Medical Policy

Policy Num:       05.001.038
Policy Name:     Erythropoiesis-Stimulating Agents
Policy ID:          [05.001.038]  [Ac / B / M+ / P+]  [5.01.04]

Last Review:      November 11, 2024
Next Review:      November 20, 2025
 

Related Policies:  None

Erythropoiesis-Stimulating Agents 

summary

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; eg, 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.

Summary of Evidence

For individuals who have chronic kidney disease and anemia who receive epoetin alfa, pegylated (PEG)-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 erythropoiesis-stimulating agents (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 U.S. FDA warnings. The evidence is also inconsistent in showing improvements in functional status and quality of life (QOL). The evidence is sufficient to determine that the technology results in an 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; PEG-epoetin beta is not approved by the FDA 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 an 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 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 an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether the use of erythropoiesis-stimulating agents improves the net health outcome in patients with chronic kidney disease and anemia; cancer-related anemia; and hepatitis C infection treated with ribavirin.

Policy statements

The use of epoetin alfa, darbepoetin, or pegylated epoetin beta may be considered medically necessary for:

• treatment of anemia associated with chronic kidney disease.^a,b,c

The use of pegylated epoetin beta is investigational for all other indications.

The use of epoetin alfa or darbepoetin may be considered medically necessary for:

• treatment of anemia in individuals with cancer with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy;^a,b

• treatment of anemia related to therapy with AZT (zidovudine) in HIV-infected individuals;^a

• reduction of allogeneic blood transfusion in surgery individuals;^a

• treatment of individuals after allogeneic bone marrow transplantation; and

• treatment of individuals with myelodysplastic syndromes to reduce transfusion dependency.

The use of epoetin alfa or darbepoetin may be considered medically necessary for:

• treatment of individuals with hepatitis C and anemia related to ribavirin treatment.

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

• The lowest dose of erythropoiesis-stimulating agents should be used to avoid red blood cell transfusions;

• Erythropoiesis-stimulating agents should not be used to raise the hemoglobin level above 12 g/dL; and

• Erythropoiesis-stimulating agent therapy should not be administered without adequate iron stores.

For medically necessary use in cancer patients, these additional U.S. Food and Drug Administration criteria apply:

• Epoetin alfa or darbepoetin treatment should not be initiated at hemoglobin levels of 10 g/dL or higher; and

• Epoetin alfa or darbepoetin treatment should be discontinued after completion of a myelosuppressive chemotherapy course.

The use of epoetin alfa or darbepoetin is investigational for:

• treatment of individuals after high-dose chemotherapy with autologous stem cell support;

• treatment of noniatrogenic chronic anemia of cancer; and

• other cancer-associated anemia except as noted above.

a FDA-approved label for epoetin alfa (Epogen, Procrit).b FDA-approved label for darbepoetin alfa (Aranesp).c FDA-approved label for pegylated epoetin beta (Mircera).

Policy Guidelines

Throughout this evidence review, unless otherwise stated:

• The term ESA refers to epoetin alfa (Epogen^®, Amgen; Procrit^®, Janssen Product) and darbepoetin alfa (Aranesp^®; Amgen).

• Non-myeloid malignancies include solid tumors and the non-myeloid hematologic malignancies include myeloma, lymphoma, and chronic lymphocytic leukemia.

Administration

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

Before commencing ESA or PEG-epoetin beta therapy, the individual's iron stores, blood ferritin, and transferrin saturation should be evaluated, adjusted, and maintained within normal physiologic limits. Therapy with ESA or PEG-epoetin beta 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. Use of ESAs and PEG-epoetin beta are contraindicated in individuals with uncontrolled hypertension.

Discontinuation

Erythropoiesis-Stimulating Agents

Individuals 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.

Erythropoiesis-Stimulating Agents and Pegylated Epoetin Beta

Individuals 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 PEG-epoetin beta dose further is unlikely to improve response and may increase risks; the lowest ESA or PEG-epoetin beta dose that maintains adequate hemoglobin 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

Clinical studies have shown that treatment with epoetin alfa and darbepoetin alfa for individuals with cancer may result in shorter overall survival and/or increased risk of progression or recurrence. Additional studies of individuals with chronic kidney disease 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, FDA implemented a risk evaluation and mitigation strategy (REMS) in 2011 under which providers and hospitals were required to counsel individuals , and each individual had to complete a provider acknowledgment form before treatment.

In April 2017, FDA eliminated the REMS for Epogen, Procrit, and Aranesp, stating 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 and Medicaid Services’ (CMS) National Coverage Determination, the American Society of Clinical Oncology, and American Society of Hematology clinical guidelines, which are evidence-based guidelines intended to provide a basis for the standard of care in clinical oncology.”

There is no REMS for PEG-epoetin beta.

In 2012, the FDA approved a REMS for peginesatide with a communication plan as its only component. The plan’s goal was to inform all health care professionals who might prescribe the drug that peginesatide is indicated only for adults with chronic kidney disease on dialysis, as well as to warn health care professionals of potentially fatal risks associated with its use in patients with chronic kidney disease not on dialysis. Peginesatide is currently discontinued.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Erythropoietin is adjudicated under the drug benefit as an injectable.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Triple S Salud Preferred Drugs Determination:

First treatment of choice will be biosimilar Retacrit.  In order to consider any other RBC's agents, patients must have documented previous use and therapeutic failure, intolerance or contraindication to Retacrit. 

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. 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 (eg, 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 due to: (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.

Red blood cell 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 (eg, 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 the appropriately indicated patients.

Table 1 summarizes the 4 ESA products that have been licensed in the U.S.; however, peginesatide is no longer manufactured.

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 and darbepoetin 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, pegylated epoetin beta, and darbepoetin alfa are approved by the U.S. Food and Drug Administration (FDA) to treat anemia in patients with CKD who are on or are not 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

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 FDA 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 acknowledgment form before treatment.

In April 2017, the FDA 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 and 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.”

Postapproval FDA Regulatory Actions

In 2006, the FDA issued an advisory on the serious cardiovascular risks from ESA therapy in patients with CKD, as evidenced in the Correction of Hemoglobin and Outcomes in Renal Insufficiency and the Normal Hematocrit Cardiac Trial studies.^1, Subsequently, the 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 hematocrit “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 patients with chronic renal failure , this recommendation was primarily based on the NHCT and the CHOIR study findings, as well as the lack of data for any specific hemoglobin or hematocrit threshold or range. Clinical data did not identify specific hemoglobin or hematocrit 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 (2018),^2, Aranesp (2024 ),^3, Epogen (2024 ),^4, and Procrit (2018)^5, 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 the 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 boxed warnings and limitations of use shown next reflect current labeling for these ESAs.^2,3,4,5,

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 acure.

• 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 Aranespare 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 acure.

• As a substitute for RBC transfusions in patients who require immediate correction of anemia.

Epogen and Procrit also are not indicated for use:

• In patients scheduled for surgery who are willing to donate autologous blood.

• In patients undergoing cardiac or vascular surgery.

In May 2018, Retacrit (epoetin alfa-epbx; Pfizer) was approved by the FDA as a biosimilar of epoetin alfa for the treatment of anemia due to CKD in patients on dialysis and not on dialysis, zidovudine in patients with HIV-infection, and the effects of concomitant myelosuppressive chemotherapy. Retacrit is also indicated for the reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery.

Rationale

This evidence review was created in December 1995 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through September 3, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a 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 a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use 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. Randomized controlled trials 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

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 performed for the Agency for Healthcare Research and Quality (AHRQ); a 2006 AHRQ report, updated in 2013, conducted by the Blue Cross Blue Shield Association Technology Evaluation Center Evidence-Based Practice Center (BCBSA TEC PEC)^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.^11, Additional primary data sources were the American Society of Clinical Oncology and American Society of Hematology 2010 and updated 2019 clinical practice guidelines on the use of epoetin and darbepoetin to treat chemotherapy-associated anemia^12,13,; 2007 briefing documents available from the U.S. Food and Drug Administration (FDA)^14,; and a 2007 decision memorandum from the Centers for Medicare & Medicaid Services on the use of ESAs for nonrenal disease indications.^15,

Information on the use of ESAs in chronic renal failure (CRF) was obtained from several sources, including a meta-analysis by Strippoli et al (2004) evaluating blood hemoglobin targets for patients with CRF-associated anemia.^16, 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 2019 updated American Society of Clinical Oncology and American Society of Hematology clinical practice guidelines on the use of ESAs considered epoetin, darbepoetin, and biosimilar epoetin alfa used at dosages recommended in current FDA approved package inserts, to be equivalent concerning effectiveness and safety.^12, The prior 2010 American Society of Clinical Oncology and American Society of Hematology clinical practice guidelines stated that 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 versus controls or placebo.^13,

Population Reference No. 1

Clinical Context and Therapy 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 chronic kidney disease (CKD).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with CKD and anemia.

Interventions

The therapies being considered are epoetin alfa, PEG-epoetin beta, and darbepoetin.

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 1 and 3 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.

Review of Evidence

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.^17, 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 (the Normal Hematocrit Cardiac Trial [NHCT] ).^18, The NHCT, reported by Besarab et al (1998), showed a trend toward increased mortality risk and significantly increased the risk for vascular access thrombosis with ESA treatment to a hematocrit (Hct) target of 42%. Subsequently, 4 published RCTs in hemodialysis patients with end-stage renal disease (ESRD) and 8 in nondialysis patients with CKD found improved physical function at higher hemoglobin targets, but none demonstrated significant improvements in cardiovascular endpoints or mortality.^19,

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.^20, 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.^21, The Cardiovascular Reduction Early Anemia Treatment Epoetin β (CREATE) study, reported by Drueke et al (2006), was similar to CHOIR but enrolled fewer patients.^22, The CREATE trial 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.^23, 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=.41) and death or ESRD (HR, 1.06; 95% CI, 0.95 to 1.19; p=.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<.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.^24,

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.^25,

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

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

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

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; n/N: number of trials/number of patients; NR: not reported; OR: odds ratio; RR: relative risk; SF-36: Short Form-36 Health Survey.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).

Chung et al (2023) updated a Cochrane meta-analysis comparing ESAs in patients with anemia related to CKD.^26, Despite the large number of studies (N=117), the studies were at high or unclear risk of bias. Overall, epoetin alfa and beta "may be superior" to placebo (low certainty evidence), and darbepoetin was deemed "probably superior" to placebo (moderate certainty evidence) for prevention of blood transfusion. Effects on death were uncertain for epoetin alfa or epoetin beta, and there was probably no difference between darbepoetin and placebo. Epoetin alfa and beta increased the odds of hypertension compared with placebo, but darbepoetin had uncertain effects on hypertension. All other comparisons were uncertain.

Amato et al (2018) published a systematic review and meta-analysis comparing ESA biosimilars with originators in patients with anemia due to CKD.^25, Thirty RCTs (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 2 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.^27, The literature search, conducted through December 2014, identified 7 RCTs (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 to 200 mg/week) 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.^28, 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 (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. The ESAs were found to improve hemoglobin and Hct levels significantly and reduce the need for blood transfusions in predialysis patients significantly. 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 that reported validated QOL outcomes.^29, 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. The QOL outcomes included the 36-Item 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 in the SF-36 is a 5-point change. The KDQ has 5 dimensions: fatigue, depression, relationships with others, frustration, and physical symptoms. A meaningful clinically important difference in KDQ is a 0.5-point change. Study quality was assessed using the Cochrane Risk of Bias tool. Only 4 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 meaningful clinically important differences 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 4 studies with low risk of bias reported nonsignificant results as well. Meta-analysis of the 4 studies using the KDQ outcome found meaningful clinically important differences 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.^30, The literature search, conducted through January 2014, identified 21 studies (N=8328 patients) for inclusion. Comparators with darbepoetin included placebo (1 study), epoetin alfa or beta (8 studies), and PEG-epoetin beta (4 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 the SF-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.^31, Outcomes of interest were vascular access thrombosis, stroke, progression to ESRD, and all-cause mortality. Five trials (N=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-Analysis Results

Adapted from Vinhas et al (2012).[Vinhas J, Barreto C, Assunção J, et al..... 1(3-4): c95-101. PMID 23182871]CI: confidence interval; ESRD: end-stage renal disease; RR: relative risk.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.^32, 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 1 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 1 trial (Administration of C.E.R.A. in CKD Patients to Treat Anemia with a Twice-Monthly Schedule [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) 1 to 3 times weekly (C.E.R.A. Administered Intravenously for Anemia Correction and Sustained Maintenance in Dialysis [AMICUS], Maintenance of Haemoglobin Excels with IV Administration of C.E.R.A. [MAXIMA], Patients Receiving C.E.R.A. Once a month for the mainTenance Of Stable hemoglobin [PROTOS], Targeting Sustained Haemoglobin in Dialysis with IV and SC C.E.R.A. Administration [RUBRA]) and to darbepoetin weekly or twice monthly (ARCTOS, Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment for Anaemia [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.

Target hemoglobin ranges in these trials included levels that have since been associated with increased mortality in CKD (ie, >11 g/dL).^33, 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 Pegylated Epoetin Beta

ESA: erythropoiesis-stimulating agents; Hb: hemoglobin; IV: intravenous; PEG: pegylated; 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=.52 for every 2 weeks PEG-epoetin beta, p=.36 for every 4 weeks PEG-epoetin beta).h Trial investigators did not report statistical testing. There was no statistical difference between groups (BCBSA calculation; p=.88).

Other Randomized Controlled Trials

Since the FDA approval, other short-term trials (24 to 40 weeks; N=841) have replicated the findings of the pivotal correction trials in patients on hemodialysis^40, and not on hemodialysis,^41,42, and of the pivotal maintenance trials in patients on hemodialysis.^43,44, Of 324 nondialysis patients in the ARCTOS correction trial, 296 (91%) entered a 24-week extension study.^45, 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.

Locatelli et al (2020) conducted a noninferiority RCT (MIRCERA PASS) evaluating cardiovascular safety and all-cause mortality between PEG-epoetin beta compared to other ESAs (epoetin alfa/beta and darbepoetin) in patients with anemia of CKD (N=2818) when targeting hemoglobin levels of 10 to 12 g/dL.^46, The primary endpoint, a composite of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, occurred in 45.4% of patients in the PEG-epoetin beta group compared to 45.7% of patients in the control group (HR, 1.03; 95% CI, 0.93 to 1.15, p=.004 for noninferiority).

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.^47, 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% to 34%).

Comparative Efficacy of Different Erythropoiesis-Stimulating Agents

A systematic review by Wilhelm-Leen et al (2015) evaluated mortality risk rates for darbepoetin alfa and epoetin alfa in patients with CKD.^48, The literature search, conducted up to October 2014, identified 10 studies (N=2149 patients) comparing darbepoetin alfa with epoetin alfa for inclusion. Eight studies included patients on dialysis and 2 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.^49, 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 (N=15,596 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 (eg, 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 (eg, all-cause and cardiovascular) and myocardial infarction, stroke, and hypertension. Overall, due to the limitations of the data, reviewers could not determine whether 1 ESA was safer or more effective than another ESA. A 2023 update to this meta-analysis by Chung et al found similar results to the initial meta-analysis, the differences between ESAs and placebo are summarized in Table 3.^26, The comparative effects of the various ESAs were uncertain.

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.^50, Reviewers included 4 RCTs (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 (N=2051 patients) that compared darbepoetin with epoetin (alfa or beta) in adults with anemia due to CKD.^30, 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: Chronic Kidney Disease 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 iron was 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 detected among the patients receiving low ESA doses compared with those receiving high ESA doses.

Pegylated 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.

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.

Population Reference No. 2

Cancer-Related Anemia

Clinical Context and Therapy Purpose

The purpose of epoetin alfa 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 cancer.

The following PICO was used to select literature to inform this review.

Populations

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

Interventions

The therapies being considered are epoetin alfa and darbepoetin.

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.

Review of Evidence

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 (1 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, 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 increased risks of mortality and possible tumor promotion from the use of ESAs. Increased mortality has been observed in patients with cancer (Breast Cancer Erythropoietin Survival Trial [BEST], Erythropoietin in Head and Neck Cancer Trial [ENHANCE], 20000161, EPO-CAN-20 studies) when ESA treatment strategies were designed to achieve and maintain hemoglobin levels above 12 g/dL.^13, Also, ESA treatment strategies intended to achieve and maintain hemoglobin levels above 12 g/dL have demonstrated poorer tumor outcomes (BEST, ENHANCE, Danish Head and Neck Cancer [DAHANCA] studies). In a meta-analysis 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.^51, The literature search, conducted through February 2016, identified 8 RCTs (N=2087 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.^52, The literature search, conducted through December 2014, identified 7 randomized trials (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.^53, Gao et al (2014) pooled 51 RCTs (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 Anemia

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

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

CI: confidence interval; NR: not reported; OR: odds ratio; RR: relative risk.

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. Quality of life, as assessed by the Functional Assessment of Cancer Therapy (FACT) fatigue scale, was improved in patients receiving ESAs but the magnitude of improvement was less than the minimal clinically important difference of 3 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)^11, supported results of the updated AHRQ review, as shown in Table 8.

Table 8. Comparison of Systematic Review Results

Adapted from Grant et al (2013)8, and Tonia et al (2012).11,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.a Results are similar between the 2 analyses.b No evidence of associations with ESAs.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.^54, 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=1050) or best standard care (n=1048). 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=.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<.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 2 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.^55, Data were extracted from 3 randomized, double-blind, placebo-controlled phase 3 trials. Patients in the 3 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.^56, Data were abstracted from 4 randomized, double-blind, placebo-controlled trials for the comparative analysis. Patients in the 4 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=3768 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

Use of 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.^57, Baseline hemoglobin level at the screening was 11 g/dL or less. Administration of PEG-epoetin beta was every 3 weeks, and darbepoetin was administered weekly or every 3 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 reported significantly lower transfusion rates and significantly higher thrombotic event rates, and no differences in mortality rates.

Use of 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.

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.

Population Reference No. 3

Hepatitis C Infection and Ribavirin-Related Anemia

Clinical Context and Therapy Purpose

The purpose of epoetin alfa 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 use of ribavirin to treat hepatitis C infection.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with hepatitis C infection treated with ribavirin who develop ribavirin-related anemia.

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.

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 8 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.

Review of Evidence

Randomized Controlled Trials

An RCT by Shiffman et al (2007) evaluated ESAs for anemia in patients with hepatitis C who were treated with ribavirin.^58, 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<.05), but the proportion of patients with sustained virologic response did not differ between groups.

At least 2 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).^59, 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 40,000 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<.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<.001). Improvement in QOL was significantly greater for the epoetin group on 7 of 8 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 8-week randomized trial.

An RCT by Dieterich et al (2003)^60, 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 40,000 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/day) than in the usual care group (-146 mg/day), but this difference was not statistically significant (p=.06). More patients in the epoetin group (83%) than in the usual care group (54%, p=.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<.001).

Section Summary: Hepatitis C Infection Treated and Ribavirin-Related Anemia

Randomized controlled trials of ESAs versus 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.

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.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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.

2012 Input

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

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Kidney Foundation

In 2012, the National Kidney Foundation published the Kidney Disease: Improving Global Outcomes clinical practice guidelines for anemia in chronic kidney disease (CKD).^61, 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 (eg, stroke, vascular access loss, hypertension). Recommendations for treatment initiation and maintenance are listed in Table 9.

Table 9. Recommendations for Initial and Maintenance Erythropoiesis-Stimulating Agent Therapy for Anemia in Chronic Kidney Disease

CKD: chronic kidney disease; ESA: erythropoiesis-stimulating agent; Hb: hemoglobin; LOR: level of recommendation; ND: nondialysis.

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

American Society of Clinical Oncology, American Society of Hematology, and National Comprehensive Cancer Network

Table 10 summarizes current clinical practice guidelines published jointly by the American Society of Clinical Oncology and the American Society of Hematology (updated in 2019)^12, and from the National Comprehensive Cancer Network (v.2.2023 ).^62,

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

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

American Society of Nephrology

In 2012, the American Society of Nephrology 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 5 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.

Medicare National Coverage

The Centers for Medicare & Medicaid Services (CMS; 2007) released a decision memorandum on the use of ESAs for nonrenal disease indications (CAG-00383N), which has since been closed.^15,

CMS also determined that “ESA treatment for anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma, and lymphocytic leukemia is reasonable and necessary under the following specified conditions^64,:

• The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is <10 g/dL (or the hematocrit is <30%).

• The starting dose for ESA treatment is the recommended FDA [Food and Drug Administration] label starting dose, no more than 150 U/kg three times weekly for epoetin and 2.25 mcg/kg weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods.

• Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is <30%) 4 weeks after initiation of therapy and the rise in hemoglobin is ≥1 g/dL (hematocrit ≥3%).

• For patients whose hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains <10 g/dL after the 4 weeks of treatment (or the hematocrit is <30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if the hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline by 8 weeks of treatment.

• Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin >1 g/dl (hematocrit >3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to <10 g/dL (or the hematocrit is <30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.

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

Pegylated epoetin beta is not addressed in the decision memorandum or National Coverage Determination.^64,

The decision by CMS allows local Medicare contractors to “continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by National Coverage Determination.”

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

References

1. 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; http://www.fda.gov/ohrms/dockets/ac/cder07.htm. Accessed September 2, 2024.
2. Hoffmann-LaRoche. Highlights of Prescribing Information: Mircera (methoxy polyethylene glycol-epoetin beta). 2018; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125164s078lbl.pdf. Accessed September 3, 2024.
3. Amgen. Highlights of Prescribing Information: Aranesp (darbepoetin alfa). 2024; https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aranesp/ckd/aranesp_pi_hcp_english.ashx. Accessed September 3, 2024.
4. Amgen. Highlights of Prescribing Information: Epogen (epoetin alfa). 2024; https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/epogen/epogen_pi_hcp_english.ashx. Accessed September 2, 2024.
5. Janssen. Highlights of Prescribing Information: Procrit (epoetin alfa). 2018; http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/PROCRIT-pi.pdf. Accessed September 3, 2024.
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): 708-14. 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; 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 02 2009; 373(9674): 1532-42. PMID 19410717
11. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. Dec 12 2012; 12(12): CD003407. PMID 23235597
12. Bohlius J, Bohlke K, Castelli R, et al. Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update. J Clin Oncol. May 20 2019; 37(15): 1336-1351. PMID 30969847
13. 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/full/10.1200/jco.2010.29.2201. Accessed September 3, 2024.
14. 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 3, 2024.
15. 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/view/ncacal-decision-memo.aspx?proposed=N&NCAId=203. Accessed September 2, 2024.
16. Strippoli GF, Craig JC, Manno C, et al. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol. Dec 2004; 15(12): 3154-65. PMID 15579519
17. KDOQI. 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
18. 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): 584-90. PMID 9718377
19. 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): 1274-82. PMID 17942772
20. 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): 2085-98. PMID 17108343
21. 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
22. Drüeke 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): 2071-84. PMID 17108342
23. 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): 2019-32. PMID 19880844
24. 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): 2903-8. PMID 22104547
25. 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
26. Chung EY, Palmer SC, Saglimbene VM, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. Feb 13 2023; 2(2): CD010590. PMID 36791280
27. 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
28. 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; 2016(1): CD003266. PMID 26790135
29. 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): 472-8. PMID 26881842
30. Palmer SC, Saglimbene V, Craig JC, et al. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. Mar 31 2014; 2014(3): CD009297. PMID 24683046
31. Vinhas J, Barreto C, Assunção 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. 2012; 121(3-4): c95-101. PMID 23182871
32. 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. 2017; 12(3): e0172735. PMID 28249030
33. Walker RG, Strippoli GF. A pegylated epoetin in anaemia of renal disease: non-inferiority for an unvalidated surrogate. Lancet. Oct 20 2007; 370(9596): 1395-6. PMID 17950848
34. 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): 337-47. PMID 18287255
35. 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
36. 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): 3654-61. PMID 18586762
37. 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): 280-9. PMID 18004064
38. Levin NW, Fishbane S, Cañedo 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): 1415-21. PMID 17950856
39. 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): 637-46. PMID 17699476
40. 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
41. 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): 112-6. PMID 24604046
42. 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): 3980-6. PMID 21505096
43. 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
44. 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
45. Kessler M, Martínez-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): 233-9. PMID 19888948
46. Locatelli F, Hannedouche T, Fishbane S, et al. Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD: A Randomized Noninferiority Trial. Clin J Am Soc Nephrol. Dec 06 2019; 14(12): 1701-1710. PMID 31420350
47. 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; 2014(5): CD003895. PMID 24872328
48. 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
49. 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; 2014(12): CD010590. PMID 25486075
50. 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): 1115-25. PMID 25288147
51. 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(2): CD009624. PMID 26845108
52. 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: 123-8. PMID 26748593
53. 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): 603-13. PMID 23959477
54. 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): 1197-207. PMID 26858335
55. 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
56. Pirker R, Hedenus M, Vansteenkiste J, et al. Effectiveness of Darbepoetin Alfa for Chemotherapy-induced Anemia When Initiated at Hemoglobin ≤10 g/dL. Clin Ther. Jan 01 2016; 38(1): 122-135.e6. PMID 26730453
57. 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
58. 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): 371-9. PMID 17559152
59. 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): 1302-11. PMID 15131791
60. Dieterich DT, Wasserman R, Bräu 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): 2491-9. PMID 14638354
61. 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): 849-59. PMID 23891356
62. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Hematopoietic Growth Factors. Version 3.2024. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1493. Accessed September 3, 2024.
63. 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): 1664-72. PMID 22977214
64. 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&SearchType=Advanced&CoverageSelection=Both&NCSelection=NCA%7cCAL%7cNCD%7cMEDCAC%7cTA%7cMCD&ArticleType=BC%7cSAD%7cRTC%7cReg&PolicyType=Both&s=All&KeyWord=Erythropoiesis+Stimulating+Agents&KeyWordLookUp=Title&KeyWordSearchType=Exact&kq=true&bc=EAAAABAAAAAA&. Accessed September 3, 2024.

Codes

Applicable Modifiers

As per correct coding guidelines

Policy History