should be administered. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

that are consistent with the boxed warning differs based on dialysis facilities’ self-reported 

characteristics. We tested for statistically significant differences. 

We used SUDAAN software to produce weighted estimates of protocol review data percentages. 

These estimates reflect our stratified sample design and are provided in Appendix A. The results 

of our statistical significance tests are provided in Appendix B.

Standards 

This study was conducted in accordance with the “Quality Standards for Inspections” approved 

by the Council of the Inspectors General on Integrity and Efficiency. 

RESULTS 

Ninety-Three Percent of Medicare-Certified Dialysis Facilities Had Protocols in Place for 

Administering ESAs, But Only 56 Percent of the Protocols Explicitly State a Target 

Hemoglobin Range 

Based on responses we received from the Medicare-certified dialysis facilities in our sample, we 

estimate that 93 percent of all facilities had protocols in place for administering ESAs at the time 

of our request. Seven percent of facilities did not have ESA protocols in place. Point estimates 

and confidence intervals for all statistics presented in the findings of this memorandum report are 

provided in Appendix A.

Table 3 displays selected types of information included in the protocols for administering ESAs, 

such as target hemoglobin range and dosage and administration guidelines. Fifty-six percent of 

protocols include a target hemoglobin range and ESA starting dose information. More than 

90 percent of protocols include information about when to increase, decrease, and withhold ESA 

doses.

Table 3: Selected Types of Information Included in ESA Protocols

Type of Information Percentage of Protocols That 

Include This Information 

Percentage of Protocols That Do 

Not Include This Information 

Target hemoglobin range 56% 44% 

Starting dose instructions 56% 44% 

Specific hemoglobin level at which to increase dose 

(epoetin alfa protocols only) 95% 5% 

Specific hemoglobin level at which to decrease dose 91% 9% 

Specific hemoglobin level at which to withhold dose 95% 5% 

Source: OIG analysis of dialysis facilities’ protocols for administering ESAs, 2009.
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

Ninety-Four Percent of Protocols That Include a Target Hemoglobin Range Are Consistent 

With the Boxed Warning on ESAs’ Labels and the Medicare Benefit Policy for ESAs 

The boxed warning on ESA labels states that providers should administer the drugs to “achieve 

and maintain hemoglobin levels within the range of 10 to 12 g/dL” for patients with chronic 

kidney failure.20 The Medicare benefit policy for ESAs reflects the target hemoglobin range 

specified in the boxed warning. Fifty-six percent of protocols explicitly state a target 

hemoglobin range. We could not determine whether the remaining 44 percent of protocols in our 

review are consistent with the boxed warning or Medicare benefit policy because they do not 

specify a target hemoglobin range. 

Of protocols that include a target hemoglobin range, 94 percent are consistent with the boxed 

warning on the FDA-approved labels and the Medicare benefit policy for ESAs. These protocols 

include a target hemoglobin range in which the upper limit of the target range is equal to or less 

than 12 g/dL. For the remaining 6 percent of protocols that include a target hemoglobin range, 

the upper limit of the target range exceeds 12 g/dL. The upper limits in these protocols range 

from 12.1 g/dL to 13 g/dL with a median of 12.5 g/dL. 

More chain facilities are consistent with the warning than nonchain facilities. We detected no 

statistically significant difference between the percentage of protocols that are consistent with the 

boxed warning based on facilities’ profit status, whether the facility is freestanding or 

hospital-based, or on facility size. However, we detected a statistically significant difference at 

the 95-percent confidence level based on whether the facility is part of a chain. Protocols from 

chain facilities are more likely to be consistent with the boxed warning than protocols from 

nonchain facilities. Specifically, 97 percent of protocols from chain facilities are consistent with 

the warning, compared to 87 percent of protocols from nonchain facilities. 

For protocols that specify a target hemoglobin range, the lower limit of the target range is 

typically 11 g/dL. The lower limit of the target range is equal to 10 g/dL for only 16 percent of 

protocols that include a target hemoglobin range. The remaining 84 percent of protocols include 

a target hemoglobin range with a lower limit that is greater than 10 g/dL. Almost all of these 

protocols (97 percent) report a lower limit of 11 g/dL. The lower limit of the hemoglobin target 

range for these protocols exceeds the lower limit of the target range on the boxed warning and in 

the Medicare benefit policy. However, it is consistent with a March 2007 National Kidney 

Foundation clinical practice recommendation that, for patients “with chronic kidney disease 

receiving ESA therapy, the selected hemoglobin target should generally be in the range of 11 to 

12 g/dL.”21

 

20 FDA, “Information on Erythropoeisis-Stimulating Agents,” loc. cit. 

21 National Kidney Foundation, “Kidney Disease Outcomes Quality Initiatives Guidelines.” Available online at 

http://www.kidney.org/professionals/KDOQI/guidelines_anemia/cpr21message.htm. Accessed on May 11, 2009. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

Some Dialysis Facilities’ Protocols Contain Information That Differs From Selected 

Guidelines on ESAs’ Labels 

The percentage of dialysis facilities’ protocols that addressed each of the selected ESA dosage 

and administration guidelines ranged from 56 percent to 95 percent. However, some of these 

protocols include information that differs from the guidelines outlined on the FDA-approved 

labels for ESAs. 

Sixteen percent of protocols that include instructions regarding starting doses instruct providers 

to administer a higher starting dose than is recommended. The FDA-approved epoetin alfa label 

states that the starting dose for adults should be 50 to 100 units per kilogram, three times per 

week. The FDA-approved darbepoetin alfa label states that the starting dose for adults should be 

0.45 micrograms per kilogram, once per week. As shown in Table 3, 56 percent of protocols 

include instructions regarding starting doses. Of these protocols, 16 percent instruct providers to 

administer a higher maximum starting dose than is recommended on ESAs’ labels. All but two 

of these protocols are specific to epoetin alfa. The maximum starting doses for these epoetin alfa 

protocols range from 125 to 200 units per kilogram, three times per week. 

Ninety-four percent of protocols that specify a hemoglobin level at which to increase patients’ 

dosages instruct providers to increase dosages when hemoglobin levels are already within the 

target range on the boxed warning. The FDA-approved label for epoetin alfa states that 

providers should increase the dose if a patient’s hemoglobin level falls below 10 g/dL.22 

Ninety-five percent of epoetin alfa protocols specify a hemoglobin level at which to increase 

patients’ dosages. Of these protocols, 94 percent instruct providers to increase the dose when a 

patient’s hemoglobin level is within the recommended target range of 10 to 12 g/dL. Most of 

these protocols instruct providers to increase the dose when a patient’s hemoglobin level is 

within the range of 11 to 12 g/dL. 

For 62 percent of the epoetin alfa protocols that specify a hemoglobin level at which to increase 

patients’ dosages, providers are also instructed to ensure that additional conditions are met before 

increasing the dose. For example, some protocols instruct providers to increase the dose when a 

patient’s hemoglobin level is equal to 12 g/dL, but only if the patient’s hemoglobin level is 

decreasing over time. Other protocols instruct providers to increase the dose when a patient’s 

hemoglobin level is 12 g/dL, but the patient’s hemoglobin level must be decreasing over time 

and the previous dose must have been below a specified amount. 

More than 40 percent of protocols that specify a hemoglobin level at which to decrease patients’ 

ESA dosages do not instruct providers to decrease dosages until hemoglobin levels are 12 g/dL 

or higher. The FDA-approved labels for ESAs state that providers should reduce the ESA dose 

if a patient’s hemoglobin level is “approaching 12 g/dL.” Ninety-one percent of protocols 

specify a hemoglobin level at which to decrease patients’ ESA dosages. Of these protocols, 

43 percent do not instruct providers to decrease a patient’s ESA dose until the patient’s 

hemoglobin level is 12 g/dL or higher. The remaining 57 percent of protocols that specify a 

 

22 The darbepoetin alfa label does not include this guideline for increasing patients’ ESA dosages. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

hemoglobin level at which to decrease patients’ ESA dosages instruct providers to reduce the 

ESA dose when a patient’s hemoglobin level is less than 12 g/dL. 

Ninety percent of protocols that specify a hemoglobin level at which to withhold patients’ ESA 

dosages do not instruct providers to withhold dosages until hemoglobin levels are 13 g/dL or 

higher. ESAs’ labels state that the dose “should be temporarily withheld” if the dose has been 

reduced because a patient’s hemoglobin level is approaching 12 g/dL and the hemoglobin level 

continues to increase despite the dose reduction. Ninety-five percent of protocols specify a 

hemoglobin level at which to withhold patients’ ESA dosages. Of these protocols, 81 percent do 

not instruct providers to withhold the dose until a patient’s hemoglobin level is in the range of 

13 to 13.4 g/dL. Whether the dose is withheld depends on additional conditions for two-thirds of 

these protocols. For example, many protocols that instruct providers to withhold ESA doses 

when hemoglobin levels are greater than 13 g/dL state that hemoglobin must exceed 13 g/dL for 

3 or more consecutive months before withholding the dose. 

An additional 9 percent of dialysis facilities’ protocols that specify a hemoglobin level at which 

to withhold patients’ ESA doses do not instruct providers to withhold the dose until a patient’s 

hemoglobin level is 13.5 to 15 g/dL.

All Protocols That Include a Target Hemoglobin Range or Level at Which To Increase the 

Dose Conform With CMS’s Monitoring Policy for ESA Claims 

CMS initiates its ESA payment monitoring policy when the hemoglobin level reported on an 

ESA claim exceeds 13 g/dL. For hemoglobin levels that exceed 13 g/dL for less than 3 months, 

CMS instructs providers to report ESA dose reductions. If providers do not report dose 

reductions, CMS will pay only for a dosage which represents a 25-percent reduction of the 

dosage reported on the claim. For claims that report hemoglobin levels that exceed 13 g/dL for 

3 or more consecutive months, CMS reimburses providers for an ESA dose that represents a 

50-percent reduction of the dose reported on the claim.23

None of the dialysis facilities’ protocols that include a target hemoglobin range report a target 

range that exceeds 13 g/dL. Six percent of protocols include a target range with an upper limit 

that is between 12.1 and 13 g/dL. For the epoetin alfa protocols that specify a hemoglobin level 

at which to increase patients’ ESA dosages, no protocol instructs providers to increase the dose 

when a patient’s hemoglobin level is equal to or greater than 13 g/dL.

CONCLUSION 

Almost all dialysis facilities that responded to our request had protocols in place for 

administering ESAs. Fifty-six percent of protocols explicitly state a target hemoglobin range 

that is, with few exceptions, consistent with the boxed warning that states ESAs should be 

administered to achieve and maintain hemoglobin levels in the range of 10 to 12 g/dL. These 

target hemoglobin ranges are also consistent with the Medicare benefit policy for ESAs. 

 

23 CMS, “Medicare Claims Processing Manual,” §§ 60.4 and 60.7. 
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OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

However, we could not determine whether the remaining 44 percent of protocols were consistent 

with the boxed warning and Medicare’s benefit policy because they did not specify a target 

hemoglobin range. 

In addition, some protocols contain instructions regarding starting doses, dose adjustments, and 

withholding ESA doses that differ from selected guidelines on ESAs’ labels. For example, the 

epoetin alfa label states that providers should increase the ESA dose if a patient’s hemoglobin 

level falls below 10 g/dL. Of protocols that specify a hemoglobin level at which to increase 

dosages, 94 percent instruct providers to increase ESA dosages when patients’ hemoglobin levels 

are already within the target range of 10 to 12 g/dL. 

Finally, all protocols that include a target hemoglobin range or guidelines regarding dose 

increases conform with the hemoglobin threshold of 13 g/dL specified in CMS’s monitoring 

policy for ESA claims. 

Although our review does not address the amount of ESAs providers actually administer to 

patients at their dialysis facilities, it does demonstrate that just over half of facilities had 

protocols for administering ESAs that are consistent with the boxed warning and Medicare’s 

benefit policy for ESAs. However, since almost half of the dialysis facilities either did not have 

protocols or did not specify a target hemoglobin range in their protocols, we cannot determine 

whether these facilities’ policies target the hemoglobin range outlined in the boxed warning that 

FDA requires on ESA labels to alert physicians and patients with chronic kidney failure about 

the increased risks associated with higher hemoglobin levels. 

This report is being issued directly in final form because it contains no recommendations. If you 

have comments or questions about this report, please provide them within 60 days. Please refer 

to report number OEI-03-09-00010 in all correspondence. 
Page 13 – Charlene Frizzera and Margaret A. Hamburg, M.D. 

OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

APPENDIX A 

Confidence Intervals for Selected Estimates 

Estimate Description n Point Estimate1 95-Percent Confidence Interval 

Percentage of dialysis facilities that have protocols 366 93.2% 90.3%–96.1% 

Percentage of dialysis facilities that do not have 

protocols 366 6.7% 3.8%–9.6% 

Percentage of protocols that include an explicit target 

hemoglobin range 357 55.9% 49.8%–62.0% 

Percentage of protocols that do not include an explicit 

target hemoglobin range 357 44.0% 37.9%–50.1% 

Of protocols that include a target hemoglobin range, 

percentage that include an upper target limit equal to 

or less than 12 grams per deciliter (g/dL) 

209 94.3% 90.8%–97.7% 

Of protocols that include a target hemoglobin range, 

percentage that include an upper target limit greater 

than 12 g/dL 

209 5.6% 2.2%–9.1% 

Of protocols that include a target hemoglobin range, 

percentage that include a lower target limit equal to 

10 g/dL 

206 15.7% 10.1%–21.2% 

Of protocols that include a target hemoglobin range, 

percentage that include a lower target limit greater 

than 10 g/dL 

206 84.3% 78.7%–89.8% 

Percentage of protocols that include a lower target 

limit greater than 10 g/dL where the lower target limit 

equals 11 g/dL 

162 97.2% 95.0%–99.4% 

Percentage of protocols that include starting dose 

information 357 56.2% 50.3%–62.1% 

Percentage of protocols that do not include starting 

dose information 357 43.7% 37.8%–49.6% 

Of protocols that include starting dose information, 

percentage that include a starting dose higher than 

labels' guidelines 

202 16.0% 10.9%–21.1% 

Percentage of epoetin alfa protocols that specify a 

hemoglobin level at which to increase dose 299 95.1% 92.6%–97.6% 

Percentage of epoetin alfa protocols that do not 

specify a hemoglobin level at which to increase dose 299 4.8% 2.3%–7.3% 

 continued on next page 
Page 14 – Charlene Frizzera and Margaret A. Hamburg, M.D. 

OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

Confidence Intervals for Selected Estimates (continued) 

Estimate Description n Point Estimate1 95-Percent Confidence Interval 

Of epoetin alfa protocols that specify a hemoglobin 

level at which to increase dose, percentage that 

instruct providers to increase dose when hemoglobin 

is 10 to 10.9 g/dL 

279 26.3% 20.6%–31.9% 

Of epoetin alfa protocols that specify a hemoglobin 

level at which to increase dose, percentage that 

instruct providers to increase dose when hemoglobin 

is 11 to 12 g/dL 

279 67.8% 61.7%–73.8% 

Of epoetin alfa protocols that specify a hemoglobin 

level at which to increase dose, percentage that 

include additional conditions for increasing dose 

279 61.6% 55.4%–67.8% 

Percentage of protocols that specify a hemoglobin 

level at which to decrease dose 357 90.6% 87.4%–93.8% 

Percentage of protocols that do not specify a 

hemoglobin level at which to decrease dose 357 9.3% 6.1%–12.5% 

Of protocols that specify a hemoglobin level at which 

to decrease dose, percentage that instruct providers to 

decrease dose when hemoglobin is 12 g/dL or higher 

307 42.5% 36.3%–48.8% 

Of protocols that specify a hemoglobin level at which 

to decrease dose, percentage that instruct providers to 

decrease dose when hemoglobin is less than 12 g/dL 

307 57.4% 51.2%–63.6% 

Percentage of protocols that specify a hemoglobin 

level at which to withhold dose 357 94.9% 92.8%–96.9% 

Percentage of protocols that do not specify a 

hemoglobin level at which to withhold dose 357 5.1% 3.0%–7.1% 

Of protocols that specify a hemoglobin level at which 

to withhold dose, percentage where specified 

hemoglobin equals 13 to 13.4 g/dL 

325 81.0% 76.4%–85.5% 

Of protocols that specify a hemoglobin level at which 

to withhold dose, percentage where specified 

hemoglobin equals 13.5 to 15 g/dL 

325 9.4% 5.9%–13.0% 

Of protocols that specify a hemoglobin level at which 

to withhold dose, percentage where specified 

hemoglobin equals 13 to 13.4 g/dL that include 

additional conditions for withholding dose 

238 66.9% 60.7%–73.1% 

Source: Office of Inspector General analysis of dialysis facilities’ protocols for administering erythropoiesis-stimulating agents, 2009. 

1

Point estimates are weighted to reflect our stratified sample design.
Page 15 – Charlene Frizzera and Margaret A. Hamburg, M.D. 

OEI-03-09-00010 Renal Dialysis Facilities’ Dosage Protocols for Administering ESAs 

APPENDIX B 

Results of Statistical Significance Tests 

Weighted Chi-Square Tests Comparing Percentages of Protocols That Were 

Consistent With the Boxed Warning Based on Dialysis Facility Characteristics 

Dialysis Facility Characteristic 

Percentage of Protocols in 

Which Upper Limit of Target 

Hemoglobin Range Was Less 

Than or Equal to 12 g/dL1

P-Value for 

Difference in 

Percentages 

For-profit facilities 95.6% 

Profit status 

Nonprofit facilities 92.9% 

0.3655 

Hospital-based facilities 89.4% 

Type of setting 

Freestanding facilities 95.0% 

0.1367 

Chain facilities 96.7% 

Chain status 

Nonchain facilities 87.3% 

0.04892

1

g/dL is grams per deciliter. 

2

The difference between the percentage of protocols from chain facilities that were consistent with the boxed warning and the 

percentage of protocols from nonchain facilities that were consistent with the warning was statistically significant at the 95-percent 

confidence level. 

Source: Office of Inspector General (OIG) analysis of dialysis facilities’ protocols for administering erythropoiesis-stimulating agents, 

2009. 

Weighted T-Test Comparing Protocols That Were Consistent With the Boxed 

Warning to Protocols That Were Not Consistent With the Boxed Warning Based on 

Dialysis Facility Size 

Mean Number of 

Dialysis Stations as 

Proxy for Facility Size 

Difference in 

Means 

P-Value for 

Difference in 

Means 

Facilities’ protocols in which upper limit of target 

hemoglobin range was less than or equal to 12 g/dL1

 18.9

Facilities’ protocols in which upper limit of target 

hemoglobin range was greater than 12 g/dL 

17.2

1.7 0.2752 

1

g/dL is grams per deciliter. 

Source: OIG analysis of dialysis facilities’ protocols for administering erythropoiesis-stimulating agents, 2009.