Description　　
Endogenous erythropoietin is a glycoprotein hematopoietic growth factor that regulates hemoglobin levels in response to changes in the blood oxygen concentration. Erythropoiesis-stimulating agents (ESAs; e.g., epoetin alfa, pegylated epoetin beta, darbepoetin) are produced using recombinant DNA technologies and have pharmacologic properties similar to endogenous erythropoietin. The primary clinical use of ESAs is to treat chronic anemia.

For individuals who have chronic kidney disease and anemia who receive epoetin alfa, pegylated epoetin beta, or darbepoetin, the evidence includes randomized controlled trials (RCTs) and systematic reviews of RCTs. Relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. All 3 ESAs have been studied and approved for this use. Most of the evidence has demonstrated an increase in hemoglobin and a decrease in blood transfusions but has failed to demonstrate any significant improvement in clinical outcomes such as mortality and morbidity. The evidence is inconsistent in showing improvements in functional status and quality of life. Many studies have demonstrated increased mortality risk and increased risk for venous access thrombosis and stroke, prompting U.S. Food and Drug Administration (FDA) warnings. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have cancer-related anemia who receive epoetin alfa or darbepoetin, the evidence includes RCTs, comparative analyses, and systematic reviews of RCTs. Relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. The available trials have demonstrated an increase in hemoglobin concentration and a decrease in the need for blood transfusions. However, the evidence has also demonstrated increased mortality rates and possible tumor promotion, as well as increased risk of thromboembolic events when target hemoglobin levels were above 12 g/dL. Comparative analyses have shown that when the target hemoglobin level was lowered to 10 g/dL, patients experienced increased hemoglobin and decreased risk for blood transfusions. Length of follow-up was short in the comparative analyses, and mortality and adverse events were therefore not addressed. Epoetin alfa and darbepoetin are the ESAs approved for use in the treatment of cancer-related anemia; pegylated epoetin beta is not FDA-approved for this indication, because studies have demonstrated increased mortality and no significant improvement in clinical outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have hepatitis C infection treated with ribavirin who receive epoetin alfa or darbepoetin, the evidence includes RCTs. Relevant outcomes are quality of life and medication use. Evidence from RCTs has demonstrated that treatment with ESAs improves the ability to maintain full-dosing of ribavirin, because anemia is often a limiting effect for treatment. There may also be a positive effect on quality of life, although this is less certain. Epoetin alfa and darbepoetin are the ESAs approved for this use. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background  
Endogenous Erythropoietin and Anemia
Endogenous erythropoietin is a glycoprotein hematopoietic growth factor synthesized by cells near the renal tubules in response to changes in the blood oxygen concentration. When a patient is anemic, the ability of the blood to carry oxygen is decreased. An oxygen-sensing protein in the kidney detects the decrease in blood oxygen concentration and induces the production of endogenous erythropoietin, which then acts on the erythroid cell line in the bone marrow to stimulate hematopoiesis, thereby effectively increasing blood hemoglobin concentrations. Suppression of erythropoietin production or suppression of the bone marrow response to erythropoietin results in anemia in several disease processes, including chronic kidney disease (CKD), many types of cancer treatment, other chronic diseases, and use of certain drugs.

The severity of anemia is defined by blood hemoglobin concentration. Normal ranges are 12 to 16 g/dL in women and 14 to 18 g/dL in men. Mild anemia is defined as hemoglobin from 10 g/dL to the lower limit of normal ranges, moderate anemia is 8 to 10 g/dL, and severe anemia is 8 g/dL or less. 

Treatment 
Erythropoiesis-stimulating agents (ESAs) are produced using recombinant DNA technologies. They were initially developed as replacement therapy to treat anemia due to endogenous erythropoietin deficiency that commonly occurs in patients with chronic renal failure secondary to CKD.¹ Patients with chronic renal failure will become severely anemic and experience severe fatigue and reduced exercise tolerance unless treated with blood transfusions or an ESA. Partial correction of anemia by ESA treatment of patients with chronic renal failure reduces the need for red blood cell (RBC) transfusions and enhances physical functioning.

In cancer, anemia occurs with varying degrees of frequency and severity. It occurs most commonly in genitourinary, gynecologic, lung, and hematologic malignancies. Anemia may be directly related to cancer type or to its treatment. Oncologic anemia occurs by a variety of mechanisms:

1. Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B12) essential for RBC production.
2. Antibodies and/or immunoregulatory abnormalities associated with certain tumor types (most commonly, B-cell malignancies) may cause increased erythrocyte destruction (hemolysis).
3. Tumors may cause blood loss via tissue invasion (e.g., gastrointestinal bleeding from colon cancer).
4. Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, and multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment.
5. In more advanced cases, there may be marrow replacement with tumor or amyloid.
6. However, marrow dysfunction can occur even in the absence of frank invasion.
7. Inflammatory proteins from interactions between the immune system and tumor cells are thought to cause inappropriately low erythropoietin production and poor iron utilization, as well as a direct suppression of RBC production.

Cancer treatments also may cause anemia: (1) Radical cancer surgery can result in acute blood loss; and (2) radiotherapy and many cytotoxic chemotherapeutic agents suppress marrow to varying degrees. Damage is due to a variety of mechanisms. For example, alkylating agents cause cumulative DNA damage; antimetabolites damage DNA indirectly; and platinum-containing agents appear to damage erythropoietin-producing renal tubule cells.

RBC transfusion is the traditional approach to ameliorate anemia symptoms quickly. However, this approach carries a risk for several potential adverse events. The highest adverse event risk (1 per 432 whole blood units transfused) is for transfusion-related acute lung injury. Adverse events due to errors in transfusion (e.g., type mismatch) are estimated to occur at a rate of 1 per 5000 to 10,000 units of blood transfused. Current transfusion medicine and blood bank practices have significantly reduced the risk of transmissible infections, primarily due to better donor selection and screening for infectious diseases. Estimated risks per unit of blood transfused for transmission of hepatitis B virus (< 1 in 400,000), hepatitis C virus (< 1 in 1,000,000), HIV (< 1 in 1,000,000), and bacterial contaminants (1 per 10,000 to 100,000) have fallen dramatically since the early 1990s. Therefore, although the initial impetus to commercialize erythropoietin replacement products was based on a reduction in the risks associated with blood transfusion, current practices have mitigated many of those risks. Nonetheless, blood shortages, transfusion errors, and risks of alloimmunization and transfusion-related acute lung injury provide sufficient rationale for the use of ESA therapy in appropriately indicated patients.

Table 1 summarizes the 4 ESA products have been licensed in the United States.

Epoetin alfa and epoetin beta have the same amino acid sequence as endogenous erythropoietin but differ from each other in glycosylation; clinical effects are considered interchangeable. However, the epoetins, darbepoetin, and peginesatide all have pharmacologic actions similar to those of the endogenous hormone. When given to individuals with functioning erythropoiesis, each binds to and activates the human erythropoietin receptor and thus increases the number of RBCs and the blood concentration of hemoglobin. Both brands of epoetin alfas, PEG-epoetin beta, and darbepoetin alfa are approved by the Food and Drug Administration to treat anemia in patients with CKD who are on or are not on dialysis. Peginesatide is approved only for adults with anemia from CKD who are on dialysis. Epoetin alfa and darbepoetin alfa also are approved for other indications.   

Regulatory Status 
Table 1 summarizes the major regulatory timelines for approval actions for new indications of ESAs.

Table 1. Erythropoiesis-Stimulating Agents Approved by the Food and Drug Administration

Drug	Manufacturer	Approval Date	Indication
Epoetin alfa
Epogen®	Amgen	1989	Approved for use in patients with anemia due to CRF
		1991	Approved for use in zidovudine-treated, HIV-infected patients
		1993	Approved for chemotherapy-induced anemia in patients with non‒myeloid malignancies
		1996	Approved for presurgical use in certain patients undergoing surgery
Procrit®	Janssen Products	See all dates and indications for Epogen®
Darbepoetin alfa
Aranesp®	Amgen	2001	Approved for use in patients with anemia due to CRF
		2002	Approved for chemotherapy-induced anemia in patients with non‒myeloid malignancies
Peginesatide
Omontys®	Takeda and Affymax	2012	Approved for use in adults with anemia due to CKD who are on dialysis
		2013	Voluntary recall of all lots due to postmarketing reports of serious hypersensitivity
Methoxy polyethylene glycol epoetin beta
Mircera®	Vifor	2007	Approved for use in patients with anemia due to CRF who are on dialysis or not on dialysis
		2009	Injunction prohibiting U.S. sales until mid-2014 due to copyright infringement
		2015	Resumption of U.S. sales

CKD: chronic kidney disease; CRF: chronic renal failure. 

Clinical studies had shown that treatment with epoetin alfa and darbepoetin alfa for patients with cancer may result in shorter overall survival and/or increased risk of progression or recurrence. Additional studies of patients with CKD and hemoglobin greater than 11 g/dL found that treatment with epoetin alfa and darbepoetin alfa resulted in increased risks of mortality or cardiovascular adverse events or stroke. In response to this data, the Food and Drug Administration implemented a risk evaluation and mitigation strategy in 2011 under which providers and hospitals were required to counsel patients and each patient had to complete a provider acknowledgement form before treatment.

In April 2017, the Food and Drug Administration eliminated the risk evaluation and mitigation strategy for Epogen^®/Procrit^® and Arenesp^®, citing that “the risks can be communicated by the current product prescribing information” and that “The appropriate use of ESAs is supported by the Centers for Medicare & Medicaid Services (CMS) National Coverage Determination, the American Society of Clinical Oncology, the American Society of Hematology clinical guidelines, which are evidence-based guidelines intended to provide a basis for the standard of care in clinical oncology.” 

Post-Approval FDA Regulatory Actions 
In 2006, FDA issued an advisory on the serious cardiovascular risks from ESA therapy in patients with CKD, as evidenced in the CHOIR and NHCT studies.² Subsequently, FDA received reports of increased risks associated with ESAs used to treat anemia in cancer patients who were receiving or not receiving chemotherapy, as well as a report of thrombotic risks in patients receiving ESAs in the perisurgical setting.

Regarding dosage information, periodic reassessment of ESA safety has determined that clinical data do not support a therapeutic hemoglobin target free of risk for mortality. Consequently, revised “Dosage and Administration” sections of the product label deleted any specific therapeutic hemoglobin or Hct “target” range for ESAs. Instead, revised labels recommended that prescribers use the lowest ESA dose that will gradually increase hemoglobin concentration to the lowest level sufficient to avoid the need for RBC transfusion. For anemic CRF patients, this recommendation was primarily based on the NHCT and CHOIR study findings, as well as the lack of data for any specific hemoglobin or Hct threshold or range. Clinical data did not identify specific hemoglobin or Hct levels that directly correlated with a “… reduction in the need for red blood cell transfusion,” the main treatment benefit supporting ESA efficacy. Label revisions allowed prescribers to use their clinical judgment in determining the “… lowest level sufficient to avoid the need for red blood cell transfusion." These data prompted a reassessment of the safety information contained in the labeling for Mircera (2014),³ Aranesp (2018),⁴ Epogen (2018),⁵ and Procrit (2018)⁶ and culminated in the approval of revised labels. These revisions clarified the evidence for safety and effectiveness of these products and provided more explicit directions and recommendations for their use.

These recommendations were consistent with those made by FDA in May 2007 and in September 2007. Revisions included strengthened boxed warnings and “Warnings and Precautions” sections, and changes to the “Indications and Usage,” “Clinical Trials Experience,” and “Dosage and Administration” sections of the product labels. The revised black box warnings and limitations of use shown next reflect current labeling for these ESAs.^3,4,5,6  

Chronic Renal Failure 

• In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL.
• No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
• Use the lowest Epogen/Procrit or Aranesp dose sufficient to reduce the need for RBC transfusions. 

Cancer 

• ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small-cell lung, head and neck, lymphoid, and cervical cancers.
• Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense an ESA to patients with cancer.
• To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.
• Use ESAs only for anemia from myelosuppressive chemotherapy.
• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
• Discontinue use after the completion of a chemotherapy course. 

Perisurgery (Epogen and Procrit Only) 

• Due to increased risk of deep venous thrombosis, prophylaxis for deep venous thrombosis is recommended. 

Limitations of Use 
Epogen, Procrit, and Aranesp have not been shown to improve quality of life, fatigue, or patient well- being (for any indication).

Epogen, Procrit, and Aranesp are not indicated for use:

• In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
• In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
• As a substitute for RBC transfusions in patients who require immediate correction of anemia.

Epogen and Procrit also is not indicated for use:

• In patients scheduled for surgery who are willing to donate autologous blood.
• In patients undergoing cardiac or vascular surgery. 

Policy

The use of epoetin alfa, darbepoetin or pegylated (PEG)- epoetin beta may be considered MEDICALLY NECESSARY for:

• Treatment of anemia associated with chronic kidney disease; 
  • Verification of iron evaluation for adequate iron stores AND
  • Verification of anemia as defined by one of the following laboratory values collected within 30 days of the request:
    • Hematocrit (Hct) < 30%
    • Hemoglobin (Hgb) < 10g/dL AND P
• Patient is on dialysis OR Patient is NOT on dialysis AND
  • The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell (RBC) transfusion AND Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal. 

The use of PEG-epoetin beta is investigational/unproven therefore considered NOT MEDICALLY NECESSARY for all other indications. 

The use of epoetin alfa or darbeopoetin may be considered MEDICALLY NECESSARY for:

• Treatment of anemia in cancer patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy.
• Treatment of anemia related to therapy with AZT (zidovudine) in HIV-infected patients when the following criteria has been met:
  • Verification of iron evaluation for adequate iron stores^
  • Verification of anemia as defined by one of the following laboratory values collected within 30 days of the request:
    • Hemoglobin (Hgb) < 12 g/dL
    • Hematocrit (Hct) < 36%
  • Serum erythropoietin level less than or equal to 500 mU/mL
• Reduction of allogeneic blood transfusion in surgery patients when the following criteria has been met:
  • Verification of anemia as defined by one of the following:
    • Most recent or average hematocrit (Hct) over a 3-month period was below 36%
    • Most recent or average hemoglobin (Hgb) over a 3-month period was below 12 g/dL
  • One of the following:
    • Decrease in the need for blood transfusion
    • Hemoglobin (Hgb) increased greater than or equal to 1g/dL from pre-treatment level
• Treatment of patients following allogeneic bone marrow transplantation.
• Treatment of patients with myelodysplastic syndromes to reduce transfusion dependency when the following criteria has been met:
  • One of the following:
    • Serum erythropoietin level less than or equal to 500 mU/mL
    • Diagnosis of transfusion-dependent MDS
  • Verification of iron evaluation for adequate iron stores
• Treatment of patients with hepatitis C and anemia related to ribavirin treatment when the following criteria has been met: 
  • Verification of iron evaluation for adequate iron stores^
  • Verification of anemia as defined by one of the following laboratory values collected within 30 days of the request:
    • Hematocrit (Hct) < 36%
    • Hemoglobin (Hgb) < 12 g/dL
  • Verification of both of the following:
  • Patient is receiving one of the following:
    • interferon alfa-2b
    • interferon alfacon-1
    • peginterferon alfa-2b
    • peginterferon alfa-2a

In the medically necessary conditions noted above, the following criteria also apply:

• The lowest dose of ESAs should be used in order to avoid red blood cell transfusions.
• ESAs should not be used to raise the Hb level above 12 g/dL.
• ESA therapy should not be administered without adequate iron stores.

For the medically necessary use in cancer patients, these additional FDA criteria also apply:

• Epoetin or darbepoetin therapy should not be initiated at Hb levels ≥ 10 g/dL. 
• Epoetin or Darbepoetin treatment should be discontinued following the completion of a myelosuppressive chemotherapy course.

The use of ESAs is investigational/unproven there is considered NOT MEDICALLY NECESSARY in the following circumstances:

• Anemia associated with cancer in patients not receiving Myelosuppressive Cancer Chemotherapy
• Anemia associated with Acute Myeloid Leukemia (AML), Chronic Myelogenous Leukemia (CML) or other Myeloid Cancers
• Anemia associated with Radiotherapy in Cancer
• To enhance athletic performance
• Anemia in patients due to acute blood loss
• Non-Anemic patients (Hemoglobin {Hb} > 13.0 g/dL) prior to surgery
• Anemia of Chronic Disease/Anemia of Chronic Inflammation (e.g., Anemia in Inflammatory Bowel Disease [Ulcerative Colitis, Crohn's Disease], Rheumatoid Arthritis, Systemic Lupus Erythematosus)
• Treatment of Aplastic Anemia
• Anemia in Heart Failure (HF)

The use of Mircera may be considered MEDICALLY NECESSARY for when the following criteria has been met:

• Treatment of anemia associated with chronic kidney disease; 
  • Patient is greater than or equal to 18 years of age
  • Verification of iron evaluation for adequate iron stores AND
  • Verification of anemia as defined by one of the following laboratory values collected within 30 days of the request:
    • Hematocrit (Hct) < 30%
    • Hemoglobin (Hgb) < 10g/dL AND P
  • Patient is on dialysis OR Patient is NOT on dialysis AND
    • The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell (RBC) transfusion AND Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
  • For pediatric patients all of the following must be met:
    • Patient is between 5 and 17 years of age
    • Patient is on hemodialysis
    • Patient’s hemoglobin level has been stabilized by treatment with another erythropoietin stimulating agent (ESA) (e.g., Aranesp, Procrit)
    • Patient is converting to Mircera from another ESA (e.g., Aranesp, Procrit)

Continuation of therapy with epoetin alfa, darbepoetin, pegylated (PEG)- epoetin or Mircera is considered MEDICALLY NECESSARY for treatment of chronic kidney disease (CKD):

• One of the following:
  • Patient is on dialysis and most recent or average Hct over 3 months is 33% or less (Hgb 11 g/dL or less)
  • Patient is not on dialysis and most recent or average (avg) Hct over 3 months is 30% or less (Hgb 10 g/dL or less)
  • Request is for a pediatric patient and most recent or average Hct over 3 months is 36% or less (Hgb 12 g/dL or less)
• One of the following:
  • Decrease in the need for blood transfusion
  • Hemoglobin (Hgb) increased greater than or equal to 1g/dL from pre-treatment level
• Verification of iron evaluation for adequate iron stores^

Continuation of therapy with epoetin alfa, darbepoetin, pegylated (PEG)- epoetin or Mircera is considered MEDICALLY NECESSARY for all other diagnosis when:

• Verification of anemia as defined by one of the following:
  • Most recent or average hematocrit (Hct) over a 3-month period was below 36%
  • Most recent or average hemoglobin (Hgb) over a 3-month period was below 12 g/dL
• One of the following:
  • Decrease in the need for blood transfusion
  • Hemoglobin (Hgb) increased greater than or equal to 1.5g/dL from pre-treatment level

“We recognize uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.”

Policy Guidelines:
Throughout this policy, unless otherwise stated:

• The term ESA refers to epoetin alfa (Epogen^®, Procrit^®) and darbepoetin alfa (Aranesp^®). 
• Nonmyeloid malignancies include solid tumors and the nonmyeloid hematologic malignancies myeloma, lymphoma, and chronic lymphocytic leukemia.

Administration
ESAs and pegylated (PEG)-epoetin beta are to be administered according to current FDA-approved labeling for each product, using recommended hemoglobin (Hb) levels for starting, stopping, and dose adjustment. This includes decreasing the dose of ESA as the Hb approaches the target level.

Before commencing ESA or PEG-epoetin beta therapy, the patient’s iron stores, blood ferritin, and transferrin saturation should be evaluated, adjusted, and maintained within normal physiological limits. ESA or PEG-epoetin beta therapy should not be administered without adequate iron stores.

Blood Pressure Monitoring
Blood pressure should be adequately controlled before initiation of ESA therapy and closely monitored and controlled during treatment. ESAs and PEG-epoetin beta are contraindicated in patients with uncontrolled hypertension.

Discontinuation
Erythropoiesis-Stimulating Agents
Patients with myelodysplastic syndromes should be initially limited to a 3-month trial period with ESA. If no response to ESA is observed, ongoing therapy would be futile.

ESAs and PEG-Epoetin Beta
Patients with chronic kidney disease who do not respond adequately over a 12-week dose escalation period should not have their ESA or PEG-epoetin beta dose increased further. Increasing ESA or PEGepoetin beta dose further is unlikely to improve response and may increase risks; the lowest ESA or PEG-epoetin beta dose that maintains adequate Hb to avoid recurrent red blood cell transfusions should be used. Other causes of anemia should be evaluated. If responsiveness does not improve, discontinue ESA or PEG-epoetin beta therapy.

Risk Evaluation and Mitigation Strategy
Epoetin alfa and darbepoetin must be prescribed and dispensed in accordance with a risk evaluation and mitigation strategy (REMS) drafted by the manufacturer and approved by FDA.¹ 

REMS for epoetin alfa and darbepoetin alfa each comprises elements to assure safe use and an implementation system.

• ESA manufacturers must ensure that all hospitals and healthcare professionals who prescribe and/or dispense ESAs to patients with cancer have enrolled and completed training in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program. The ESA APPRISE program began on March 24, 2010 after FDA’s initial approval of separate but similar REMS for epoetin alfa and darbepoetin alfa on Feb. 16, 2010. Both REMS were subsequently modified, most recently on Dec. 31, 2013.
• Healthcare providers and hospitals that prescribe and/or dispense an ESA for chronic kidney disease (CKD) must provide each patient with a copy of the REMS Medication Guide included in the product label and ensure that patients are adequately informed of the risks associated with ESA treatment. However, prescribers are not required to enroll in and complete the ESA APPRISE program. 

PEG-epoetin beta does not have a REMS. 

On March 27, 2012, FDA approved a REMS for peginesatide with a communication plan as its only component. The plan’s goal was to inform all healthcare professionals who might prescribe the drug that peginesatide is indicated only for adult patients with CKD on dialysis, and of potentially fatal risks associated with its use in CKD patients not on dialysis. Peginesatide is currently discontinued.

Benefit Application
Erythropoietin is adjudicated under the drug benefit as an injectable.

Rationale
This evidence review was created in December 1995 with searches of the MEDILNE database. The most recent literature update was performed through Aug. 5, 2019. 

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function — including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

Primary data sources for oncology included a 2006 comparative meta-analysis on the outcomes of epoetin or darbepoetin for managing anemia in patients undergoing cancer treatment, which was prepared for the Agency for Healthcare Research and Quality (AHRQ), and the 2006 AHRQ report, updated in 2013^6,7,8 and 2 meta-analyses using individual patient data for outcomes of erythropoiesis-stimulating agent (ESA) therapy in patients with cancer,^9,10 with additional outcomes reported in 2012.¹² Additional primary data sources were the American Society of Clinical Oncology and American Society of Hematology 2010 clinical practice guidelines on the use of epoetin and darbepoetin to treat chemotherapy-associated anemia¹¹; 2007 briefing documents available from the U.S. Food and Drug Administration (FDA)¹²; and a 2007 decision memorandum from the Centers for Medicare & Medicaid Services on the use ofESAs for nonrenal disease indications.¹³ 

Information on the use of ESAs in chronic renal failure (CRF) was obtained from several sources, including 2007 briefing documents from the FDA on a reassessment of ESA risks¹⁴; and a meta-analysis by Strippoli et al. (2004) evaluating blood hemoglobin targets for patients with CRF-associated anemia.^15,The FDA-approved labels for ESAs available in the U.S. comprised additional data sources for this evidence review, in particular, recommended dosing information for the different clinical settings covered. 

The 2010 American Society of Clinical Oncology and American Society of Hematology clinical practice guidelines on the use of ESAs considered epoetin and darbepoetin, used at dosages recommended in current FDA-approved package inserts, to be equivalent concerning effectiveness and safety. Epoetin and darbepoetin are identical concerning the following: (1) indications for use in chemotherapy-induced anemia, (2) hemoglobin limits for adjusting doses, initiating or discontinuing treatment, (3) warnings and cautions to consider, and (4) increased rates of thromboembolic events in the experimental arms of separate trials on each product vs controls or placebo.¹¹ 

Chronic Kidney Disease and Anemia 
Clinical Context and Test Purpose 
The purpose of epoetin alfa, pegylated (PEG)-epoetin beta or darbepoetin is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with anemia related to CKD and anemia. 

The question addressed in this evidence review is: Does the use of ESAs improve the net health outcome in patients with CKD-related anemia? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with CKD-related anemia. 

Interventions 
The therapies being considered are epoetin alfa, PEGepoetin beta, and darbepoetin. Patients with CKD-related anemia are actively managed by nephrologists in an outpatient setting. 

Comparators 
The following practice is currently being used to treat anemia related to CKD: standard of care. Treatment for CKD-related anemia commonly includes a diet change involving a reduction in sodium consumption. 

Outcomes 
The general outcomes of interest are symptoms, morbid events, medication use, treatment-related mortality, and treatment-related morbidity. Follow-up at one and three years is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs. 
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded. 

Epoetin Alfa, Epoetin Beta, and Darbepoetin 
Pivotal Trials 
At initial approval of epoetin in 1989, the primary objective of treatment was to raise hemoglobin concentration sufficiently to avoid transfusion, with a target range of 9 to 10 g/dL in anemic patients with CKD. The first National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines in 1997 recommended a hemoglobin concentration of 11 g/dL, a level that was increased in the 2007 National Kidney Foundation Kidney Disease Outcomes Quality Initiative anemia guidelines to 11 to 13 g/dL.¹⁶ With increased experience in the use of ESAs, it became unclear whether higher hemoglobin target concentrations, including normalization, would yield additional benefits such as physical function and improved cardiovascular outcomes. Clinical doubts were raised with the publication of the first large RCT of hemoglobin normalization using epoetin alfa in hemodialysis patients (Normal Hematocrit Cardiac Trial [NHCT]).¹⁷ NHCT, reported by Besarab et al. (1998), showed a trend toward increased mortality risk and significantly increased the riskfor vascular access thrombosis with ESA treatment to a hematocrit (Hct) target of 42%. Subsequently, four published RCTs in hemodialysis patients with end-stage renal disease (ESRD) and eight in nondialysis patients with CKD found improved physical function at higher hemoglobin targets, but none demonstrated significant improvements in cardiovascular endpoints or mortality.¹⁸ 

The Epogen/Procrit labeling was modified in 1996 to include results of NHCT, which showed a higher mortality rate for anemic dialysis patients randomized to an Hct of 42%, compared with an Hct of 30%. The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study, reported by Singh et al. (2006), found worse cardiovascular outcomes for anemic CRF patients who were not undergoing dialysis and who were randomized to a target hemoglobin level of 13.5 g/dL or to a hemoglobin level of 11.3 g/dL.¹⁹ Subsequent analyses of CHOIR outcomes showed shorter times to progression of kidney disease and higher rates of renal replacement therapy and death among patients randomized to the higher hemoglobin target.²⁰ The Cardiovascular Reduction Early Anemia Treatment Epoetin β (CREATE) study, reported by Drueke et al. (2006), was similar to CHOIR but enrolled fewer patients.²¹ CREATE did not demonstrate statistically significant differences in adverse cardiovascular outcomes for the higher hemoglobin group, but the general trend of major cardiovascular outcomes was similar to the CHOIR findings. In the Trial to Reduce Cardiovascular Events With Aranesp^® Therapy (TREAT) study, Pfeffer et al. (2009) randomized 4038 patients with type 2 diabetes, hemoglobin levels of 11 g/dL or less, and CKD not on dialysis.²² Patients in 1 arm were treated with darbepoetin to a target hemoglobin level of 13 g/dL, and those in the other arm received darbepoetin only if hemoglobin fell below 9 g/dL. Risks for 2 endpoints did not differ significantly between arms: death or a cardiovascular event (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.94 to 1.17; p = 0.41) and death or ESRD (HR = 1.06; 95% CI, 0.95 to 1.19; p = 0.29). However, fatal or nonfatal stroke was significantly increased among patients randomized to the higher hemoglobin target (HR = 1.92; 95% CI, 1.38 to 2.68; p < 0.001). Multivariate analysis found no statistically significant correlations between increased stroke risk and any baseline characteristic; effects on blood pressure, hemoglobin, or platelet count; or darbepoetin dose.²³ 

Systematic Reviews 
Tables 2 and 3 summarize the characteristics and results of the systematic reviews assessed. A brief narrative of each review is provided below the tables. The systematic review by Amato et al. (2018), discussed below, is not included in the tables due to the heterogeneity of outcome measures.²⁴ 

Table 2. Characteristics of Systematic Reviews Assessing Chronic Kidney Disease and Anemia 

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Roger et al. (2017)25	1995 – 2007	7	Patients with CKD on dialysis	615	RCT	NR
Cody and Hodson (2016)26	1989 – 2008	19	Patients with anemia and CKD	993 (8 – 186)	RCT and quasi-RCT	8 wk – 36 mo
Collister et al. (2016)27	1995 – 2014	17	Patients with anemia and CKD	NR	RCT	NR
Palmer et al. (2014)28	2002 – 2011	21	Patients with anemia and CKD	8328 (18 – 507)	RCT and quasi-RCT	Varied
Vinhas et al. (2012)29	1998 – 2009	5	Patients with anemia and CKD	7904 (596 – 4038)	RCT	14 – 36 mo

CKD: chronic kidney disease; NR: not reported; RCT: randomized controlled trials. 

Table 3. Results of Systematic Reviews Assessing Chronic Kidney Disease and Anemia 

Study	VAT	Stroke	Progress to ESRD	All-Cause Mortality	Need Blood Transfusion	Hb, g/L	Hct, %	HRQOL	ESA Dose Reduction, %
Roger et al. (2017)25									23 (7 to 55)
Weighted change (range)									-23 (-7 to -55)
Cody and Hodson (2016)26
MD					-	1.90	9.85
RR					0.32	-	-
95% CI					0.12 to 0.83	-2.34 to -1.47	8.35 to 11.34
Collister et al. (2016)27
SF-36 (95% CI)								(0)
KDQ (95% CI)								0.5 (-2.2 to 1.2)
Palmer et al. (2014)28
RR				1.05	0.60
95% CI				0.93 to 1.19	0.53 to 0.69
Vinhas et al. (2012)29
n/N	2/1829	4/7305	3/6073	5/7902
RRa	1.34	1.74	1.09	1.15
95% CI	1.16 to 1.55	1.32 to 2.28	0.99 to 1.20	0.98 to 1.35

CI: confidence interval; ESA: erythropoiesis-stimulating agent; ESRD: end-stage renal disease; Hb: hemoglobin; Hct: hematocrit; HRQOL: health-related quality of life; KDQ: Kidney Dialysis Questionnaire; MD: mean difference; n/N: number of trials/number of patients; RR: relative risk; SF-36: Short Form-36 Health Survey; VAT: vascular access thrombosis. 
^a Relative risk for outcome at higher Hb targets (13.0 – 15.0 g/dL) vs. lower Hb targets (9.5 – 11.5 g/dL). 

Amato et al. (2018) published a systematic review and meta-analysis comparing ESA biosimilars with originators in patients with anemia due to CKD.²⁴ Thirty RCTs (total n = 7843 patients) were included. When comparing epoetin alfa with the biosimilar, epoetin alfa with darbepoetin alfa, epoetin beta with methoxy polyethylene glycol-epoetin beta, and darbepoetin alfa with methoxy polyethylene glycol-epoetin beta, no differences were observed for any outcome except for favorable results for blood transfusion for darbepoetin alfa compared with epoetin alfa. Besides two studies comparing epoetin beta and methoxy polyethylene glycol-epoetin beta (moderate), all included studies were judged to have low to very low quality of evidence. The review was limited to bibliographic sources mentioned in methodologic sections. 

Roger et al. (2017) published a systematic review on the use of intravenous iron to optimize ESA response and reduce ESA dose in patients with CKD on dialysis.²⁵ The literature search, conducted through December 2014, identified 7 RCTs (total n = 615 patients) for inclusion. Quality of the studies was assessed using the risk of bias criteria outlined by Cochrane. Few studies provided randomization details, and almost half did not conduct intention-to-treat analyses. Results from a meta-analysis showed a statistically significant reduction in ESA dose when optimal iron (defined as 100 – 200 mg/wk) was administered with the ESA. 

A Cochrane review by Cody et al. (2016) evaluated the use of ESAs as a treatment for anemia due to CKD in patients not requiring dialysis.²⁶ This review updated a 2005 review, which updated the initial 2001 review. The literature search, conducted through June 2015, identified 4 additional studies to include in the update, for a total of 19 studies (total n = 993 patients). Selected studies were assessed for bias in selection, performance, detection, attrition, and reporting. Risk of bias was determined to be mostly unclear among the studies. ESAs were found to improve hemoglobin and Hct levels significantly and reduce significantly the need for blood transfusions in predialysis patients. Improvements were also found in the QOL and exercise capacity in the treatment group. Follow-up times of the studies were not sufficient to determine the effect of ESAs on CKD progression or the timing of dialysis initiation. 

Collister et al. (2016) focused on studies of ESAs for treating patients with anemia due to CKD these studies reported validated QOL outcomes.²⁷ The literature search, conducted up to November 2015, identified 17 studies for inclusion. Four studies included only patients on dialysis, 12 studies included only nondialysis patients, and another included both. Comparisons were between erythropoietin alfa and placebo (3 studies), darbepoetin and placebo (2 studies), erythropoietin alfa and darbepoetin (1 study), and erythropoietin alfa and erythropoietin alfa (11 studies). Follow-up ranged from 8 weeks to 36 months. QOL outcomes included the 36-Item the Short-Form Health Survey (SF-36; 13 studies) and Kidney Dialysis Questionnaire (KDQ; 4 studies). The SF-36 consists of 8 domains: physical function, physical role, bodily pain, general health, vitality, emotional role, social function, and mental health. A minimum clinically important difference (MCID) in the SF-36 is a 5-point change. The KDQ has five dimensions: fatigue, depression, relationships with others, frustration, and physical symptoms. An MCID in KDQ is a 0.5-point change. Study quality was assessed using the Cochrane Risk of Bias tool. Only four studies had a low-risk of bias. Many did not adequately conceal allocation, which could have influenced the results of subjective QOL measures. Meta-analyses of the 13 studies using the SF-36 outcome found MCIDs in 2 domains, though the differences were not statistically significant (95% CI, -5.6 to 0.4 for physical function; 95% CI, -5.1 to 3.7 for physical role). Meta-analyses including only the four studies with low-risk of bias reported nonsignificant results as well. Meta-analysis of the 4 studies using the KDQ outcome found MCIDs in 3 dimensions, though the differences again were not statistically significant (95% CI, -2.2 to 1.2 for physical symptoms; 95% CI, -1.6 to 0.5 for fatigue; 95% CI, -1.1 to 0.8 for depression). 

A Cochrane review by Palmer et al. (2014) evaluated darbepoetin for the treatment of anemia due to CKD.²⁸ The literature search, conducted through January 2014, identified 21 studies (total n = 8328 patients) for inclusion. Comparators with darbepoetin included placebo (one study), epoetin alfa or beta (eight studies), and PEG-epoetin beta (four studies). The remaining studies compared different dosages of darbepoetin and different methods of administration (intravenous vs subcutaneous). Risk of bias, based on randomization, concealment, incomplete data, and blinding, was considered high or unclear among the included studies. The single-study comparing darbepoetin with placebo found that the treatment significantly reduced the need for blood transfusions, but did not affect all-cause mortality, or theSF-36 energy or physical functioning scores. Studies comparing method of administration found no significant differences in need for blood transfusions or adverse events between intravenous and subcutaneous methods. Results from studies comparing darbepoetin with other ESAs are discussed in the Comparative Efficacy of Different ESAs section below. 

A meta-analysis by Vinhas et al. (2012) included only large RCTs (n > 500) with a minimum follow-up of 1 year.²⁹ Outcomes of interest were vascular access thrombosis, stroke, progression to ESRD, and all-cause mortality. Five trials (7902 patients), including the CHOIR, CREATE, NHCT, and TREAT trials, were selected. As shown in Table 4, higher hemoglobin targets were associated with increased risks of vascular access thrombosis and stroke but not with progression to ESRD or all-cause mortality. 

Table 4. Meta-Analytic Results 

Outcomes	No. of Trials/Patients	Relative Riska	95% CI	I2, %b
Vascular access thrombosis	2/1829	1.34	1.16 to 1.55	0
Stroke	4/7305	1.74	1.32 to 2.28	0
Progression to end-stage renal disease	3/6073	1.09	0.99 to 1.20	0
All-cause mortality	5/7902	1.15	0.98 to 1.35	0

Adapted from Vinhas et al. (2012).²⁹ 
CI: confidence interval.
^a Relative risk for outcome at higher hemoglobin targets (13.0 – 15.0 g/dL) vs lower hemoglobin targets (9.5 – 11.5 g/dL). 
^b Describes the proportion of total variation across studies due to heterogeneity rather than chance. 

Randomized Controlled Trials 
Saglimbene et al. (2017) published an RCT investigating whether a lower dose of ESA could reduce the risk of death and other adverse events in patients with anemia due to CKD.³⁰ Patients were randomized to a fixed low-dose ESA (n = 324) (epoetin alfa or beta 4000 IU or darbepoetin alfa 20 μg weekly) or a fixed high-dose ESA (n = 332) (epoetin alfa or beta 18000 IU or darbepoetin alfa 90 μg weekly) and were followed at 6 and 12 months. Primary outcomes were serum transferrin, ferritin, albumin, and C-reactive protein. Secondary outcomes were a composite of death or cardiovascular event, all-cause mortality, other adverse events, blood transfusion, and health-related QOL. There were no significant differences at the final follow-up in any of the primary outcomes between the low- and high-dose ESA groups. Significant differences were not detected between the groups in all-cause mortality, nonfatal or fatal myocardial infarction, thrombosis, or hospitalizations due to cardiovascular events. Risk estimates could not be calculated for stroke or seizures due to no events in one or both treatment groups. Patients in the low-dose ESA group reported a significantly higher QOL scores in emotional and physical functioning domains compared with patients in the high-dose ESA group. Patients in the low-dose group were at a significantly higher risk of blood transfusions than patients in the high-dose group. 

Pegylated Epoetin Beta 
Pivotal Trials 
The FDA’s 2007 approval of PEG-epoetin beta (Mircera) was based on 6, phase 3, international, open-label, RCTs in patients with anemia due to CKD (see Table 5). In 2 trials (n = 505 patients), patients did not receive ESA therapy (correction trials), and in 6 trials (n = 1894 patients), hemoglobin was stable on maintenance ESA therapy (maintenance trials). All but one trial (ARCTOS) enrolled dialysis-dependent patients. The primary efficacy outcome in all trials was the maintenance of hemoglobin levels over 24 to 52 weeks, adjusted for baseline hemoglobin and center, in the intention-to-treat and per-protocol patient samples. For this outcome, the trials demonstrated noninferiority of PEG-epoetin beta once or twice monthly to epoetin (alfa or beta) one to three times weekly (AMICUS, MAXIMA, PROTOS, RUBRA) and to darbepoetin weekly or twice monthly (ARCTOS, STRIATA). In the correction trials (ARCTOS, AMICUS), the median time to response was longer in the PEG-epoetin beta groups (43 days vs. 57 days, respectively) compared with the darbepoetin (29 days) and epoetin (31 days) groups. 

Although target hemoglobin ranges in these trials included levels that have since been associated with increased mortality in CKD (i.e., > 11 g/dL).³¹ the FDA’s summary review of safety (based on 1789 PEG-epoetin beta-treated patients [64% for > 1 year] and 948 ESA-treated patients) reported that mortality was similar between the 2 groups (10% vs. 11%, respectively).Incidence of serious adverse events also was similar between groups (37% vs. 40%, respectively), although serious bleeding events (5.2% vs. 4%), serious gastrointestinal bleeding events (1.2% vs. 0.2%), and thrombocytopenia less than 100´10⁹ platelets/L (7.5% vs. 4.4%) occurred more commonly in PEG-epoetin beta-treated patients. The FDA reviewers attributed these imbalances to the greater proportion of patients on hemodialysis in the PEG-epoetin beta group (84% vs. 80%) and considered the risks of hemorrhage and thrombocytopenia similar to or slightly increased above that for other ESAs. Trials excluded patients with poorly controlled hypertension; 27% of enrolled patients required increases in antihypertensive therapy. 

Table 5. Pivotal Trials of PEG-Epoetin Beta 

Study (Trial)	N	Initial Dose	Results
			Percent Respondersa	Mean ΔHb,b g/dL
Correction trials in patients not receiving ESA therapy
Macdougall et al. (2008) (ARCTOS)32,c
PEG-epoetin beta	162	0.6 μ/kg SC q2wk	98	2.15
Darbepoetin	162	0.45 μ/kg SC q1wk	96	2.00
p			< 0.001d	< 0.001e
Klinger et al. (2007) (AMICUS)33
PEG-epoetin beta	135	0.4 μ/kg IV q2wk	93	2.70
Epoetin alfa/beta	46	Per product label IV 3´/wk	91	2.56
p			< 0.001d	< 0.001e
Maintenance trials in patients receiving ESA therapy
Canaud et al. (2008) (STRIATA)34		PEG-epoetin beta dose based on maintenance ESA dose Comparator ESA dose was continuation of maintenance dose
PEG-epoetin beta IV q2wk	157		66	0.06
Darbepoetin IV q1-2wk	156		72	-0.12
p			0.25	< 0.001e
Spinowitz et al. (2008) (RUBRA)35
PEG-epoetin beta SC/IV q2wk	168		69	0.09
Epoetin alfa/beta SC/IV q1-2wk	168		68	-0.03
p			-h	< 0.001e
Levin et al. (2007) (MAXIMA)36
PEG-epoetin beta IV q2wk	223		-	-0.71
PEG-epoetin beta IV q4wk	224		-	-0.25
Epoetin alfa/beta IV q1-3x/wk	226		-	-0.75
p vs. control			-	< 0.001e,f
Sulowicz et al. (2007) (PROTOS)37
PEG-epoetin beta SC q2wk	190		76	-0.03
PEG-epoetin beta SC q4wk	191		66	-0.13
Epoetin alfa/beta SC q1-3x/wk	191		72	-0.11
p vs. control			-g	< 0.001e,f

ESA: erythropoiesis-stimulating agents; Hb: hemoglobin; IV: intravenous; PEG: pegylated; qwk: every week; q1wk: every week; q2wk: every 2 weeks; q4wk: every 4 weeks; SC: subcutaneous.
^a Defined as:

• ARCTOS: Hb level ≥ 11 g/dL and increased ≥ 1.0 g/dL from baseline at 28 wk; target Hb 11 – 13 g/dL
• AMICUS: Hb level ≥ 11 g/dL and increased ≥ 1.0 g/dL from baseline at 24 wk; target Hb 11 – 13 g/dL
• PROTOS, STRIATA: Mean Hb within ±1 g/dL of baseline values through 52 wk; target Hb 10 – 13.5 g/dL

^b Change from baseline Hb at 24 wk (AMICUS), 28 wk (ARCTOS), 36 wk (MAXIMA, STRIATA, RUBRA), or 52 wk (PROTOS).
^c Patients with stage 3 or 4 chronic kidney disease (creatinine clearance < 59 mL/min) who were not on dialysis.
^d For noninferiority to a predefined minimum of 60%.
^e For noninferiority to comparator; noninferiority margin for difference in mean Hb level (PEG-epoetin beta - comparator), -0.75 g/dL.
^f Both comparisons.
^g Trial investigators did not report statistical testing. Neither PEG-epoetin beta group differed statistically from comparator (BCBSA calculation; p = 0.52 for q2wk PEG-epoetin beta, p = 0.36 for q4wk PEG-epoetin beta).
^h Trial investigators did not report statistical testing. There was no statistical difference between groups (BCBSA calculation; p = 0.88).

Other Randomized Controlled Trials
Since the FDA approval, other short-term trials (24 – 40 weeks; total n = 841) have replicated the findings of the pivotal correction trials in patients on hemodialysis³⁸ and not on hemodialysis,^39,40 and of the pivotal maintenance trials in patients on hemodialysis.^41,42 Of 324 nondialysis patients in the ARCTOS correction trial, 296 (91%) entered a 24-week extension study.⁴³ Patients who responded to PEG-epoetin beta biweekly (n = 145) were re-randomized 1:1 to biweekly or monthly dosing to maintain hemoglobin levels between 11 g/dL and 13 g/dL. Mean hemoglobin levels were 11.9 g/dL, 11.7 g/dL, and 11.9 g/dL in the PEG-epoetin biweekly, PEG-epoetin monthly, and darbepoetin (weekly or biweekly) groups (n = 151), respectively. Within-patient variation in hemoglobin levels was similar across groups.

Systematic Reviews
A Cochrane review by Hahn et al. (2014) included random-effects meta-analyses of the 5 trials that enrolled dialysis patients listed in Table 5 and reported no statistical between-group differences in final hemoglobin level (vs. epoetin), overall mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis.⁴⁴ In the STRIATA trial, final hemoglobin level was statistically higher in the PEG-epoetin group compared with the darbepoetin group (mean difference, 0.30 g/dL; 95% CI, 0.05 to 0.55). Risk of bias was rated as low to moderate, and statistical heterogeneity was low to moderate (I² range, 0%-34%).

Peginesatide
The FDA approved Omontys (peginesatide) to treat anemia in CKD patients on dialysis in 2012 based on 2 randomized active-controlled noninferiority trials, which were summarized in a TEC Specialty Pharmacy Report (2012).⁴⁵ The first trial, Safety and Efficacy of Peginesatide for the Maintenance Treatment of Anemia in Hemodialysis Patients Previously Treated With Epoetin Alfa (EMERALD-1), enrolled 803 patients in the U. S., and controls received epoetin alfa (Epogen, Procrit). The second trial, Safety and Efficacy of Peginesatide for the Maintenance Treatment of Anemia in Hemodialysis Patients Previously Treated With Epoetin (EMERALD-2), enrolled 823 patients in the U. S. and Europe, and controls received epoetin alfa or epoetin beta (not available in the U. S.). Adults on dialysis for at least 3 months with stable hemoglobin concentrations (between 10.0 g/dL and 12.0 g/dL) on ESA therapy for at least 8 weeks were eligible for randomization to peginesatide once monthly or continued epoetin 1 to 3 times weekly for 36 weeks. Results for the primary efficacy outcome (between-arm difference of the change from baseline hemoglobin levels to the mean value during weeks 29 to 36 [the evaluation period], with a noninferiority margin of -1.0 g/dL) demonstrated the noninferiority of peginesatide in each trial (-0.15 g/dL in EMERALD-1, +0.10 g/dL in EMERALD-2). The relative risk (RR) for red blood cell transfusion also did not differ significantly between arms (RR = 1.21; 95% CI, 0.76 to 1.92 in EMERALD 1; RR = 0.79; 95% CI, 0.50 to 1.24 in EMERALD-2).

Two other trials ( Safety and Efficacy of Peginesatide for the Correction of Anemia in Patients With Chronic Renal Failure Not on Dialysis [PEARL-1] and Safety and Efficacy of Peginesatide for the Correction of Anemia in Patients With Chronic Renal Failure Not on Dialysis [PEARL-2]; total 656 randomized to peginesatide, 327 to darbepoetin) assessed patients with CKD who were not on dialysis.⁴⁵ The trials prospectively evaluated cardiovascular risk of ESAs. The 4 trials together were powered for a primary safety outcome, which was to rule out an increase of 30% or more in the risk of the composite safety endpoint, based on a 2-sided 90% CI. The composite safety endpoint comprised death, stroke, myocardial infarction, and hospitalization for congestive heart failure, unstable angina or arrhythmia. Incidence of the composite safety outcome did not differ significantly between groups randomized to peginesatide or an active comparator (HR = 1.06; 95% CI, 0.89 to 1.26). In an analysis limited to the 2 trials of patients on dialysis (EMERALD-1 and -2), the 2 groups again did not differ concerning theincidence of the composite safety endpoint (HR = 0.95; 90% CI, 0.79 to 1.13). However, peginesatide significantly increased the incidence of this composite safety endpoint in a pooled analysis of the 2 trials for patients, not on dialysis (PEARL-1 and -2; HR = -1.32; 90% CI, 1.02 to 1.72). Cardiovascular harms in the nondialysis population were considered unacceptably high, and the indication was abandoned.

In 2013, Affymax, Takeda, and the FDA announced a voluntary recall of all lots of peginesatide due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis. Serious reactions occurred within 30 minutes of the first dose of peginesatide; serious reactions after subsequent doses have not been reported. Among approximately 25000 patients who received peginesatide postapproval, the estimated overall incidence of hypersensitivity reactions was 2 per 1000, and the estimated incidence of fatal reactions was 2 per 10000. The FDA currently lists peginesatide (Omontys) as “discontinued” on its website.

Comparative Efficacy of Different ESAs
A systematic review by Wilhelm-Leen et al. (2015) evaluated mortality risk rates for darbepoetin alfa and epoetin alfa in patients with CKD.⁴⁶ The literature search, conducted up to October 2014, identified 10 studies (total Nn = 2149 patients) comparing darbepoetin alfa with epoetin alfa for inclusion. Eight studies included patients on dialysis and two included patients not requiring dialysis. No quality assessment of the studies was discussed. Meta-analyses found no significant difference in mortality rates between patients receiving darbepoetin alfa and patients receiving epoetin alfa.

A Cochrane network meta-analysis, published by Palmer et al. (2014), used indirect comparisons via network meta-analysis to evaluate comparative efficacy.⁴⁷ This analysis included RCTs published through February 2014 that compared 1 ESA with placebo, no treatment, or another ESA for the treatment of CKD. A total of 56 studies (total n = 15596 patients) were selected, the majority of which were judged to have a high or uncertain risk of bias. While all ESAs were found to be better than placebo in reducing the need for blood transfusions, the network meta-analysis did not detect differences in the efficacy of the various agents in preventing blood transfusions. Very few studies included patient-reported outcomes (e.g., QOL or energy level) and, as a result, the evidence base was insufficient to draw conclusions on the comparative efficacy of the different ESAs on these functional outcomes. Data were also limited on mortality outcomes (e.g., all-cause and cardiovascular) and myocardial infarction, stroke, and hypertension. Overall, due to the limitations of the data, reviewers could not determine whether one ESA was safer or more effective than another ESA.

A systematic review by Alsalimy et al. (2014) evaluated the efficacy of PEG-epoetin beta and darbepoetin for treatment of anemia in patients with CKD who are not dialysis-dependent.⁴⁸ Reviewers included 4 RCTs (total n = 1155 patients) and concluded that there were no differences between PEG-epoetin beta and darbepoetin on the change in hemoglobin levels.

A Cochrane review by Palmer et al. (2014) evaluated darbepoetin for treating anemia; it included 8 trials (total n = 2,051 patients) that compared darbepoetin with epoetin (alfa or beta) in adults with anemia due to CKD.²⁸ No statistically significant differences between ESAs were observed in random-effects meta-analyses of final hemoglobin level or mean change in hemoglobin level, overall mortality, cardiovascular events or cardiovascular mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis. Risk of bias was rated as moderate to high, and statistical heterogeneity was minimal (I² = 0%) for all outcomes.

Section Summary: CKD and Anemia
Three ESAs are FDA-approved for use in patients with CRF: epoetin alfa, PEG-epoetin beta, and darbepoetin alfa. Placebo-controlled trials have established that epoetin alfa and darbepoetin alfa effectively increase hemoglobin concentrations and decrease the need for blood transfusions. Evidence does not support an improvement in other clinical outcomes such as mortality and morbidity. The evidence is also inconsistent in showing significant improvements in functional status or QOL. Some trials and a meta-analysis published in 2012 reported increased cardiovascular events and/or increased mortality in patients treated with ESAs. These trials have treated to a hemoglobin level of 12 g/dL or higher. The optimal recommended target hemoglobin has been lowered, though there is no evidence that treating to lower hemoglobin levels avoids adverse events. Recent meta-analyses have addressed ESA administration issues. One meta-analysis reported that intravenous and subcutaneous ESA administration methods were equally effective in reducing the risk of blood transfusions and had similar adverse event profiles. Another meta-analysis showed that significantly lower ESA doses could be used when ironwas administered with the ESAs. A recent RCT has reported that patients receiving lower ESA doses experienced significantly higher QOL scores but were at higher risk of needing blood transfusions than patients receiving higher ESA doses. Differences in all-cause mortality and cardiovascular events were not detectedamong the patients receiving low ESA doses compared with those receiving high ESA doses.

PEG-epoetin beta has shown noninferiority to epoetin and darbepoetin for correcting or maintaining hemoglobin levels in RCTs of patients on dialysis or not on dialysis. In meta-analyses of trials involving dialysis patients, no statistical differences were reported in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. Evidence on the comparative effectiveness of the different agents is lacking. A Cochrane network meta-analysis did not detect differences in efficacy or adverse events among the different ESAs due to limited comparative evidence.

Peginesatide has been compared with other ESAs in randomized trials. Peginesatide has shown to be noninferior to epoetin for adults with CRF on dialysis. There are no trials reporting a benefit for peginesatide for other indications or in pediatric patients with kidney disease. Currently, peginesatide is unavailable and should not be used.

Cancer-Related Anemia
Clinical Context and Test Purpose
The purpose of epoetin alfa and darbepoetin is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with cancer-related anemia.

The question addressed in this evidence review is: Does the use of ESAs improve the net health outcome in patients with cancer-related anemia?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with cancer-related anemia.

Interventions
The therapies being considered are epoetin alfa and darbepoetin. Patients with cancer-related anemia are actively managed by oncologists in an outpatient setting.

Comparators
The following practice is currently being used to treat cancer-related anemia: standard of care. Treatment for cancer-related anemia commonly includes chemotherapy.

Outcomes
The general outcomes of interest are symptoms, morbid events, medication use, treatment-related mortality, and treatment-related morbidity. Follow-up at 12 and 37 weeks is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Epoetin Alfa and Darbepoetin
In 1993, the FDA approved Procrit and Epogen (epoetin alfa) to treat anemia in patients receiving cancer chemotherapy based on data from 2 multicenter randomized placebo-controlled, double-blind trials (one enrolled 344 adults, the other enrolled 222 pediatric patients). An additional pooled analysis of 6 smaller double-blind RCTs enrolled 131 patients. Patients in all 3 studies received at least 12 weeks of concurrent chemotherapy and were randomized (1:1) to receive Procrit or Epogen or placebo subcutaneously for 12 weeks. Overall, the data showed a reduction in the proportion of patients requiring a blood transfusion during the second and third months of epoetin treatment.

The approval of Aranesp (darbepoetin alfa) in 2002 for the treatment of anemia associated with cancer chemotherapy was based on demonstration of a significant reduction in the proportion of patients transfused during chemotherapy from week 5 through the end of treatment. Study 980297, a phase 3, double-blind, placebo-controlled randomized (1:1) multicenter, a multinational trial of darbepoetin alfa enrolled 314 anemic patients with previously untreated non-small-cell or small-cell lung cancer receiving at least 12 weeks of platinum-containing chemotherapy. 

After the first approval of an ESA for treatment of chemotherapy-associated anemia in 1993, additional data became available regarding for increased risks of mortality and possible tumor promotion from the use of ESAs. Increased mortality has been observed in patients with cancer (BEST, ENHANCE, 20000161, EPO-CAN-20 studies) when ESA treatment strategies were designed to achieve and maintain hemoglobin levels above 12 g/dL.¹¹ Also, ESA treatment strategies intended to achieve and maintain hemoglobin levels above 12 g/dL have demonstrated poorer tumor outcomes (BEST, ENHANCE, DAHANCA studies). In a meta-analyses using individual patient data on 13,933 subjects from 53 RCTs, Bohlius et al. (2009) reported significantly greater on-study mortality (HR = 1.17; 95% CI, 1.06 to 1.30) and poorer survival to end of follow-up (HR = 1.06; 95% CI, 1.00 to 1.12), with little heterogeneity between trials.^9,10 Results were qualitatively similar when the analysis was limited to 10,441 patients receiving concurrent chemotherapy in 38 trials, and there was little evidence for a difference between trials of patients receiving different chemotherapy regimens. 

Data from multiple trials, consistent with data presented to the FDA in 2004, led to revised product labeling with broader and more detailed warnings against ESA treatment strategies targeting hemoglobin levels above 12 g/dL. More recent data, including the individual patient data meta-analysis summarized above,^9,10 suggested that factors such as the planned hemoglobin ceiling for stopping ESA therapy had little influence on increased mortality resulting from ESA treatment. Although risks of hemoglobin targets greater than needed to avoid transfusions are now well-established, data from adequate, well-controlled studies employing recommended ESA doses and hemoglobin targets are insufficient to assess effects on survival or tumor promotion. The only data provided to the FDA which used the recommended dose and hemoglobin target was from Amgen Study 20010103, which demonstrated significantly shorter survival in cancer patients receiving ESAs compared with those supported by transfusion alone. However, this study was not adequately designed to assess the effects on tumor promotion or on thrombotic risks. 

Despite these caveats, data from available studies were sufficient for the FDA to reassess the safety of ESAs in patients with cancer and to re-evaluate the net clinical benefit of ESAs in this setting. 

Systematic Reviews 
A Cochrane review by Mhaskar et al. (2016) investigated the use of iron as a supplement to ESAs.⁴⁹ The literature search, conducted through February 2016, identified 8 RCTs (total n = 2,087 patients) that compared iron plus ESA with ESA alone for the treatment of patients with chemotherapy-induced anemia. Meta-analyses showed that patients receiving intravenous iron plus ESA achieved hematopoietic response significantly more often than patients receiving ESA alone. However, there was no difference in hematopoietic response among patients receiving oral iron plus ESA compared with patients receiving ESA alone. With the addition of iron to ESAs, there was no significant difference in the QOL or risk of thromboembolic events compared with ESA alone. None of the trials reported overall survival. 

Marchetti et al. (2016) investigated the use of ESAs, focusing on patients with gynecologic malignancies receiving myelosuppressive treatment.⁵⁰ The literature search, conducted through December 2014, identified 7 randomized trials (total n = 892 patients) for inclusion. Outcomes of interest included incidence of transfusions, thrombotic events, deaths, and treatment failures (defined as disease persistence or progression, or recurrence). The odds ratio (OR) for transfusion reduction was significantly lower for the ESAs group than the control group (0.3; 95% CI, 0.2 to 0.7). The OR for thrombotic events was significantly higher for the ESAs group than the control group (2.8; 95% CI, 1.3 to 6.2). Five trials (n = 559 patients) included data on death events. The pooled analyses showed no effect of ESAs on overall mortality (OR = 1.1; 95% CI, 0.8 to 1.5) or on treatment failures (OR = 1.7; 95% CI, 0.9 to 3.2). 

A meta-analysis examined the incidence of thromboembolic events in patients with solid and hematologic cancers who received ESAs and found a similar result.⁵¹ Gao et al. (2014) pooled 51 RCTs (total n = 12,115 patients) and reported a 75% increased odds of thromboembolic events among patients receiving ESAs (pooled OR = 1.75; 95% CI, 1.50 to 2.05; I² = 0%). 

Tables 6 and 7 summarize the characteristics and results of selected systematic reviews. 

Table 6. Characteristics of Systematic Reviews Assessing Cancer-Related Anemi 

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Mhaskar et al. (2016)49	2004 – 2011	8	Patients diagnosed with CIA	2087 (73 – 396)	RCT	≤ 20 wk
Marchetti et al. (2016)50	1997 – 2011	7	Patients with gynecologic cancer	892 (35 – 256)	RCT	NR
Gao et al. (2014)51	1993 – 2012	51	Patients with CIA	12,115 (NR)	RCT	NR

IA: chemotherapy-induced anemia; NR: not reported; RCT: randomized controlled trial. 

Table 7. Results of Systematic Reviews Assessing Cancer-Related Anemia 

Study	Increased Odds of TE	Hematopoietic Response	Red Blood Cell Transfusions	Transfusion Reduction	Overall Mortality
Mhaskar et al. (2016)49
RR		1.17	0.74
95% CI		1.09 to 1.26	0.6 to 0.92
P		< 0.001	0.007
Marchetti et al. (2016)50
OR				0.35	1.10
95% CI				0.19 to 0.65	0.82 to 1.49
p				0.008	0.53
Gao et al. (2014)51
POR	1.75
95% CI	1.50 to 2.05

CI: confidence interval; OR: odds ratio; POR: pooled odds ratio; RR: relative risk; TE: thromboembolic events. 

Results of the updated AHRQ comparative effectiveness review conducted by Grant et al. (2013)⁸ were consistent with those reported by Seidenfeld et al. (2006).⁶ Among patients receiving chemotherapy and/or radiotherapy for malignancy, use of ESAs to treat anemia reduced the risk of transfusion and increased the risk of thromboembolic events and on-study mortality. Both thromboembolic events and on-study mortality were reduced (but not eliminated) when ESA treatment was initiated at hemoglobin levels less than 10 g/dL. Although the reviewed evidence incorporated higher baseline and target hemoglobin levels than those currently recommended, sensitivity analyses suggested that these findings were robust. QOL, as assessed by the Functional Assessment of Cancer Therapy fatigue scale, was improved in patients receiving ESAs but the magnitude of improvement was less than the minimal clinically important difference of three points. Fifteen included trials did not support an association between ESA use and tumor response or progression; meta-analysis was not possible due to varying outcome definitions.

The AHRQ update incorporated the individual patient data meta-analysis previously described.^9,10 Despite differing inclusion criteria and methodologies, additional analyses of these data by Tonia et al. (2012)⁵² supported results of the updated AHRQ review, as shown in Table 8. 

Table 8. Comparison of Systematic Review Results 

Outcomes	2013 AHRQ		2012 Individual Patient Data
	n/N	TE (95% CI)	n/N	TE (95% CI)
Transfusions, RR	38/10,809	0.58 (0.53 to 0.64)	70/16,093	0.65 (0.62 to 0.68)
Thromboembolic events, RRa	37/12,570	1.51 (1.30 to 1.74)	57/15,278	1.52 (1.33 to 1.73)
On-study mortality, HRa	37/11,266	1.17 (1.04 to 1.31)	70/15,935	1.17 (1.06 to 1.29)
Tumor response, RRa	15/5577	Not pooledb	15/5012	1.02 (0.98 to 1.06)
FACT-fatigue, mean difference	14/3643	2.74c (1.69 to 3.78)	18/4965	2.08c (1.43 to 2.72)
Overall survival, HR for death	44/14,278	1.04 (0.99 to 1.10)	78/19,003	1.05 (1.00 to 1.11)
Hypertension, RR	16/4318	1.48 (1.07 to 2.06)	31/7228	1.12 (0.94 to 1.33)
Thrombocytopenia/hemorrhage, RRa	12/3714	1.17 (1.01 to 1.36)	21/4507	1.21 (1.04 to 1.42)

Adapted from Grant et al. (2013)⁸ and Tonia et al. (2012).⁵²
AHRQ: Agency for Healthcare Research and Quality; CI: confidence interval; FACT: Functional Assessment of Cancer Therapy; HR: hazard ratio; n/N: number of trials/number of patients; RR: relative risk; TE: treatment effect.
^a Results are similar between the two analyses.
^b No evidence of associations with erythropoiesis-stimulating agents.
^c Point estimate is less than the minimal clinically important difference (3 points).

Randomized Controlled Trials
In an RCT published after the systematic reviews, Leyland-Jones et al. (2016) compared epoetin alfa with standard of care for the treatment of patients with metastatic breast cancer who developed anemia due to chemotherapy.⁵³ Women included in the trial had histologically confirmed metastatic breast cancer, receiving first- or second-line chemotherapy, with hemoglobin levels of 11 g/dL or less. Participants were randomized to epoetin alfa (n = 1,050) or best standard care (n = 1,048). The primary endpoint was progression-free survival. Secondary endpoints included overall survival, time to tumor progression, thrombotic vascular events, and transfusions. The median duration of follow-up was 37 weeks. The median progression-free survival was 7.4 months in both groups (HR = 1.1; 95% CI, 0.9 to 1.2). The median overall survival was 17.2 months in the treatment group and 17.4 months in the standard of care group (HR = 1.1; 95% CI, 0.9 to 1.2). The median time to tumor progression was 7.5 months in both groups (HR = 1.1; 95% CI, 1.0 to 1.2). Thrombotic events were infrequent in both groups, though twice as many occurred in the ESA group (n = 29) compared with the standard of care group (n = 15; p = 0.04). Transfusions were infrequent in both groups, though significantly fewer in the ESA group (n = 61) than in the standard of care group (n = 119; p < 0.001).

Comparative Studies
In response to the FDA’s decision to lower the ESA treatment threshold to hemoglobin levels of 10 g/dL or less, Amgen sponsored two analyses, extracting data from several phase 3 trials, including only patients who initiated ESA treatment with a baseline hemoglobin level of 10 g/dL or less.

Boccia et al. (2016) compared the efficacy of darbepoetin alfa in patients with stage IV cancer and chemotherapy-induced anemia who initiated ESA treatment with baseline hemoglobin levels of 10 g/dL or less.⁵⁴ Data were extracted from three randomized, double-blind, placebo-controlled phase 3 trials. Patients in the three RCTs were diagnosed with nonmyeloid malignancies, lung cancer, or small-cell lung cancer. There were 213 patients meeting inclusion criteria, 115 receiving darbepoetin alfa and 98 receiving a placebo. Efficacy outcomes were hemoglobin level increase of 1 g/dL or more, hemoglobin level increase of 2 g/dL or more, and blood transfusion requirements. Data were limited to a follow-up of 12 weeks. Analyses showed that patients receiving ESA were significantly more likely to experience hemoglobin level increases of 1 g/dL or more and 2 g/dL or more (HR = 2.9; 95% CI, 1.9 to 4.4) compared with patients receiving placebo (HR = 3.0; 95% CI, 1.7 to 5.2). Patients receiving ESA were significantly less likely to need transfusions (HR = 0.4; 95% CI, 0.3 to 0.7).

Pirker et al. (2016) also conducted a comparative analysis as described in Boccia et al. (2016), as well as a separate analysis of data from single-arm studies of patients receiving darbepoetin alfa.⁵⁵ Data were abstracted from four randomized, double-blind, placebo-controlled trials for the comparative analysis. Patients in the four RCTs were diagnosed with nonmyeloid malignancies, lung cancer, small-cell lung cancer, or lymphoproliferative malignancies. There were 534 patients meeting inclusion criteria, 261 receiving darbepoetin alfa and 273 receiving a placebo. Fifteen studies (n = 3,768 patients) were included in the darbepoetin alfa-only analysis; the most common cancers were lung, gastrointestinal, breast, and hematologic. Analyses showed that patients receiving ESA were significantly more likely to experience hemoglobin level increases of 1 g/dL or more and 2 g/dL or more (HR = 2.1; 95% CI, 1.6 to 2.6) compared with patients receiving placebo (HR = 2.9; 95% CI, 2.1 to 4.1). Patients receiving ESA were significantly less likely to need transfusions (HR = 0.6; 95% CI, 0.4 to 0.8). Calculations from the single-arm studies showed similar percentages of ESA-treated patients experiencing hemoglobin level increases of 1 g/dL or more and 2 g/dL or more, and similar percentages requiring transfusions as ESA-treated patients in the comparative analyses.

Pegylated Epoetin Beta
PEG-epoetin beta is not FDA-approved for anemia due to cancer chemotherapy. A phase 2, open-label RCT by Gascon et al. (2010), conducted at 71 sites in Europe, Asia, and Australia, compared 3 doses of subcutaneous PEG-epoetin beta with subcutaneous darbepoetin in 153 patients receiving first-line chemotherapy for stage IIIB or IV non-small-cell lung cancer.⁵⁶ Baseline hemoglobin level at the screening was 11 g/dL or less. PEG-epoetin beta was administered every three weeks, and darbepoetin was administered weekly or every three weeks. The primary efficacy outcome (mean change from baseline hemoglobin level during weeks 5 to 13) did not differ between groups and indicated inadequate treatment responses in all groups (0.17 g/dL in the PEG-epoetin beta group vs 0.26 g/dL in the darbepoetin group). At week 12, the trial was terminated due to more deaths in the 3 PEG-epoetin beta groups (29 [25%] of 114 patients) than in the darbepoetin group (4 [10%] of 39 patients). Post hoc analyses did not convincingly demonstrate that baseline imbalances accounted for the mortality difference.

Section Summary: Cancer-Related Anemia
Epoetin alfa and darbepoetin alfa are approved by the FDA for patients with anemia associated with concurrent cancer chemotherapy. These ESAs effectively increase hemoglobin concentrations and decrease the need for blood transfusions in patients with anemia caused by chemotherapy. The evidence does not support an improvement in other clinical outcomes such as mortality, morbidity, functional status, or QOL. Some trials have reported higher thromboembolic events and/or mortality in cancer patients treated with ESAs, and 2 meta-analyses published in 2012 and 2013 also reported increases in mortality and thromboembolic events. Trials that reported increased adverse events have treated to a hemoglobin level of 12 g/dL or higher, and adverse events appear to correlate with higher treatment targets. These concerns over potential harm from ESAs led the FDA to reassess the risk-benefit ratio and to modify the labeled indications. Current FDA labeling recommends against starting ESA therapy in a cancer patient whose hemoglobin level exceeds 10 g/dL. Two comparative analyses found that patients receiving ESA therapy with the lower recommended hemoglobin threshold did experience benefits from the treatment, with significant increases in hemoglobin and decreases in transfusion needs. However, the data were limited to 12 weeks of follow-up, and the risk of thromboembolic events and other adverse events were not evaluated in this subgroup of patients. It is therefore unclear whether treating to a lower hemoglobin level reduces or eliminates these adverse events. When recent investigations focused on the use of ESAs for specific cancers, similar results were found compared with analyses that included various forms of cancer. A meta-analysis of RCTs including only gynecologic malignancies and an RCT focused on women with metastatic breast cancer. Both the meta-analysis and the RCT reported significantly lower transfusion rates and significantly higher thrombotic event rates and no differences in mortality rates.

PEG-epoetin beta is not FDA-approved for patients with anemia due to cancer chemotherapy. A phase 2 RCT demonstrated increased mortality among patients with advanced non-small-cell lung cancer who received PEG-epoetin beta compared with those who received darbepoetin.

Hepatitis C Infection and Ribavirin-Related Anemia
Clinical Context and Test Purpose
The purpose of epoetin alfa and darbepoetin is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with anemia related to use of ribavirin to treat hepatitis C infection.

The question addressed in this evidence review is: Does the use of ESAs improve the net health outcome in patients with hepatitis C infection who develop ribavirin-related anemia?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with anemia induced by the use of ribavirin to treat hepatitis C infection.

Interventions
The therapies being considered are epoetin alfa and darbepoetin.

Standard treatment for hepatitis C infection includes ribavirin. Anemia related to ribavirin use often is the limiting step in treatment. Options for treatment of ribavirin-related anemia are a reduction in the dose of ribavirin and use of ESAs and/or blood transfusions as needed. However, a reduction in ribavirin dose has been associated with less favorable response rates, and some experts use ESAs to maintain full-dose ribavirin.

Patients with anemia related to treatment for hepatitis C infection are actively managed by gastroenterologists, hepatologists, and infectious disease doctors in an outpatient clinical setting.

Comparators
The following practice is currently being used to treat anemia in those with hepatitis C infection: standard of care.

Outcomes
The general outcomes of interest are the QOL and medication use. Treatment of eight weeks is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Randomized Controlled Trials
An RCT by Shiffman et al. (2007) evaluated ESAs for anemia in patients with hepatitis C who were treated with ribavirin.⁵⁷ This trial randomized 150 patients to 3 groups at the onset of treatment: (1) ribavirin at standard dose; (2) ribavirin at standard dose plus epoetin alfa; and (3) ribavirin at higher dose plus epoetin alfa. Primary endpoints were a reduction in ribavirin dose and the proportion of patients with a sustained virologic response. Fewer patients treated with epoetin required dose reduction (10%) compared with patients not treated with epoetin (40%, p < 0.05) but the proportion of patients with sustained virologic response did not differ between groups.

At least two controlled trials have randomized patients with hepatitis C virus and ribavirin-related anemia to epoetin alfa or usual care. The larger of these was conducted by Afdhal et al. (2004).⁵⁸ This trial included 185 patients with a hemoglobin level of 12 g/dL or less who were randomized to 8 weeks of epoetin alfa at a dose of 40000 units weekly or placebo. Outcomes included the proportion of patients who were able to maintain full-dose treatment with ribavirin, mean hemoglobin level, and QOL as measured by SF-36. More patients in the epoetin group (88%) than in the placebo group (60%, p < 0.001) maintained full-dose ribavirin. Increase in mean hemoglobin level was higher in the epoetin group (2.2 g/dL) than in the usual care group (0.1 g/dL, p < 0.001). Improvement in QOL was significantly greater for the epoetin group on seven of eight domains, with incremental improvement ranging from 1.3 to 10.0 for patients on epoetin. Similar improvements were reported for patients from the placebo group who switched to epoetin alfa in the open-label phase, which followed the eight-week randomized trial.

An RCT by Dieterich et al. (2003)⁵⁹ was similar in design to the Afdhal et al. (2004) trial. Dieterich et al.(2003) enrolled 64 patients with hepatitis C and ribavirin-related anemia, as defined by a hemoglobin level of 12 g/dL or less. Patients were followed for 16 weeks and randomized to epoetin alfa 40000 units weekly or standard of care for anemia management (ribavirin dose reduction or discontinuation, or transfusions). Primary endpoints were ribavirin dose and hemoglobin level. The mean ribavirin dose decreased less in the epoetin group (-34 mg/d) than in the usual care group (-146 mg/d) but this difference was not statistically significant (p = 0.06). More patients in the epoetin group (83%) than in the usual care group (54%, p = 0.02) maintained full-dose ribavirin. The mean hemoglobin level was higher in the epoetin group (13.8 g/dL) than in the usual care group (11.4 g/dL; p < 0.001).

Section Summary: Hepatitis C Infection Treated and Ribavirin-Related Anemia
RCTs of ESAs vs placebo for patients with hepatitis C and ribavirin-related anemia have demonstrated that use of ESAs can improve hemoglobin levels and allow more patients to maintain treatment at full ribavirin doses. One RCT also reported improvement in the QOL for patients treated with ESAs. Improvements in these parameters may lead to health outcome benefits, although no study has reported an improvement in clinical outcomes such as sustained virologic response or survival.

Summary of Evidence
For individuals who have CKD and anemia who receive epoetin alfa, PEG-epoetin beta, or darbepoetin, the evidence includes RCTs and systematic reviews of RCTs. The relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. All three ESAs have been studied and approved for this use. Most of the evidence has demonstrated an increase in hemoglobin and a decrease in blood transfusions but has failed to demonstrate any significant improvement in clinical outcomes such as mortality and morbidity. Many studies have demonstrated increased mortality risk and increased risk for venous access thrombosis and stroke, prompting FDA warnings. The evidence is also inconsistent in showing improvements in functional status and QOL. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have cancer-related anemia who receive epoetin alfa or darbepoetin, the evidence includes RCTs, comparative analyses, and systematic reviews of RCTs. The relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. The available trials have demonstrated an increase in hemoglobin concentration and a decrease in the need for blood transfusions. However, the evidence has also demonstrated increased mortality rates and possible tumor promotion, as well as increased risk of thromboembolic events when target hemoglobin levels were above 12 g/dL. Comparative analyses have shown that when the target hemoglobin level was lowered to 10 g/dL, patients experienced increased hemoglobin and decreased risk for blood transfusions. Length of follow-up was short in the comparative analyses, and mortality and adverse events were therefore not addressed. Epoetin alfa and darbepoetin are the ESAs approved for use in the treatment of cancer-related anemia; PEG-epoetin beta is not approved by the FDA this indication, because studies have demonstrated increased mortality and no significant improvement in clinical outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have hepatitis C infection treated with ribavirin who receive epoetin alfa or darbepoetin, the evidence includes RCTs. The relevant outcomes are QOL and medication use. Evidence from RCTs has demonstrated that treatment with ESAs improves the ability to maintain full-dosing of ribavirin because anemia is often a limiting effect for treatment. There may also be a positive effect on the QOL, although this is less certain. Epoetin alfa and darbepoetin are the ESAs approved for this use. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 4 academic medical centers and 2 specialty societies while this policy was under review in 2012. Reviewers agreed with the current medically necessary indications. There was support for the treatment of patients with hepatitis C and ribavirin-related anemia. For investigational indications, reviewers agreed with the current policy statements.

Practice Guidelines and Position Statements
National Kidney Foundation
The National Kidney Foundation (2012) published the Kidney Disease: Improving Global Outcomes clinical practice guidelines for anemia in chronic kidney disease (CKD).⁶⁰ A consensus of an international group of experts created comprehensive, evidence-based guidance for the treatment of anemia in CKD. The Kidney Disease: Improving Global Outcomes recommendation on initiation and maintenance of erythropoiesis-stimulating agents (ESAs) was based on balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension). Recommendations for treatment initiation and maintenance are listed in Table 9.

Table 9. Recommendations for Initial and Maintenance ESA Therapy for Anemia in CKD

Recommendation	LOR
Initial therapy
“We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy ... a history of stroke or a history of malignancy.”	1B 1B 2C
“For adult CKD ND patients with Hb concentration ≥ 10.0 g/dl (≥ 100 g/l) we suggest that ESA therapy not be initiated.”	2D
“For adult CKD ND patients with Hb concentration ≤ 10.0 g/dl (< 100 g/l) we suggest that the decision whether to initiate ESA therapy be individualized based on the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia.”	2C
“For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the Hb concentration fall below 9.0 g/dl (90 g/l) by starting ESA therapy when the hemoglobin is between 9.0 – 10.0 g/dl (90 – 100g/l).”	2B
Maintenance therapy
“… we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adult patients with CKD.”	2C
“Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hb concentration above 11.5 g/dl (115 g/l) and will be prepared to accept the risks.”	Not graded
“… we recommend that ESAs not be used to intentionally increase the Hb concentration above 13 g/dl (130 g/l).”	1A

CKD: Chronic Kidney Disease; ESA: erythropoiesis-stimulating agent; Hb: hemoglobin; LOR: level of recommendation; ND: nondialysis.

American Society of Clinical Oncology et al.
Table 10 summarizes current clinical practice guidelines published jointly by the American Society of Clinical Oncology and the American Society of Hematology¹¹ and from the National Comprehensive Cancer Network (v.2.2019).⁶¹

Table 10. Summary of Guidelines on ESA Therapy to Treat Anemia in Cancer Patients

Indications	ASCO/ASH 2010 Clinical Practice Guidelines	NCCN Guidelines (v.2.2019)
ESAs are indicated for:	Depending on clinical circumstances, ESAs may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin (HgB) has declined to < 10 g/dl. RBC transfusion is also an option, depending on the severity of anemia or clinical circumstances (Type: EB; EQ: high; SOR: strong)	· Based on patient preference and values, patients undergoing palliative treatment or myelosuppressive chemotherapy without curative intent may be treated with ESAs using FDA-approved indications/dosing/dosing adjustments OR may be treated with RBC transfusions per provided guidelines
ESAs are NOT indicated for:	Patients with chemotherapy-associated anemia whose cancer treatment is curative in intent (Type: EB; EQ: intermediate; SOR: strong) ESAs should not be offered to most patients with nonchemotherapy-associated anemia (Type: IC; EQ: low; SOR: strong)	· ESA treatment is not recommended when patients are treated with myelosuppressive chemotherapy with curative intent · ESA treatment is not recommended when patients are not receiving therapy or palliative treatment, or those on non-myelosuppressive therapy
ESA treatment symptom outcomes	Not discussed	Not discussed
Hb levels for ESA initiation	ESAs may be offered to patients with lower risk myelodysplastic syndromes and a serum erythropoietin level ≤ 500 IU/L (Type: EB; EQ: intermediate; SOR: moderate)	If Hb is < 11 g/dL or > 2 g/dL below baseline, an evaluation for possible causes of anemia is suggested. If a cause is not identified, then anemia due to myelosuppressive chemotherapy is considered
Span of ESA treatment	Not discussed	Physicians advised not to administer ESAs outside the treatment period of cancer-related chemotherapy
ESA dosing modifications	It is recommended that starting and modifying doses of ESAs follow FDA guidelines (Type: IC; EQ: intermediate; SOR: moderate)	Dosing and titration directions for epoetin alfa and darbepoetin alfa are reproduced from FDA-approved labels; alternative dosing regimens are provided, e.g., every 2 or 3 wk instead of weekly injections
Hb target	Hgb may be increased to the lowest concentration needed to avoid or reduce the need for RBC transfusions, which may vary by patient and condition (Type: IC; EQ: intermediate: SOR: moderate)	No Hb target is mentioned; notes that the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to a target Hb < 12 g/dL
Iron	Iron replacement may be used to improve HgB response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation, or ferritin levels is recommended (Type: EB; EQ: intermediate; SOR: weak)	Iron studies and supplementation of functional iron deficiency are recommended for patients treated with ESAs. These include serum iron, TIBC, and serum ferritin. Any patient with cancer who develops a sudden loss of response to ESAs, accompanied by severe anemia and a low reticulocyte count, should be evaluated for the etiology of loss of effect
Thromboembolic risk	In patients with myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia, clinicians should observe the hematologic response to cancer treatment before considering an ESA. Particular caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases where risk of thromboembolic complications is increased. In all cases, blood transfusion is a treatment option that should be considered (Type: IC; EQ: low; SOR: moderate) ESAs increase the risk of thromboembolism, and clinicians should carefully weigh the risks of thromboembolism and use caution and clinical judgment when considering use of these agents (Type EB; EQ: high; SOR: strong)	Patients with previous risk factors for thrombosis may be at higher risk when administered ESAs and should undergo risk assessment
Response to treatment	ESAs should be discontinued in patents who do not respond within 6 to 8 weeks. Patients who do not respond to ESA treatment should be reevaluated for underlying tumor progression, iron deficiency, or other etiologies for anemia (Type: IC; EQ: intermediate; SOR: strong)	ESA therapy should be discontinued if a patient shows no response despite iron supplementation after 8 wks of treatment. ESA dose-adjustment decisions are based on the goal of a gradual increase in Hb level that remains sufficient to avoid transfusion

EB: evidence-based; EQ: evidence quality; SOR: strength of recommendation; IC: informal consensus; ASCO: American Society of Clinical Oncology; ASH: American Society of Hematology; ESA: erythropoiesis-stimulating agent; FDA: Food and Drug Administration; HgB: hemoglobin; NCCN: National Comprehensive Cancer Network; RBC: red blood cell; TIBC: total iron-binding capacity.

American Society of Nephrology
The American Society of Nephrology (2012) released its evidence-based recommendations for the Choosing Wisely campaign to improve patient care and resource use.⁶² The Society included the following among its top five recommendations: “Do not administer erythropoiesis-stimulating agents to CKD patients with hemoglobin levels ≥ 10 g/dL without symptoms of anemia.”

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Currently, ongoing or unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02890602	A Phase II Study of Erythropoietin for Management of Anemia Caused by Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma	53	Dec 2018
NCT03010579	Efficacy and Safety of Erythropoietin in the Treatment of Anemia in Patients with Lymphoma after Autologous Stem Cell Transplantation	70	Dec 2018 (unknown)
Unpublished
NCT02052310a	Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of the Efficacy and Safety of FG-4592 (Roxadustat) in the Treatment of Anemia in Incident-Dialysis Patients	900	Sep 2018 (completed)
NCT01581073	Prevention of End-Stage Kidney Disease by Darbepoetin Alfa in Chronic Kidney Disease Patients with nondiabetic Kidney Disease	476	Dec 2017 (completed)
NCT00773513a	A Randomized, Controlled, Open-Label, Multicenter, Parallel-Group Study to Assess All-cause Mortality and Cardiovascular Morbidity in Patients with Chronic Kidney Disease on Dialysis and Those Not on Renal Replacement Therapy Under Treatment with Mircera® or Reference ESAs	2,825	Jul 2017 (completed)
NCT00338286a	A Randomized Open-Label, Multicenter, Phase 3 Study of Epoetin Alfa Plus Standard Supportive Care Versus Standard Supportive Care in Anemic Patients with Metastatic Breast Cancer Receiving Standard Chemotherapy	2,098	Jan 2017 (completed)
NCT01383460	Efficacy of Granulocyte Colony-stimulating Factor and Erythropoietin for Patients with Acute-on-chronic Liver Failure	55	Jan 2013 (completed)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.  

References: 

1. Food and Drug Administration (FDA). Postmarket Drug Safety Information for Patients and Providers: Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp). 2017; https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm109375.htm. Accessed September 29, 2018.
2. Hoffmann-LaRoche. Highlights of Prescribing Information: Mircera<ae> (methoxy polyethylene glycol-epoetin beta). 2014; https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125164s062lbledt.pdf. Accessed September 29, 2018.
3. Amgen. Highlights of Prescribing Information: Aranesp<ae> (darbepoetin alfa). 2018; https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aranesp/ckd/aranesp_pi_hcp_english.ashx. Accessed September 29, 2018.
4. Amgen. Highlights of Prescribing Information: Epogen<ae> (epoetin alfa). 2018; https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/epogen/epogen_pi_hcp_english.ashx. Accessed September 29, 2018.
5. Janssen. Highlights of Prescribing Information: Procrit<ae> (epoetin alfa). 2018; http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/PROCRIT-pi.pdf. Accessed September 29, 2018.
6. Seidenfeld J, Piper M, Bohlius J, et al. Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment (Comparative Effectiveness Review No. 3). Rockville, MD: Agency for Healthcare Research and Quality; 2006.
7. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta- analysis of 57 studies including 9353 patients. J Natl Cancer Inst. May 17 2006;98(10):708-714. PMID 16705125.
8. Grant MD, Piper M, Bohlius J, et al. Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update (Comparative Effectiveness Review No. 113). Rockville, MD: Agency for Healthcare Research and Quality; 2013.
9. Bohlius J, Schmidlin K, Brillant C, et al. Erythropoietin or Darbepoetin for patients with cancer--meta-analysis based on individual patient data. Cochrane Database Syst Rev. Jul 08 2009(3):CD007303. PMID 19588423.
10. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. May 2 2009;373(9674):1532-1542. PMID 19410717.
11. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. https://ascopubs.org/doi/pdf/10.1200/JCO.18.02142. Accessed August 5, 2019.
12.  Food and Drug Administration (FDA) ODAC. FDA Briefing Document: Continuing reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with cancer chemotherapy. 2007; https://wayback.archive- it.org/7993/20170405053529/https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf. Accessed September 29, 2018.
13. Centers for Medicare & Medicaid Services (CMS). Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N). 2007; https://www.cms.gov/medicare-coverage- database/details/nca-decision- memo.aspx?NCAId=203&ver=12&NcaName=Erythropoiesis+Stimulating+Agents+&bc=BEAAAAAAIAAA. Accessed September 29, 2018.
14. Food and Drug Administration (FDA). FDA Advisory Committee Briefing Document: Joint meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Committee. Reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with chronic renal failure. 2007; https://wayback.archive- it.org/7993/20170405051117/https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4315b1-01-FDA.pdf. Accessed September 29, 2018.
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16. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. Sep 2007;50(3):471-530. PMID 17720528.
17. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. Aug 27 1998;339(9):584-590. PMID 9718377.
18. Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol. Nov 2007;2(6):1274-1282. PMID 17942772.
19. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. Nov 16 2006;355(20):2085-2098. PMID 17108343.
20. Inrig JK, Barnhart HX, Reddan D, et al. Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. Am J Kidney Dis. Sep 2012;60(3):390-401. PMID 22537421.
21. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. Nov 16 2006;355(20):2071-2084. PMID 17108342.
22. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. Nov 19 2009;361(21):2019-2032. PMID 19880844.
23. Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation. Dec 20 2011;124(25):2903-2908. PMID 22104547.
24. Amato L, Addis A, Saulle R, et al. Comparative efficacy and safety in ESA biosimilars vs. originators in adults with chronic kidney disease: a systematic review and meta-analysis. J Nephrol. Jun 2018;31(3):321-332. PMID 28646375.
25. Roger SD, Tio M, Park HC, et al. Intravenous iron and erythropoiesis-stimulating agents in haemodialysis: A systematic review and meta-analysis. Nephrology (Carlton). Dec 2017;22(12):969-976. PMID 27699922.
26. Cody JD, Hodson EM. Recombinant human erythropoietin versus placebo or no treatment for the anaemia of chronic kidney disease in people not requiring dialysis. Cochrane Database Syst Rev. Jan 20 2016(1):CD003266. PMID 26790135.
27. Collister D, Komenda P, Hiebert B, et al. The effect of erythropoietin-stimulating agents on health-related quality of life in anemia of chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. Apr 05 2016;164(7):472-478. PMID 26881842.
28. Palmer SC, Saglimbene V, Craig JC, et al. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. Mar 31 2014;3(3):CD009297. PMID 24683046.
29. Vinhas J, Barreto C, Assuncao J, et al. Treatment of anaemia with erythropoiesis-stimulating agents in patients with chronic kidney disease does not lower mortality and may increase cardiovascular risk: a meta-analysis. Nephron Clin Pract. Nov 2012;121(3-4):c95-101. PMID 23182871.
30. Saglimbene V, Palmer SC, Craig JC, et al. Low versus high dose erythropoiesis-stimulating agents in hemodialysis patients with anemia: A randomized clinical trial. PLoS One. Mar 1 2017;12(3):e0172735. PMID 28249030.
31. Walker RG, Strippoli GF. A pegylated epoetin in anaemia of renal disease: non-inferiority for an unvalidated surrogate. Lancet. Oct 20 2007;370(9596):1395-1396. PMID 17950848.
32. Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol. Mar 2008;3(2):337-347. PMID 18287255.
33. Klinger M, Arias M, Vargemezis V, et al. Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. Am J Kidney Dis. Dec 2007;50(6):989-1000. PMID 18037099.
34. Canaud B, Mingardi G, Braun J, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrol Dial Transplant. Nov 2008;23(11):3654-3661. PMID 18586762.
35. Spinowitz B, Coyne DW, Lok CE, et al. C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. Am J Nephrol. 2008;28(2):280-289. PMID 18004064.
36. Levin NW, Fishbane S, Canedo FV, et al. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet. Oct 20 2007;370(9596):1415-1421. PMID 17950856.
37. Sulowicz W, Locatelli F, Ryckelynck JP, et al. Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clin J Am Soc Nephrol. Jul 2007;2(4):637-646. PMID 17699476.
38. Oh J, Joo KW, Chin HJ, et al. Correction of anemia with continuous erythropoietin receptor activator in Korean patients on long-term hemodialysis. J Korean Med Sci. Jan 2014;29(1):76-83. PMID 24431909.
39. Vankar SG, Dutta P, Kohli HS, et al. Efficacy & safety of continuous erythropoietin receptor activator (CERA) in treating renal anaemia in diabetic patients with chronic kidney disease not on dialysis. Indian J Med Res. Jan 2014;139(1):112-116. PMID 24604046.
40. Roger SD, Locatelli F, Woitas RP, et al. C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis. Nephrol Dial Transplant. Dec 2011;26(12):3980-3986. PMID 21505096.
41. Al-Ali FS, El-Sayed Abdelfattah M, Fawzy AA, et al. Erythropoietin-stimulating agents in the management of anemia of end-stage renal disease patients on regular hemodialysis: a prospective randomized comparative study from Qatar. Hemodial Int. Jan 2015;19(1):33-43. PMID 24894344.
42. Hirai T, Nishizawa Y, Nakazono H, et al. Hemoglobin maintenance and dosing strategies using intravenous continuous erythropoietin receptor activator in Japanese hemodialysis patients. Ther Apher Dial. Oct 2013;17(5):498-503. PMID 24107278.
43. Kessler M, Martinez-Castelao A, Siamopoulos KC, et al. C.E.R.A. once every 4 weeks in patients with chronic kidney disease not on dialysis: The ARCTOS extension study. Hemodial Int. Apr 2010;14(2):233-239. PMID 19888948.
44. Hahn D, Cody JD, Hodson EM. Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients. Cochrane Database Syst Rev. May 28 2014;5(5):CD003895. PMID 24872328.
45. Technology Evaluation Center (TEC). TEC Specialty Pharmacy Reports: Peginesatide: #6-2012. Chicago, IL; 2012.
46. Wilhelm-Leen ER, Winkelmayer WC. Mortality risk of darbepoetin alfa versus epoetin alfa in patients with CKD: systematic review and meta-analysis. Am J Kidney Dis. Jul 2015;66(1):69-74. PMID 25636816.
47. Palmer SC, Saglimbene V, Mavridis D, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. Dec 08 2014;12(12):CD010590. PMID 25486075.
48. Alsalimy N, Awaisu A. Methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa for anemia in non- dialysis-dependent CKD: a systematic review. Int J Clin Pharm. Dec 2014;36(6):1115-1125. PMID 25288147.
49. Mhaskar R, Wao H, Miladinovic B, et al. The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents. Cochrane Database Syst Rev. Feb 04 2016;2:CD009624. PMID 26845108.
50. Marchetti C, De Felice F, Palaia I, et al. Erythropoiesis-stimulating agents in gynecological malignancies: A study-level meta-analysis. Crit Rev Oncol Hematol. Mar 2016;99:123-128. PMID 26748593.
51. Gao S, Ma JJ, Lu C. Venous thromboembolism risk and erythropoiesis-stimulating agents for the treatment of cancer-associated anemia: a meta-analysis. Tumour Biol. Jan 2014;35(1):603-613. PMID 23959477.
52. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. Dec 12 2012;12:CD003407. PMID 23235597.
53. Leyland-Jones B, Bondarenko I, Nemsadze G, et al. A randomized, open-label, multicenter, phase III study of epoetin alfa versus best standard of care in anemic patients with metastatic breast cancer receiving standard chemotherapy. J Clin Oncol. Apr 10 2016;34(11):1197-1207. PMID 26858335.
54. Boccia RV, Henry DH, Belton L, et al. Efficacy and safety of darbepoetin alfa initiated at hemoglobin ≤10 g/dL in patients with stage IV cancer and chemotherapy-induced anemia. Cancer Med. Dec 2016;5(12):3445-3453. PMID 27882724.
55. Pirker R, Hedenus M, Vansteenkiste J, et al. ffectiveness of darbepoetin alfa for chemotherapy-induced anemia when initiated at hemoglobin ≤ 10 g/dL. Clin Ther. Jan 01 2016;38(1):122-135.e126. PMID 26730453.
56. Gascon P, Pirker R, Del Mastro L, et al. Effects of CERA (continuous erythropoietin receptor activator) in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy: results of a phase II study. Ann Oncol. Oct 2010;21(10):2029-2039. PMID 20335369.
57. Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology. Aug 2007;46(2):371-379. PMID 17559152.
58. Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. May 2004;126(5):1302-1311. PMID 15131791.
59. Dieterich DT, Wasserman R, Brau N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. Nov 2003;98(11):2491-2499. PMID 14638354.
60. Kliger AS, Foley RN, Goldfarb DS, et al. KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. Am J Kidney Dis. Nov 2013;62(5):849-859. PMID 23891356.
61. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Hematopoietic Growth Factors. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf. Accessed August 5, 2019.
62. Williams AW, Dwyer AC, Eddy AA, et al. Critical and honest conversations: the evidence behind the Choosing Wisely campaign recommendations by the American Society of Nephrology. Clin J Am Soc Nephrol. Oct 2012;7(10):1664-1672. PMID 22977214.
63. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (110.21). 2007; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=322&ncdver=1&bc=AAAAgAAAAAAAAA%3d%3d&. Accessed September 29, 2018. 

Coding Section

Codes	Number	Description
CPT	96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
	96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
ICD-9 Procedure	99.29	Injection or infusion of other therapeutic or prophylactic substance
ICD-9 Diagnosis	042	HIV disease
	070.44, 070.54	Chronic hepatitis C codes
	238.71 – 238.75	Neoplasm of uncertain behavior of other and unspecified sites and tissues; other lymphatic and hematopoietic tissues (includes myelodysplastic syndrome)
	285.9	Anemia, unspecified (There is no classification for anemia specifically related to renal failure, AZT use, or chemotherapy)
	585.1 – 585.9	Chronic renal failure; code range
	V42.81 – V42.82	Status posttransplant of bone marrow (V42.81) or peripheral stem cells (V42.82)
HCPCS	J0881	Injection, darbepoetin alfa, 1 mcg (non-ESRD use)
	J0882	Injection, darbepoetin alfa, 1 mcg (for ESRD on dialysis)
	J0885	Injection, epoetin alfa, (for non-ESRD use), 1000 units
	J0886	Injection, epoetin alfa, 1000 units (for ESRD on dialysis)
	J0887	Injection, epoetin beta, 1 microgram (non-ESRD use) (new code 01/01/15)
	J0888	Injection, epoetin beta, 1 microgram (for ESRD on dialysis)(new code 01/01/15)
	J0890	Injection, peginesatide, 0.1 mg ( for ESRD on dialysis)
	Q4081	Injection, epoetin alfa, 100 units (for ESRD on dialysis)
	Q5105	Injection, epoetin alfa, biosimilar, (RETACRIT) (for ESRD on dialysis), 100 units
	Q5106	Injection, epoetin alfa, biosimilar, (RETACRIT) (for non-ESRD use), 1000 units
	Q9972	Injection, epoetin beta, 1 microgram (for ESRD on dialysis) (code deleted 12/31/14)
	Q9973	Injection, epoetin beta, 1 microgram (non-ESRD use) (code deleted 12/31/14)
icd-10-cm (effective 10/01/15)	B18.2	Chronic viral hepatitis C
	B20	Symptomatic HIV
	D46.9	Myelodysplastic syndromes
	D47.0 – D47.9	Other neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue, code range
	D63.1	Anemia in chronic kidney disease (EPO resistant anemia)
	D64.2	Secondary sideroblastic anemia due to drugs and toxins
	D64.81	Anemia due to antineoplastic chemotherapy
	N18.1 – N18.9	Chronic renal failure, code range
	Z94.81	Bone marrow transplant status
	Z94.84	Stem cells transplant status
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services. There are no ICD-10-PCS codes for drugs.
	3E033GC,3E043GC, 3E053GC, 3E063GC	Administration, introduction, percutaneous, other therapeutic substance, code by body part (peripheral vein, central vein, peripheral artery, or central artery)
Type of Service	Prescription Drug (Injection)
Place of Service	Inpatient, Outpatient, Physician’s office, Home

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward     

02/20/2024	Interim review, updating policy coverage and criteria.
01/25/2023	Annual review, no change to policy intent
01/24/2022	Adding clarifying language regarding chronic kidney disease and dialysis. No other changes made.
01/27/2021	Interim review to add Q5105 and Q5106 to the coding.
01/19/2021	Annual review, no change to policy intent.
01/21/2020	Annual review, no change to policy intent. Updating rationale and references.
01/29/2018	Annual review, no change to policy intent. Updating background, regulatory status, rationale, references, and coding.
01/30/2018	Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references.
01/24/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
01/28/2016	Annual review. No change to policy intent.
01/28/2015	Annual review, added verbiage regarding medical necessity & investigational uses of PEG-epoetin beta. Updated guidelines, rationale, references, description and background. Adding coding.
01/27/2014	Updated description, rationale, references and exclusions, added medical necessity verbiage for myelodysplastic syndrome.