Erythropoiesis Stimulating Agents

Number: 0195

Policy

Note: There are several brands of epoetins on the market, including Retacrit (epoetin alfa-epbx), Epogen (epoetin alfa) and Procrit (epoetin alfa). There is a lack of reliable evidence that any one brand of epoetin is superior to other brands for medically necessary indications. Retacrit brand of epoetin ("least cost brand of epoetin") is less costly to Aetna. Consequently, because Epogen and Procrit brands of epoetins are more costly than the least cost brand of epoetin, and least cost brand of epoetin is at least as likely to produce equivalent therapeutic results, these brands of epoetin will be considered medically necessary only if the member has a contraindication, intolerance or ineffective response to the least cost brand of epoetin, Retacrit.

1. Aetna considers erythropoietin therapy (e.g., EPO, Epogen [epoetin alfa], Procrit, r-HuEPO, Retacrit (epoetin alpha-epbx) and darbepoetin alfa therapy (Aranesp) medically necessary when any of the following selection criteria is met (see Appendix for specific criteria):

   1. Anemia from myelodysplastic syndrome; or 
   2. Anemia of prematurity; or
   3. Special circumstance members who will not or cannot receive whole blood or components as replacement for traumatic or surgical loss; or
   4. Treatment of anemic members scheduled to undergo high-risk surgery who are at increased risk of or intolerant to transfusions; or 
   5. Treatment of anemia associated with chronic renal failure, whether or not on dialysis; or 
   6. Treatment of anemia in members receiving chemotherapy for hepatitis C; or 
   7. Treatment of anemia of chronic disease other than cancer when an underlying chronic disease associated with anemia has been identified (see Appendix); or 
   8. Treatment of anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphomas and lymphocytic leukemia, where the chemotherapy intent is not curative; or 
   9. Treatment of anemia due to zidovudine in HIV-infected persons; or
   10. Treatment of myelofibrosis-associated anemia when serum EPO is less than 500 mU/mL and member is not transfusion-dependent.

2. Aetna considers methoxy polyethylene glycol-epoetin beta (Mircera) medically necessary for the treatment of anemia associated with chronic kidney disease in persons on dialysis and persons not on dialysis (see Appendix for specific criteria).

3. Aetna considers the simultaneous use of multiple erythropoesis stimulating agents (ESAs) (Aranesp, Procrit, Epogen, Retacrit or Mircera) in combination experimental and investigational because the effectiveness and safety of combinational use of ESAs has not been established.

4. Aetna considers sodium ferric gluconate complex in sucrose injection (Ferrlecit) medically necessary when used as a first line treatment of iron deficiency anemia in members undergoing chronic hemodialysis who are receiving supplemental erythropoietin or darbepoetin therapy (see CPB 0575 - Intravenous Iron Therapy). 

5. Aetna considers erythropoiesis stimulating agents experimental and investigational for all other indications, including the following conditions, because its use in these situations is not supported by the peer-reviewed medical literature (not an all-inclusive list): 

Note: Peginesatide (Omontys) has been withdrawn from the market.

Background

Erythropoietin therapy (e.g., EPO, Epogen [epoetin alfa], Procrit [r-HuEPO], Retacrit (epoetin alfa-epbx, Mircera [methoxy polyethylene glycol-epoetin beta], and Aranesp [darbepoietin alfa]) is used to stimulate red blood cell (RBC) production in the bone marrow, thereby correcting anemia, minimizing the need for transfusion requirements, and improving the quality of life for patients.

Epogen and Procrit

Epoetin alpha (Epogen and Procrit) is a glucoprotein manufactured by DNA technology which has the same biological effects as endogenous erythropoietin. Erythropoietin is a glucoprotein which stimulates the production, maturation, and release of red blood cells.

Epoetin alfa contains the identical amino acid sequence of isolated natural erythropoietin and thus maintains a proliferating pool of red blood cell progenitors and stimulates maturation of these cells into functional red blood cells.

Epoetin alfa (Epogen and Procrit) is approved for the treatment of anemia in metastatic non-myeloid neoplastic disease due to chemotherapy, anemia of chronic renal failure, anemia due to zidovudine adverse reaction, and prophylaxis of allogeneic bolld transfusion related to surgical procedures.

Prior to initiation of therapy, the patient's iron stores, including transferrin saturation and serum ferritin, should be evaluated.  According to the literature, transferrin saturation should be at least 20 % and ferritin at least 100 ng/ml.  In addition, since ferritin is an acute phase reactant, it may be falsely elevated (to the normal range) in iron deficient dialysis patients.  Therefore, the best guide for iron supplementation in this group of patients is an iron saturation greater than 20 %. 

In addition, the patient should have adequate serum folate levels (3.6 to 20 ng/ml) and normal Vitamin B12 levels (reference range varies and must be provided).

According to the the United States Food and Drug Administration (FDA)-approved labeling of Procrit, the initial recommended dose of erythropoietin for anemia due to cancer chemotherapy in adults is 150 units/kg 3 times per week, or 40,000 units weekly.  For pediatric patients, a starting dose of 600 Units/kg (maximum 40,000 units) is recommended. The labeling recommends reducing the dose by 25 % when the hemoglobin approaches 12g/dL, or the hemoglobin increases by more than 1 g/dL in any 2-week period.  The labeling recommends that the dose be withheld if the patient's hemoglobin exceeds 12 g/dL, until the hemoglobin falls below 11 g/dL, at which point the dose should then be restarted at 25 % below the previous dose.  For persons receiving erythropoietin 3 times per week, the labeling recommends that the dose of erythropoietin be increased to 300 units/kg 3 times per week if the response is not satisfactory (i.e., there is no reduction in transfusion requirements or a rise in hemoglobin) after 8 weeks to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for transfusions and not to exceed 12 g/dL.  For persons receiving erythropoietin on a weekly dosing schedule, the dose should be increased to 60,000 units weekly in adults (900 units/kg in children) if response is not satisfactory (i.e., if hemoglobin fails to increase by 1 g/dL after 4 weeks of therapy) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for transfusions not to exceed 12 g/dL.

According to the FDA-approved labeling of Procrit, the recommended range for the starting dose of erythropoietin alpha for chronic renal failure is 50 to 100 units/kg 3 times weekly for adult patients.  The recommended starting dose for pediatric patients on dialysis is 50 units/kg 3 times a week.  A Cochrane review by Cody et al (2005) found that there is no significant difference between once-weekly versus thrice-weekly subcutaneous administration of rHuEPO for patients with chronic renal failure on dialysis.  According to the literature, dosing should be discontinued if the hematocrit has not increased within 16 weeks, indicating a non-responder.  Accepted guidelines state that dosage should be decreased if the hematocrit increases by more than 4 g/dL in any 2-week period.  Dosing is adjusted after 8 weeks and at monthly intervals thereafter as necessary to maintain a hematocrit of 30 to 36 %.  The FDA-approved labeling for Procrit states that the dose of erythropoietin should be reduced as the hemoglobin approaches 11 g/dL or increases by more than 1 g/dL in any 2-week period.  The dose should be adjusted for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion and not to exceed 11 g/dL.  The labeling states that the dost of erythropoietin should be increased if the hemoglobin does not increase by 2 g/dL after 8 weeks of therapy, and the hemoglobin remains at a level not sufficient to avoid the need for a transfusion.  The labeling states that the maintenance dose of erythropoietin should be individually titrated to achieve and maintain the lowest hemoglobin sufficient to avoid the need for transfusions and not to exceed 11 g/dL.

The FDA-approved labeling for Procrit states that increases in dose should not be made more frequently than once a month.  If the hemoglobin is increasing and approaching 11 g/dL, the dose should be reduced by approximately 25 %.  If the hemoglobin continues to increase, dose should be temporarily withheld until the hemoglobin begins to decrease, at which point therapy should be reinitiated at a dose approximately 25 % below the previous dose.  If the hemoglobin increases by more than 1 g/dL in a 2-week period, the dose should be decreased by approximately 25 %.  The labeling states that, if the increase in hemoglobin is less than 1 g/dL over 4 weeks and iron stores are adequate, the dose of erythropoietin may be increased by approximately 25 % of the previous dose.  Further increases may be made at 4-week intervals until the specified hemoglobin is obtained.

Epogen alpha is available as Epogen in 2,000 units, 3,000 units, 4,000 units, 10,000 units, and 40,000 units.

Epogen alpha is available as Procrit in 2,000 units, 3,000 units, 4,000 units, 10,000 units and 40,000 units.

ESAs have a black box warning that ESAs increase the risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access and tumor progression or recurrence.

For persons with chronic kidney disease, in controlled trials, patients experienced greater risks for death, serious cardiovascualr reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL. The labeling states that no trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. The FDA labeling recommens using the lowest ESA dose sufficient to reduce the need for red blood cell (RBC) transfusions.

For persons with 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. To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, the labeling recommends using the lowest dose needed to avoid RBC transfusions. The labeling recommends using ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiveing myelosupressive chemotherapy when the anticipated outcome is cure. The labeling recommends discontinuing ESAs following completion of a chemotherapy course.

For use of ESAs perisurgery, due to the increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended.

Procrit and/or Epogen should not be used in persons with a known hypersensitivity to mammalian cell-derived products or a known hypersensitivity to human albumin. ESAs should not be used in patients with known erythropoetin-type resistance due to neutralizing antibodies.

Uncontrolled hypertension-hypertensive encephalopathy and seizures have been observed. Blood pressure should be adequately controlled prior to initiation of ESA therapy, and must be closely monitored and controlled during therapy.

ESAs should not be used prophylactically to prevent chemotherapy induced anemia or to reduce tumor hypoxia.

Epoetin alfa treatment in patients with grossly elevated serum erythropoietin levels (e.g., greater than 200 milliunits/milliliter) is not recommended.

ESAs are not recommended for persons with a previous episode of pure red cell aplasia during treatment with epoetin alpha, darbepoetin alfa, or methoxy polyehtylene glycol-epoetin beta.

ESAs should not be used in any anemia in cancer that is due to bone marrow fibrosis.

Retacrit

The U.S. FDA approved epoetin alfa-epbx (Retacrit), a biosimilar to Epogen and Procrit (epoetin alfa), for all indications of the reference product.

The FDA approval was based on a data package submitted by the manufacturer demonstrating a high degree of similarity between Retacrit and its U.S. reference product, Epogen and Procrit.

Aranesp

Aranesp (darbepoetin alfa), also known as novel erythropoiesis stimulating protein (NESP), is an erythropoiesis stimulating protein closely related to erythropoietin that is produced in Chinese hamster ovary cells by recombinant DNA technology.  This FDA- approved drug stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.  A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia.  Erythropoietin interacts with progenitor stem cells to increase red cell production.  Production of endogenous erythropoietin is impaired in patients with chronic renal failure, and erythropoietin deficiency is the primary cause of their anemia. 

Aranesp (darbepoetin alfa) is a 165-amino acid protein that differs from recombinant human erythropoetin (epoetin alfa) by containing five N-linked oligosaccharide chains, whereas epoetin alfa contains three chains. Darbepoetin alfa stimulates erythropoesis by the same mechanism as endogenous erythropoetin (EPO). EPO is a glycoprotein that regulates the production of red blood cells by stimulating the division and differentiation of committed erythrooid progenitor cells in the bone marrow.

Aranesp is approved by the FDA for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis.  In addition, Aranesp is indicated for anemia in non-myeloid neoplastic disease due to chemotherapy.  Increased hemoglobin levels are not generally observed until 2 to 6 weeks after initiating treatment with Aranesp.  Aranesp has an approximately 3-fold longer terminal half-life than Epoetin alfa when administered by either the IV or SC route as a single weekly injection.  The dose should be started and slowly adjusted based on hemoglobin levels.  The dose should be adjusted for each patient to achieve and maintain a target hemoglobin level not to exceed 12 g/dL.

Darbepoetin alfa is available as Aranesp in 25 mcg, 40 mcg, 60 mcg, 100 mcg, 150 mcg, 200 mcg, 300 mcg, and 500 mcg injections.

The safety and efficacy of darbepoetin in pediatric patients less than 18 years old with cancer has not been established. The safey and efficacy in pediatric patients less than one year of age with chronic renal failure has not been established.

Mircera

Mircera (methoxy polyethylene glycol‐epoetin beta) is an erythropoietin receptor activator with greater activity in vivo as well as increased half‐life, in contrast to erythropoietin. A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with erythroid progenitor cells to increase red cell production. Production of endogenous erythropoietin is impaired in patients with chronic kidney disease (CKD) and erythropoietin deficiency is the primary cause of their anemia.

The  U.S. Food and Drug Administration (FDA) approved methoxy polyethylene glycol-epoetin beta (Mircera) for the treatment of anemia associated with chronic kidney disease (CKD) in patients on dialysis and patients not on dialysis (Roche, 2007). Mircera was approved by the FDA in 2007, but due to the outcome of a patent infringement case in favor of Amgen, introduction of Mircera in the United States was delayed until mid-2014. 

Mircera has a longer half-life than other FDA-approved erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin (Roche, 2007). Mircera is approved to correct and maintain stable hemoglobin levels with once-monthly or once-every-two-week dosing. The manufacturer states that Mircera offers the added convenience of storage at room temperature for extended time periods when necessary. 

The Phase III data supporting the FDA approval for Mircera consisted of two correction and four maintenance studies exploring intravenous (IV) and subcutaneous (SC) Mircera at extended administration intervals (Roche, 2007). The initial registration clinical program for Mircera consisted of 10 global studies involving more than 2,700 patients from 29 countries.

In clinical trials, Mircera was as effective as commercially available agents in correcting renal anemia in patients with CRF on dialysis and not on dialysis (Roche, 2007). Up to 97.5 percent of patients who were not currently receiving an ESA achieved target Hb levels (>=11g/dL) with once-every two week dosing of Mircera. Patients maintained stable Hb levels (±1g/dL) when switched to once-monthly Mircera from a shorter-acting frequently administered ESA treatment regimen. 

Mircera has a safety profile comparable to other erythropoietic agents (Roche, 2007). The most common adverse reactions are hypertension, diarrhea, nasopharyngitis, headache, and upper respiratory tract infection.   In chronic renal failure, patients experienced greater risks for death and serious cardiovascular events when administered ESAa to target higher versus lower hemoglobin levels. 

Mircera is contraindicated in patients with uncontrolled hypertension and in patients with a history of hypersensitivity or allergy to Mircera (Roche, 2007). Mircera is not indicated for the treatment of anemia due to cancer chemotherapy. 

Pure red cell aplasia (PRCA) and severe anemia have been associated with the development of neutralizing antibodies to erythropoietin in patients treated with ESAs (Roche, 2007). PRCA was not observed with Mircera in clinical  trials. The labeling recommends that, if anti-erythropoietin antibody-associated anemia is suspected, Mircera and other ESAs should be withheld. 

Mircera (methoxy polyethylene glycol‐epoetin beta) is not indicated and is not recommended: in the treatment of anemia due to cancer chemotherapy; as a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia; nor to improve symptoms, physical functioning, or health‐related quality of life.

Methoxy polyethylene glycol‐epoetin beta is available as Mircera in 50 mcg, 75 mcg, 100 mcg, and 200 mcg in 0.3 mL solution in single‐use prefilled syringes.

Mircera should not be used in persons with a known hypersensitivity to the active product or any of its excipients. Mircera should also not be used in persons with a previous episode of pure red cell aplasia during treatment with epoetin alfa, darbepoetin alfa, or methoxy polyethylene glycol‐epoetin beta.

Safety and efficacy in pediatric patients less than 18 years old with cancer have not been established. Safety and efficacy in pediatric patients less than one year of age with chronic renal failure have not been established.

There is a lack of relliable evidence that one brand of erythropoietin alpha (Procrit or Epogen) is more effective than another brand.  In addition, there is a lack of reliable evidence that darbepoetin (Aranesp) is more or less effective than erythropoietin alpha for darbepoetin's established indications.

Concurrent use of ESAs wth thalidomide is not recommended (increased risk of thromboembolism).

Peginesatide

Peginesatide is a synthetic, pegylated, peptide-based ESA that aids in the formation of RBCs.  It works by stimulating the bone marrow to produce more RBCs to reduce the need for transfusions in patients with CKD.  Doss and Schiller (2010) statedthat peginesatide is a peptide-based ESA for increasing and maintaining Hb.  In phase 2 studies, peginesatide increases and maintains target Hb levels in patients with CKD, both those on hemodialysis and those not on hemodialysis; phase 3 trials have recently been completed.  The authors discussed unmet needs in the management of anemia of CKD, presented peginesatide attributes, reviewed the results of select peginesatide clinical studies, and discussed the potential value of peginesatide as an alternative anemia management option.

Macdougall et al (2011) examined the safety and effectiveness of peginesatide in correcting renal anemia in a population of 139 non-dialysis CKD patients.  Chronic kidney disease patients who were not on dialysis and not receiving treatment with ESAs in the 12 weeks before study drug administration were sequentially assigned to 1 of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and frequency of administration (every 2 or 4 weeks).  Across all cohorts, 96 % of patients achieved a Hb response.  A dose-response relationship was evident for Hb increase.  Comparable subcutaneous and intravenous peginesatide doses produced similar Hb responses.  Rapid rates of Hb rise and Hb excursions greater than 13 g/dL tended to occur more frequently with every 2-weeks dosing than they did with every 4-weeks dosing.  The range of final median doses in the every 4-weeks dosing groups was 0.019 to 0.043 mg/kg.  Across all cohorts, 20 % of patients reported serious adverse events (1 patient had a possibly drug-related serious event) and 81 % reported adverse events (11.5 % reported possibly drug-related events); these events were consistent with those routinely observed in this patient population.  The authors concluded that the findings of this study suggested that peginesatide administered every 4 weeks can increase and maintain Hb in non-dialysis CKD patients.  They stated that additional long-term data in larger groups of patients are required to further elucidate the safety and efectiveness of this peptide-based ESA.

On March 27, 2012, the FDA approved peginesatide (Omontys) to treat anemia in adult dialysis patients who have CKD.  Omontys represents the first new FDA-approved and marketed ESA for this condition since 2001.  The approval of Omontys was based on 2 randomized, active-controlled, open-label, multi-center clinical trials, which showed the safety and effectiveness of Omontys in patients with CKD who were on dialysis.  The trials randomly selected a total of 1,608 patients with Hb levels initially stabilized by ESA to receive either Omontys once-monthly or to continue their current ESA (epoetin) treatment.  Results showed that Omontys was as safe and effective as epoetin in maintaining Hb levels within the studies’ pre-specified range of 10 to 12 g/dL.  The most common side effects observed in 10 % or more of dialysis patients treated with Omontys were arthralgia, diarrhea, hypertension and vomiting.

According to the FDA-approved labeling, Omontys should not be used in patients with CKD who are not receiving dialysis or in patients with cancer-related anemia.  Furthermore, it should not be used as a substitute for RBC transfusions in patients who require immediate correction of anemia.  Omontys is administered as a once-monthly injection. 

On February 24, 2013, the FDA alerted health care providers and patients of a voluntary nationwide recall of all lots of Omontys injection by Affymax, Inc. (Palo Alto, CA) and Takeda Pharmaceuticals Company Limited (Deerfield, IL).  The recall is due to reports of anaphylaxis.  The FDA stated that until further notice, health care providers should stop using Omontys and return the product to Takeda Pharmaceuticals.  According to the companies, serious and fatal hypersensitivity reactions have been reported in some patients receiving their first dose of Omontys, given by intravenous injection.  The reactions have occurred within 30 minutes following the dose.  There have been no reports of reactions following subsequent dosing, or in patients who have completed their dialysis session.   The FDA was notified by Affymax of 19 reports of anaphylaxis from dialysis centers in the United States; 3 of the anaphylaxis cases resulted in death.  Other patients required prompt medical intervention and in some cases hospitalization.  Some of the reports included patients who were able to be resuscitated by doctors.

MacDougall et al (2013) evaluated the safety and efficacy of peginesatide, as compared with darbepoetin, in 983 such patients who were not undergoing dialysis.  In 2 randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg/kg of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 μg/kg.  Doses of both drugs were adjusted to achieve and maintain Hb levels between 11.0 and 12.0 g per deciliter for 52 weeks or more.  The primary efficacy end point was the mean change from the baseline Hb level to the mean level during the evaluation period; non-inferiority was established if the lower limit of the 2-sided 97.5 % confidence interval [CI] was -1.0 g/dL or higher.  Cardiovascular safety was evaluated on the basis of an adjudicated composite end point.  In both studies and at both starting doses, peginesatide was non-inferior to darbepoetin in increasing and maintaining Hb levels.  The mean differences in the Hb level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g/dL (97.5 % [CI]: -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g/dL (97.5 % CI: 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g/dL (97.5 % CI: -0.09 to 0.36) and 0.31 g/dL (97.5 % CI: 0.08 to 0.54), respectively.  The hazard ratio for the cardiovascular safety end point was 1.32 (95 % CI: 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide.  The authors concluded that the efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels.  However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis.  They stated that there is a need for additional data to clarify the benefit-risk profile of peginesatide in this patient population.

In an editorial that accompanied the afore-mentioned study, Drueke (2013) stated that “Peginesatide has been recently approved in the United States for patients undergoing hemodialysis, but not for patients who are not receiving hemodialysis.  Is there any advantage of using peginesatide rather than the existing ESAs?  Less frequent dosing may be an advantage under certain circumstances.  Peginesatide does not induce pure red-cell aplasia, but antibody development against this compound, although infrequent, may reduce its efficacy.  As with any new class of drugs, prolonged experience and monitoring are necessary.  Another important issue is cost.  At a time when the prescription of much cheaper, biologically similar ESAs is steadily growing outside the United States, expensive new drugs will be competitive only if proven to result in better patient outcomes.  Such outcomes remain to be demonstrated for peginesatide and other new types of ESAs that are in development”.

ESA Risks 

Recent data indicate that about half of patients undergoing dialysis in the United States have their hemoglobin levels maintained at values above the maximum target (12 g/dL that was specified in the product labeling for erythropoietin analogs at the time the study was performed (Steinbrook, 2007).  Some investigators have posited that maintaining higher hemoglobin levels may benefit patients' quality of life.  However, the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study found that maintaining higher hemoglobin levels increases patients' risk of serious and life-threatening cardiovascular complications, including death (Singh et al, 2006).  The CHOIR study found that targeting a hemoglobin level of 13.5 g/dL (as compared with 11.3 g/dL) in patients with chronic kidney disease who did not yet need dialysis was associated with a significantly increased risk of a composite end point of death, myocardial infarction, hospitalization for congestive heart failure (without renal-replacement therapy), and stroke.  On November 16, 2006, the day the CHOIR study was published, the FDA issued a public health advisory to "underscore the importance of following the currently approved prescribing information" by raising hemoglobin levels no higher than 12 g/dL (FDA, 2006; Steinbrook, 2006).

More recently, the FDA (2011) announced that, for patients on dialysis, erythropoiesis-stimulating agent (ESA) therapy can start when the hemoglobin level is less than 10 g/dL.  But, if the hemoglobin level approaches or goes over 11 g/dL, the dose of the drug should be lowered or therapy stopped.  FDA's announcement applies to patients with early-stage kidney failure as well as those on dialysis, the treatment for late-stage kidney failure. The previous labeling of ESAs recommended keeping patients' hemoglobin levels between 10 g/dL and 12 g/dL.  The new label does away with that specific target range, stating only that physicians should initiate ESAs if patients' hemoglobins fall below 10 g/dL."  This labeling change was prompted by studies that have found that hemoglobin levels greater than 11 g/dL of blood increase the risk of stroke, heart attack, heart failure and thromboembolism and haven't been proven to provide any additional benefit to patients.  The revised labeling of ESAs states that for patients with chronic kidney disease not on dialysis, ESA therapy can be started when the hemoglobin level is less than 10 g/dL. However, the goal of treatment should not be to increase hemoglobin levels to 10 or more g/dL.  The FDA recommends that, if the hemoglobin level exceeds 10 g/dL, the dose of ESA should be reduced or interrupted.  For patients on dialysis, ESA therapy can start when the hemoglobin level is less than 10 g/dL.  But, if the hemoglobin level approaches or goes over 11 g/dL, the dose of the drug should be lowered or therapy stopped, the FDA said.

The FDA was notified in February 2007 of the preliminary results of a 681-patient, multi-center, randomized, open-label, non-inferiority study of erythropoietin alphoa compared with the standard of care in adult patients undergoing elective spinal surgery.  Erythropoietin alpha was administered according to the dosage and administration section of the label for pretreatment hemoglobin values greater than 10 and less than 13 g/dL.  The frequency of deep venous thrombosis in patients treated with erythropoietin alpha was 4.7 % (16 patients), more than twice that of patients who received usual blood conservation care (frequency of 2.1 %, 7 patients).  

The FDA-approved labeling for erythropoietin analogs has revised product labeling that includes updated warnings, a new boxed warning, and modifications to the dosing instructions (FDA, 2007).  The new boxed warning advises physicians to monitor hemoglobin and to adjust the erythropoietin analogs dose to maintain the lowest hemoglobin level needed to avoid the need for blood transfusions.  The labeling states that physicians and patients should carefully weigh the risks of erythropoietin analogs against transfusion risks.

In 2007, the FDA ordered changes to the labeling of ESAs, restricting their use.  The FDA instructed manufacturers to change the labeling to reflect three major changes: the drugs are "not indicated for those receiving myelosuppressive therapy when the anticipated outcome is cure"; therapy should not be initiated at hemoglobin levels of 10 g/dL and above; and doses should be withheld if hemoglobin levels exceed a level needed to avoid transfusion.  The black-box warnings for ESAs were updated with information on the increased risk for death and tumor progression in patients with early breast cancer and cervical cancer.  The warnings note that ESAs pose higher risks when dosed to achieve hemoglobin levels of 12 g/dL or higher, and risks at lower hemoglobin targets have not been excluded.  Accordingly, physicians are advised to use the lowest dose needed to avoid RBC transfusions.  Previous warnings have highlighted the risks for patients with non-small-cell lung, head and neck, and lymphoid cancers.

Futhermore, the NCCN Drugs & Biologics Compendium (2017) states erythropoiesis-stimulating agents (i.e. Epogen, Procrit, and Aranesp) are “not recommended when myelosuppressive chemotherapy is given with curative intent, for patients with cancer who are not receiving therapy, or for patients receiving non-myelosuppressive therapy” (NCCN category 2A).

Erythropoiesis stimulating agents have not been proven to be effective for the treatment of aplastic anemia.  Erythropoietin levels are markedly elevated in most patients with aplastic anemia.  Guidelines from the British Society of Haematology (2002) state that the routine use of erythropoietin for aplastic anemia is "not recommended."  The guidelines note the limitations of evidence for erythropoietin in aplastic anemia.  In addition, the guidelines note that erythropoietin has the potential for inducing severe and sudden worsening of anemia due to red cell aplasia from anti-erythropoietin antibodies.  The guidelines also note that there is a potential for toxicity when erythropoietin is used in combination with other drugs used routinely to treat aplastic anemia, such as cyclosporin.

Several randomized controlled trials (RCTs) have examined the effectiveness of erythropoietin in aplastic anemia.  The most recent (Zeng et al, 2006) found that the addition of growth factors (erythropoietin plus granulocyte colony stimulating factor [G-CSF]) to immunosuppressive therapy did not improve outcomes over immunosuppressive therapy alone.  An earlier RCT by Bessho et al (1997) compared G-CSF plus erythropoietin to erythropoietin alone, but did not include an appropriate comparison to immunosuppressive therapy, which is the current standard of care for aplastic anemia.  Another earlier RCT by Shao et al (1998) compared immunosuppressive therapy to G-CSF plus erythropoietin.  Limitations of the study by Shao et al (1998) compared to the most recent study by Zeng et al (2006) include its smaller size and its measurement of only intermediate outcomes (response rates) rather than survival.  Both studies are limited by the use of G-CSF with erythropoietin, which does not allow us to isolate the effect of erythropoietin.

The lack of proven effectiveness of erythropoietin in aplastic anemia, coupled with the potential noted by the British Society of Haematology for the sudden and severe worsening of anemia due to red cell aplasia due to the induction of erythropoietin antibodies, plus the synergistic toxic effects of erythropoietin when combined with cyclosporin and other drugs for aplastic anemia, counsel against the use of erythropoietin as a treatment for aplastic anemia.

Several studies have documented an increased risk of venous thromboembolism (VTE) in patients with cancer-associated anemia who are treated with the erythropoietin and darbepoetin.  In an updated investigation of safety concerns related to erythropoiesis stimulating agents, Bennett and colleagues (2008) analyzed data from Phase III clinical trials published or presented between January 1993 and January 2007 to assess ESA-associated risks of VTE and mortality.  The authors report that anemic patients with cancer who were treated with ESAs had a 1.55-fold increased risk of VTE and a 1.10-fold increased risk of mortality compared with patients who received placebo or standard care.

A number of clinical studies have examined the effect of erythropoietin analogs on cancer progression, apart from its effect on chemotherapy-induced anemia.  Clinical observations in patients with multiple myeloma and animal studies have suggested that epoetin has an anti-myeloma effect, mediated via the immune system through activation of CD8+ T cells.  Thus, the role of epoetin may go well beyond that of increasing hemoglobin levels in anemic patients, although additional studies are needed to confirm these promising results.

There are other studies, however, which raise suspicion about negative effects of erythropoietin on tumor size and survival in cancer patients (DACEHTA, 2004).  In a multi-center, RCT, Leyland-Jones et al (2005) assessed the effect on survival and quality of life of maintaining hemoglobin (Hb) in the range of 12 to 14 g/dL with epoetin alfa versus placebo in women with metastatic breast cancer (MBC) receiving first-line chemotherapy.  Eligible patients were randomly assigned to receive epoetin alfa 40,000 units once-weekly or placebo for 12 months.  Study drug was initiated if baseline Hb was less than or equal to 13 g/dL or when Hb decreased to less than or equal to 13g/dL during the study.  The primary end point was 12-month overall survival (OS).  The study drug administration was stopped early in accordance with a recommendation from the Independent Data Monitoring Committee because of higher mortality in the group treated with epoetin alfa.  Enrollment had been completed, with 939 patients enrolled (epoetin alfa, n = 469; placebo, n = 470).  Most patients had Hb more than 12 g/dL at baseline (median Hb, 12.8 g/dL) or during the study.  From the final analysis, 12-month OS was 70 % for epoetin alfa recipients and 76 % for placebo recipients (p = 0.01).  Optimal tumor response and time to disease progression were similar between groups.  The reason for the difference in mortality between groups could not be determined from additional subsequent analyses involving both study data and chart review.  These researchers concluded that the use of epoetin alfa to maintain high Hb targets in women with MBC, most of whom did not have anemia at the start of treatment, was associated with decreased survival.  Additional research is needed to clarify the potential impact of erythropoietic agents on survival when the Hb target range is 10 to 12 g/dL.

In a multicenter, randomized, double-blind, placebo-controlled trial, Wright et al (2007) found decreased OS in anemic patients with advanced non-small-cell carcinoma of the lung (NSCLC) treated with epoetin alpha.  In this clinical study, the proposed sample size was 300 patients.  Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin (Hgb) levels less than 12 g/dL.  Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo, targeting Hgb levels between 12 and 14 g/dL.  The study was intended to evaluate the effect of epoietin administration on quality of life.  However, reports of thrombotic events in other trials of erythropoietin analogs prompted an unplanned safety analysis after 70 patients had been randomly assigned (33 to the active arm and 37 to the placebo arm).  This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (63 verus 129 days; hazard ratio, 1.84; p = 0.04).  Because of the poorer outcomes in the erythropoietin-treated patients, the Steering Committee closed the trial.  The authors concluded that this unplanned safety analysis suggested decreased OS in patients with advanced NSCLC treated with epoetin alfa.

Randomized controlled clinical studies of the use of erythropoietin analogs in other types of cancer (head and neck cancer, lung cancer, lymphoproliferative disorders) have similarly found no improvements in progression-free survival or OS (Hedenus et al, 2005).

Interim results from the Danish Head and Neck Cancer Study Group trial (DAHANCA 10), an open-label, randomized trial that compared radiation therapy alone to radiation plus darbepoietin in treatment of advanced head and neck cancer found that 3-year loco-regional control was significantly worse for patients in the darbepoetin arm (p = 0.01) and OS favored those not treated with Aranesp, but the difference was not statistically significant (FDA, 2007).  The trial was terminated December 2006.  Results similar to the DAHANCA 10 study -- increased tumor progression and decreased survival -- were reported by Henke et al at the May 4, 2004, meeting of the FDA's Oncologic Drugs Advisory Committee.

In January 2007 the FDA was notified of the results of a 989-patient, multi-center, double-blind, randomized, placebo-controlled study of darbepoetin in anemic cancer patients who are not receiving chemotherapy (FDA, 2007).  The target hemoglobin in the darbepoetin treatment group was 12 g/dL.  The study results provided to the FDA show darbepoetin did not reduce the need for RBC transfusions and showed an increase in mortality in patients receiving Aranesp compared to those receiving placebo (hazard ratio 1.25; 95 % confidence interval [CI]: 1.04 to 1.51).

The FDA was notified in February 2007 of the final results of a double-blind, placebo controlled study to evaluate whether use of epoetin alpha in anemic NSCLC patients not on chemotherapy improved their quality of life (FDA, 2007).  The epoetin alfa dose was titrated to maintain a hemoglobin level of 12 to 14 g/dL; epoetin alfa was dosed at 40,000 International Units (IU) every week.  The study was terminated early when the data safety monitoring committee determined that the median time to death was 68 days in the epoetin alfa arm versus 131 days in the placebo arm (p = 0.040) and the majority of deaths were due to disease progression.  Also treatment with epoetin alfa did not significantly reduce the need for transfusion or improve the quality of life.

In February 2007, the FDA was notified by Roche that it was suspending a study of a new ESA because of safety concerns (FDA, 2007).  The study was a multi-center, randomized, dose-finding assessment of a pegylated epoetin beta product in anemic patients with Stage IIIB or IV NSCLC who were receiving first line chemotherapy.  Three dosing regimens of the investigational drug were being compared with Aranesp (given according to an FDA-approved dosing regimen).  The dose of pegylated epoetin beta was titrated to maintain the hemoglobin level between 11 and 13 g/dL.  An interim analysis, after randomization of 153 patients, demonstrated a numerical imbalance in the number of deaths across the 4 arms of the study.

Based on the results of a recent clinical trial of darbepoetin in cancer-related anemia, National Comprehensive Cancer Network (NCCN) updated its guidelines to recommend against the administration of erythropoetin to patients with cancer related anemia similar to the darbepoetin trial conducted by Amgen (NCCN, 2007).  The NCCN panel added a statement to the “Adverse Effects of Erythropoietic Therapy” section of the guidelines, stating that, until new research evidence changes current benefit/risk estimates, physicians should be advised not to administer erythropoietin to patients similar to those in the Amgen trial.

Regarding use of erythropoietin analogs as a treatment for cancer, a technology assessment by the Danish Centre for Evaluation and Health Technology Assessment (DACEHTA, 2004) concluded: “At present there is not sufficient evidence that EPO [erythropoietin] treatment has an effect on the cancer disease itself.  Therefore, EPO treatment should not be regarded as a treatment of cancer as such, but rather as a treatment of the side effects of the chemotherapy.”

An assessment by the National Institute for Health and Clinical Excellence (NICE, 2008) of erythropoietin analog therapy for cancer chemotherapy induced anemia recommended that erythropoietin only be used as part of clinical trials that are constructed to generate robust and relevant data in order to address the gaps in the currently available evidence.  The assessment reported that some studies had shown benefits with erythropoietin in terms of improved survival, but that the results of other studies were consistent with a detrimental effect.  The assessment also noted that there are biologically plausible reasons to suggest possible growth-enhancing effects of erythropoietin on some tumors.  The assessment therefore concluded that the true effect of erythropoietin on survival remains unknown.  The assessment noted that clinical trials examining the effects of erythropoietin on various measures of health-related quality of life had significant methodological weaknesses.  Although most studies suggested that erythropoietin improved health-related quality of life, the additional benefits over standard care (i.e., blood transfusions and iron therapy where indicated) were small.  The assessment found that the benefits of erythropoietin in reducing the need for blood transfusions were modest: in trials comparing erythropoietin therapy to standard care involving blood transfusions, erythropoietin therapy reduced the requirement for blood transfusions by approximately 1 unit per patient overall.  The assessment also reported that fatigue in patients with cancer has a number of potential contributory factors, and that it is difficult in individual cases to determine the exact contribution of anemia to this symptom.

Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, and reduced survival) derived from clinical trials in several cancer and non-cancer populations prompted the CMS to review its coverage of erythropoietin analog therapy.  CMS (2007) determined that erythropoietin analog therapy is not reasonable and necessary for the following clinical conditions, either because of a deleterious effect of erythropoietin analogs on the underlying disease or because the underlying disease increases their risk of adverse effects related to erythropoietin analog use.  These conditions include:

• Anemia due to cancer treatment if patients have uncontrolled hypertension;
• Any anemia associated only with radiotherapy;
• Any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis;
• Patients with erythropoietin-type resistance due to neutralizing antibodies;
• Prophylactic use to prevent chemotherapy-induced anemia;
• Prophylactic use to reduce tumor hypoxia;
• The anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers; and
• The anemia of cancer not related to cancer treatment;

In a phase III, multi-center, randomized, double-blind, placebo-controlled study, Smith and colleagues (2008) examined the effects of darbepoetin alpha (DA) for the treatment of anemia in patients with active cancer not receiving or planning to receive chemotherapy or radiotherapy.  Patients were administered placebo or DA 6.75 microg/kg every 4 weeks (Q4W) for up to 16 weeks with a 2-year follow-up for survival.  Patients who completed 16 weeks of treatment could receive the same treatment as randomized Q4W for an additional 16 weeks.  The primary end point was all occurrences of transfusions from weeks 5 through 17; safety end points included incidence of adverse events and survival.  The incidence of transfusions between weeks 5 and 17 was lower in the DA group but was not statistically significantly different from that of placebo.  Darbepoetin alpha was associated with an increased incidence of cardiovascular and thromboembolic events and more deaths during the initial 16-week treatment period.  Long-term survival data demonstrated statistically significantly poorer survival in patients treated with DA versus placebo (p = 0.022).  This effect varied by baseline co-variates including, sex, tumor type, and geographic region; statistical significance diminished (p = 0.12) when the analysis was adjusted for baseline imbalances or known prognostic factors.  The authors concluded that DA was not associated with a statistically significant reduction in transfusions.  Shorter survival was observed in the DA arm; thus, this study does not support the use of ESA in this subset of patients with anemia of cancer.

The Centers for Medicare and Medicaid Services (CMS, 2007) has developed evidence based guidelines for dosing of erythropoietin analog therapy in persons with end-stage renal disease.  CMS issued a final policy, effective April 2006, that, for claims for erythropoietin analog therapy in persons with  hematocrit readings above a threshold of 39.0 % (or hemoglobin above 13.0 g/dL), the dose should be reduced by 25 % over the preceding month.  Since that time, there have been several publications and an FDA “black box” warning that emphasize the risks facing end-stage renal disease patients who receive large doses of erythropoietin analogues and have higher hematocrits.  In response to those concerns, CMS modified its erythropoietin analog therapy monitoring policy to provide greater restrictions on the amount of erythropoietin analogs for which payment is made at higher levels of hemoglobin.  Effective for dates of service on or after January 1, 2008, for requests for payments or claims for erythropoietin analog therapy for end-stage renal disease patients receiving dialysis in renal dialysis facilities and reporting a hematocrit level exceeding 39.0 % (or hemoglobin exceeding 13.0 g/dL) for 3 or more consecutive billing cycles immediately prior to and including the current billing cycle, the erythropoietin analog dose for which payment may be made shall be reduced by 50 % of the reported dose.

The discovery that erythropoietin and its receptor are located in regions outside the erythropoietic system has led to interest in the potential role of epoetin in other tissues, such as the central nervous system (Boogaerts et al, 2005).  Bath and Sprigg (2005) report that erythropoietin was neuroprotective in experimental stroke and increased functional recovery, effects possibly mediated by inhibiting apoptosis in the penumbra.  They note that, in a small clinical trial, erythropoietin was well-tolerated in stroke patients.  Erythropoietin for stroke is currently being assessed in Phase II clinical trials.  Bath and Sprigg (2005) reported that derivatives of erythropoietin which do not alter red cell kinetics but retain their neuroprotective activity have been developed, but clinical studies of these have yet to be reported. 

However, more recent evidence suggests that erythropoiesis stimulating agents may increase stroke risk.  The FDA (2008) stated that erythropoietin may carry heightened mortality risk when used to improve functional outcomes in stroke patients.  In a clinical trial conducted in Germany, patients with acute ischemic stroke who received intravenous Eprex brand of erythropoietin (40,000 units daily for 3 days) were more likely to die within 90 days than were those on placebo (16 % versus 9 %).  In particular, death from intracranial hemorrhage occurred in 4 % of Eprex recipients and 1 % of placebo recipients.  The FDA noted, however, that the dose used was "considerably higher" than the erythropoietin doses approved for the treatment of anemia.

Erythropoesis stimulating agents have not been proven to improve outcomes in persons with heart failure and anemia. The American College of Physicians clinical practice guidelines on the treatment of anemia in heart failure (Qaseem, et al., 2013) recommends against the use of erythropoiesis-stimulating agents in patients with mild to moderate anemia and heart failure or coronary heart disease (strong recommendation based on moderate quality evidence; equivalent to Grade 1B). The available evidence does not support the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with heart failure and suggests an increased risk of venous thromboembolism (Colucci, 2018).

In the randomized, double-blind, placebo-controlled Study of Anemia and Heart Failure Trial (STAMINA-HeFT), investigators evaluated the effects of treating anemia in patients with heart failure (Ghali et al, 2008).  A total of 319 patients with symptomatic heart failure were randomized to placebo or darbepoetin for 52 weeks.  The median hemoglobin level in the darbepoetin group increased by 1.5 g/dL from baseline to 12 to 14 weeks of treatment; target hemoglobin concentrations were maintained in the darbepoetin group for the remainder of the study period.  At week 27, however, the groups did not differ significantly in mean change from baseline in either exercise duration or New York Heart Association functional class.

Kansagara et al (2013) evaluated the benefits and harms of treatments for anemia in adults with heart disease.  Data sources included MEDLINE, EMBASE, and Cochrane databases; clinical trial registries; reference lists; and technical advisors.  English-language trials of blood transfusions, iron, or ESAs in adults with anemia and congestive heart failure or coronary heart disease and observational studies of transfusion were selected for analysis.  Data on study design, population characteristics, Hb levels, and health outcomes were extracted.  Trials were assessed for quality.  Low-strength evidence from 6 trials and 26 observational studies suggested that liberal transfusion protocols do not improve short-term mortality rates compared with less aggressive protocols (combined relative risk among trials, 0.94 [95 % CI: 0.61 to 1.42]; I2 = 16.8 %), although decreased mortality rates occurred in a small trial of patients with the acute coronary syndrome (1.8 % versus 13.0 %; p = 0.032).  Moderate-strength evidence from 3 trials of intravenous iron found improved short-term exercise tolerance and quality of life in patients with heart failure.  Moderate- to high-strength evidence from 17 trials of ESA therapy found they offered no consistent benefits, but their use may be associated with harms, such as VTE.  The authors concluded that higher transfusion thresholds do not consistently improve mortality rates, but large trials are needed.  Intravenous iron may help to alleviate symptoms in patients with heart failure and iron deficiency and also warrants further study.  Moreover, they stated that ESAs do not seem to benefit patients with mild-to-moderate anemia and heart disease and may be associated with serious harms.

The American College of Obstetricians and Gynecologists' (ACOG, 2008) practice bulletin on anemia in pregnancy makes no recommendation for use of erythropoietin in pregnancy (2008).  The bulletin states: "Few studies have examined the role of erythropoietin in pregnant patients with anemia."  The ACOG practice bulletin cited two randomized controlled clinical studies of erythropoietin plus iron versus iron alone in anemia of pregnancy and postpartum anemia, with contrasting results (citing Breymann et al, 2001; Wagstrom et al, 2007). 

Pfeffer and colleagues (2009) stated that anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease (CKD).  Although darbepoetin alfa can effectively increase Hb levels, its effect on clinical outcomes in these patients has not been adequately tested.  In this study involving 4,038 patients with diabetes, CKD, and anemia, these investigators randomly assigned 2,012 patients to darbepoetin alfa to achieve a Hb level of about 13 g/dL and 2,026 patients to placebo, with rescue darbepoetin alfa when the Hb level was less than 9.0 g/dL.  The primary end points were the composite outcomes of death or a cardiovascular event (non-fatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.  Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa versus placebo, 1.05; 95 % CI: 0.94 to 1.17; p = 0.41).  Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95 % CI: 0.95 to 1.19; p = 0.29).  Fatal or non-fatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95 % CI: 1.38 to 2.68; p < 0.001).  Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (p < 0.001).  There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.  The authors concluded that the use of darbepoetin alfa in patients with diabetes, CKD, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the 2 primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke.  For many persons involved in clinical decision making, this risk will out-weigh the potential benefits.

The findings by Pfeffer et al (2009) are in agreement with those of the CHOIR study (Singh et al, 2006) as well as the CREATE study (Drüeke et al, 2006).  Singh and colleagues reported that targeting a Hb level of 13.5 g/dL (as compared with 11.3 g/dL) in patients with CKD who did not yet need dialysis was associated with a significantly increased risk of a composite end point of death, myocardial infarction, hospitalization for congestive heart failure (without renal-replacement therapy), and stroke.  Furthermore, Drüeke and associates found that in patients with stage 3 or stage 4 CKD, early complete correction of anemia (Hb levels of 13.0 to 15.0 g/dL) does not reduce the risk of cardiovascular events.

Ehrenreich et al (2009) stated that many pre-clinical findings and a clinical pilot study suggested that recombinant human EPO provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke.  Although EPO has been considered to be a safe and well-tolerated drug over 20 years, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or CKD.  Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial was designed to evaluate safety and effectiveness of EPO in stroke.  This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population).  Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40,000 IU each).  Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for.  Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4 %).  On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (p = 0.45) nor any of the other outcome parameters showed favorable effects of EPO.  There was an overall death rate of 16.4 % (n = 42 of 256) in the EPO and 9.0 % (n = 24 of 266) in the placebo group (odds ratio [OR], 1.98; 95 % CI: 1.16 to 3.38; p = 0.01) without any particular mechanism of death unexpected after stroke.  The authors concluded that based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

In an editorial that accompanied the afore-mentioned study, Velmahos (2010) stated that the results serve more to provoke questions than provide answers.  One of the questions is that "ESA was administered subcutaneously, a method with notorious unreliable absorption among critically ill patients.  How do the authors assure us about adequate levels of the drug?  If drug levels are inadequate in the blood stream and organ tissues, how can we accept causation between ESA and the purported outcome improvement?".  Velmahos also noted that "[n]o information is provided about the timing of ESA administration, except that it was administered "within the first 2 weeks".  However, according to Figure 2 most deaths also occurred within the first 2 weeks in the no-ESA group.  This means that ESA saved patients from relatively early deaths.  One should assume that a single injection prevented a patient from dying the next day.  What exactly is this powerful quality of ESA that can reverse death so drastically?  If the effects act through an amelioration of a rampant post-traumatic cascade, how is it that ESA patients suffered more complications?"

Ehrenreich and colleagues (2007) stated that the neurodegenerative aspects of chronic progressive multiple sclerosis (MS) have received increasing attention in recent years, since anti-inflammatory and immunosuppressive treatment strategies have largely failed.  However, successful neuroprotection and/or neuroregeneration in MS have not been demonstrated yet.  Encouraged by the multi-faceted neuroprotective effects of rHuEPO in experimental models, these researchers performed an investigator-driven, pilot open-label study (phase I/IIa) in patients with chronic progressive MS.  Main study objectives were

1. evaluating safety of long-term high-dose intravenous rHuEPO treatment in MS, and
2. collecting first evidence of potential efficacy on clinical outcome parameters. 

A total of 8 MS patients -- 5 randomly assigned to high-dose (48,000 IU), 3 to low-dose (8000 IU) rHuEPO treatment; and, as disease controls, 2 drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: A 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase.  Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale (EDSS), and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for 3 to 6 months after cessation of EPO application.  In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested.  There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings.  The authors concluded that the findings of this pilot study demonstrated the necessity and feasibility of RCTs using high-dose rHuEPO in chronic progressive MS.

Endre and colleagues (2010) performed a double-blind, placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in 2 general intensive care units.  As a guide for choosing the patients for treatment, these researchers measured urinary levels of 2 biomarkers:

1. the proximal tubular brush border enzymes gamma-glutamyl transpeptidase, and
2. alkaline phosphatase. 

Randomization to either placebo or 2 doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days.  Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample.  There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups.  The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient.  Early intervention with high-dose erythropoietin was safe but did not alter the outcome.  Although these 2 urine biomarkers facilitated early intervention, their transient increase compromised effective triaging.  Furthermore, this study showed that a composite of these 2 biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

In a review on the potential of cytokines and growth factors in the treatment of ischemic heart disease, Beohar et al (2010) stated that cytokine therapy promises to provide a non-invasive treatment option for ischemic heart disease.  Several cytokines mobilize progenitor cells from the bone marrow or are involved in the homing of mobilized cells to ischemic tissue.  The recruited cells contribute to myocardial regeneration both as a structural component of the regenerating tissue and by secreting angiogenic or anti-apoptotic factors, including cytokines.  To date, RCTs have not reproduced the efficacy observed in pre-clinical and small-scale clinical investigations.  Nevertheless, the list of promising cytokines continues to grow, and combinations of cytokines, with or without concurrent progenitor cell therapy, warrant further investigation.  In particular, the authors noted that a long-acting EPO analog, darbepoetin alpha, was safely administered to patients with acute myocardial infarction (MI), but provided no functional benefit.  The administration of EPO to patients with acute MI continues to be investigated in the ongoing HEBE III and REVEAL clinical trials.

The 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 (Rizzo et al, 2010) stated that for patients undergoing myelosuppressive chemotherapy who have a Hgb level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (e.g., thromboembolism, shorter survival) and benefits (e.g., decreased transfusions) of ESAs and compare these with potential harms (e.g., serious infections, immune-mediated adverse reactions) and benefits (e.g., rapid Hgb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia.  The Committee cautions against ESA use under other circumstances.  If used, ESAs should be administered at the lowest dose possible and should increase Hgb to the lowest concentration possible to avoid transfusions.  Available evidence does not identify Hgb levels greaterthan or equal to 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy.  Starting doses and dose modifications after response or non-response should follow FDA-approved labeling.  Erythropoiesis-stimulating agents should be discontinued after 6 to 8 weeks in non-responders; they should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes.  Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications.

Endre et al (2010) performed a double-blind placebo-controlled trial to study whether early treatment with EPO could prevent the development of AKI in patients in 2 general intensive care units.  As a guide for choosing the patients for treatment, these researchers measured urinary levels of 2 biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase.  Randomization to either placebo or 2 doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days.  Of 529 patients, 162 were randomized within an average of 3.5 hrs of a positive sample.  There was no difference in the incidence of EPO-specific adverse events or in the primary outcome between the placebo and treatment groups.  The triggering biomarker concentration product selected patients with more severe illness and at greater risk of AKI, dialysis, or death; however, the marker elevations were transient.  Early intervention with high-dose EPO was safe but did not alter the outcome.  Although these 2 urine biomarkers facilitated early intervention, their transient increase compromised effective triaging.  Further, this study showed that a composite of these 2 biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

In a systematic review of randomized trials on erythropoietin as a treatment of anemia in heart failure, Kotecha et al (2011) reviewed the effects of ESAs in chronic heart failure.  An extensive search strategy identified 11 RCTs with 794 participants comparing any ESA with control over 2 to 12 months of follow-up.  Published and additionally requested data were incorporated into a Cochrane systematic review (CD007613).  A total of 9 studies were placebo controlled, and 5 were double blinded.  Erythropoiesis-stimulating agent treatment significantly improved exercise duration by 96.8 seconds (95 % CI: 5.2 to 188.4, p = 0.04) and 6-min walk distance by 69.3 m (95 % CI: 17.0 to 121.7, p = 0.009) compared with control.  Benefit was also noted for peak oxygen consumption (+2.29 ml/kg/min, p = 0.007), New York Heart Association class (-0.73, p < 0.001), ejection fraction (+5.8 %, p < 0.001), B-type natriuretic peptide (-226.99 pg/ml, p < 0.001), and quality-of-life indicators with a mean increase in hemoglobin level of 2 g/dL.  There was a significantly lower rate of heart failure-related hospitalizations with ESA therapy (odds ratio 0.56, 95 % CI: 0.37 to 0.84, p = 0.005).  No associated increase in adverse events or mortality (odds ratio 0.58, 95 % CI: 0.34 to 0.99, p = 0.047) was observed, although the number of events was limited.  The authors concluded that meta-analysis of small RCTs suggested that ESA treatment can improve exercise tolerance, reduce symptoms, and have benefits on clinical outcomes in anemic patients with heart failure.  Moreover, they stated that confirmation requires larger, well-designed studies with careful attention to dose, attained Hb level, and long-term outcomes.  This is in agreement with the observations of Lipsic et al (2011) as well as Santilli et al (2011).  Lipsic and colleagues (2011) stated that large-scale trials with ESAs are needed to examine the safety and effectiveness of anemia treatment in patients with heart failure.   Santilli and associates (2011) stated that further studies are needed to define the magnitude of the problem and establish appropriate therapeutic strategies.  It is likely that more reliable data will be derived from an ongoing randomized, double-blind, multi-center study, the RED-HF (Reduction Event with Darbepoetin alfa in Heart Failure), which aims at evaluating morbidity and mortality in a cohort of 2,600 heart failure patients with anemia treated with darbepoetin alfa.

In a prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase, Najjar et al (2011) evaluated the safety and effectiveness of a single intravenous bolus of epoetin alfa in patients with acute ST-segment elevation myocardial infarction (STEMI).  The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 U.S. sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.  Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of re-perfusion.  Main outcome measure was infarct size, expressed as percentage of left ventricle (LV) mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 +/- 2 weeks later (second CMR).  In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8 % LV mass [95 % CI: 13.3 to 18.2 % LV mass] for the epoetin alfa group versus 15.0 % LV mass [95 % CI: 12.6 to 17.3 % LV mass] for the placebo group; p = 0.67) or on the second CMR scan (n = 124; 10.6 % LV mass [95 % CI: 8.4 to 12.8 % LV mass] versus 10.4 % LV mass [95 % CI: 8.5 to 12.3 % LV mass], respectively; p = 0.89).  In a pre-specified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9 % LV mass; 95 % CI: 14.0 to 25.7 % LV mass) than in the placebo group (11.7 % LV mass; 95 % CI: 7.2 to 16.1 % LV mass) (p = 0.03).  In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0 %; 95 % CI: 1.31 % to 9.09 %) but in none of the 97 who received placebo (p = 0.04).  The authors concluded that in patients with STEMI who had successful re-perfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events.  Subgroup analyses raised concerns about an increase in infarct size among older patients.

In an editorial that accompanied the afore-mentioned study, Bhatt (20110 stated that "[b]ecause these findings appeared in a blinded trial, they raise further questions about the safety of epoetin alfa in the context of acute MI .... Until compelling data become available to support routine sue of these agents in patients with anemia, it would be prudent to minimize their use, especially in patients at high risk for cardiovascular disease or with an acute ischemic syndrome".

In a review on “Guillain-Barre syndrome”, Yuki and Hartung (2012) states that “eculizumab, erythropoietin, and fasudil, which have been used in the treatment of other, unrelated medical conditions, have shown promise in animal models of the Guillain-Barre syndrome, but clinical studies are lacking”.

In a review on “Mechanisms and management of retinopathy of prematurity”, Hartnett and Penn (2012) stated that “Very-low-birth-weight infants are at high risk not only for retinopathy of prematurity but also for subsequent neurodevelopmental impairment.  Interest in erythropoietin as a neuroprotective agent is increasing.  When administered in preterm infants, erythropoietin was associated with improved cognition in childhood.  Laboratory studies have shown that early administration of erythropoietin reduced phase 1 avascularization in both mouse and rat models of oxygen-induced retinopathy.  However, retrospective studies have shown an association between erythropoietin and severe oxygen-induced retinopathy in preterm infants.  Erythropoietin was also found to promote intravitreal angiogenesis in a transgenic mouse model of oxygen-induced retinopathy.  Some investigators have proposed administering erythropoietin early in preterm infants to promote physiologic retinal vascular development and attempt to reduce the risk of development of stage 3 retinopathy of prematurity, but additional studies are needed to determine the window of time for relatively safe administration”.  The authors concluded that current therapies for severe retinopathy of prematurity focuses on laser therapy as well as visual rehabilitation, and potential new treatment strategies include targets within oxidative pathways, erythropoietin, and anti-vascular endothelial growth factor agents.

Moebus et al (2013) noted that the AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks versus conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients.  These researchers evaluated the safety and effectiveness of epoetin alfa in a second randomization of the IDD arm.  A total of 1,284 patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group.  Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non- ESA control group.  Primary efficacy end-points included change in Hb level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion.  Relapse-free survival, overall survival, and intra-mammary relapse were secondary end-points estimated with Kaplan-Meier and Cox regression methods.  Except for the primary hypothesis, all statistical tests were 2-sided.  Epoetin alfa avoided the decrease in Hb level (no decrease in the epoetin alfa group versus -2.20 g/dL change for the control group; p < 0.001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8 % versus 28.1 %; p < 0.0001).  The incidence of thrombotic events was 7 % in the epoetin alfa arm versus 3 % in the control arm.  After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intra-mammary relapse.  The authors concluded that epoetin alfa resulted in improved Hb levels and decreased transfusions without an impact on relapse-free or overall survival.  However, epoetin alfa had an adverse effect, resulting in increased thrombosis.

In a Cochrane review, Marti-Carvajal et al (2013) evaluated the clinical benefits and harms of ESAs for anemia in rheumatoid arthritis.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (issue 7 2012), Ovid MEDLINE and Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (1948 to August 7, 2012), OVID EMBASE (1980 to August 7, 2012), LILACS (1982 to August 7, 2012), the Clinical Trials Search Portal of the World Health Organization, reference lists of the retrieved publications and review articles.  They did not apply any language restrictions.  These researchers included RCTs in patients aged 16 years or over, with a diagnosis of rheumatoid arthritis affected by anemia.  They considered health-related quality of life, fatigue and safety as the primary outcomes.  Two authors independently performed trial selection, risk of bias assessment, and data extraction.  They estimated difference in means with 95 % CIs for continuous outcomes.  They estimated risk ratios with 95 % CIs for binary outcomes.  These investigators included 3 RCTs with a total of 133 participants.  All trials compared human recombinant erythropoietin (EPO), for different durations (8, 12 and 52 weeks), versus placebo.  All RCTs assessed health-related quality of life.  All trials had high or unclear risk of bias for most domains, and were sponsored by the pharmaceutical industry.  Two trials administered EPO by a subcutaneous route while the other used an intravenous route.  These researchers decided not to pool results from trials, due to inconsistencies in the reporting of results.  Health-related quality of life: subcutaneous EPO -- 1 trial with 70 patients at 52 weeks showed a statistically significant difference in improvement of patient global assessment (median and interquartile range 3.5 (1.0 to 6.0) compared with placebo 4.5 (2.0 to 7.5) (p = 0.027) on a visual analog scale (VAS) scale (0 to 10)).  The other shorter-term trials (12 weeks with subcutaneous EPO and 8 weeks with intravenous administration) did not find statistically significant differences between treatment and control groups in health-related quality of life outcomes.  Change in Hb: both trials of subcutaneous EPO showed a statistically significant difference in increasing Hb levels;

1. at 52 weeks (1 trial, 70 patients), intervention Hb level (median of 134, interquartile range 110 to 158 g/L) compared with the placebo group level (median of 112, interquartile range; 86 to 128 g/L) (p = 0.0001);
2. at 12 weeks (1 trial, 24 patients) compared with placebo (difference in means of 8.00, 95 % CI: 7.43 to 8.57). 

Intravenous EPO at 8 weeks showed no statistically significant difference in increasing hematocrit level for EPO versus placebo (difference in means of 4.69, 95 % CI: -0.17 to 9.55; p = 0.06).  Information on withdrawals due to adverse events was not reported in 2 trials, and 1 trial found no serious adverse events leading to withdrawals.  None of the trials reported withdrawals due to high blood pressure, or to lack of efficacy or to fatigue.  The authors concluded that there are conflicting data for ESAs to increase quality of life and Hb level by treating anemia in patients with rheumatoid arthritis.  However, this conclusion was based on RCTs with a high-risk of bias, and relies on trials assessing EPO.  They stated that the safety profile of EPO is unclear; and future trials assessing ESAs for anemia in rheumatoid arthritis should be conducted by independent researchers and reported according to the CONSORT statements.

Tran et al (2014) noted that ESAs are widely used in treating anemia associated with renal failure.  They are also now used peri-operatively to reduce the use of allogeneic blood transfusions (ABTs) in patients undergoing surgery with anticipated high blood loss.  Although they can reduce the risks associated with ABT and improve quality of life, the use of ESAs is still associated with adverse effects.  These investigators performed a systematic review to examine the current evidence for the safety and effectiveness of peri-operative ESAs use.  A search of PubMed and Medline databases has been performed using a combination of search terms including erythropoietin, peri-operative, surgical, safety and efficacy.  The authors concluded that current evidence supported the use of peri-operative ESAs to reduce the need for ABT.  However, large studies assessing safety in anemic patients with chronic renal disease have found adverse effects including cardiovascular, stroke and thromboembolic events.  However, whether these concerns can be conferred onto the surgical population remains to be seen as the peri-operative dosing strategies have been more variable in timing, dose and duration in comparison with those used for chronic diseases.  Moreover, they stated that future research needs to address the questions of optimal dosing strategies in order to maximize the positive effects and minimize adverse events.

Lai et al (2014) noted that ESAs to treat anemia in breast cancer patients who are treated with chemotherapy is a matter of ongoing debate.  Several recent randomized trials challenged conventional wisdom, which holds that ESAs are contraindicated for breast cancer patients undergoing curative treatment.  These investigators performed the first large national population-based study to analyze the association between ESA use and breast cancer patient outcomes.  Cytotoxic chemotherapy-treated invasive breast cancer patients were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.  Non-ESA users were sequentially 1:1 matched to 2,000 randomly sampled ESA users on demographics (age, diagnosis year, race, marital status, and socioeconomic status), tumor presentation (stage, grade, and status of hormone receptors), and treatments (surgery, radiation, and sub-types of chemotherapy) using a minimum distant strategy.  Breast cancer-specific survival of ESA and matched non-ESA users was compared using Fine and Gray competing risk model.  Compared to ESA users, non-ESA users exhibited dramatically different baseline characteristics such as less advanced tumor, and fewer co-morbidities.  Non-ESA users had a significantly more favorable breast cancer-specific survival (subdistribution hazard ratio [sHR] = 0.75, p < 0.0001).  This survival disparity was progressively diminished in the sequential matching of demographics (sHR = 0.74, p = 0.0004), presentation (sHR = 0.86, p = 0.06), and treatment (sHR = 0.89, p = 0.17) variables.  Stratified analyses identified subgroups of patients whose breast cancer-specific survival were not different between ESA and non-ESA users.  In the SEER-Medicare database, ESA usage did not appear to be associated with unfavorable breast cancer-specific survival in breast cancer patients receiving cytotoxic chemotherapy.  The authors concluded that the ESA-breast cancer prognosis association is complex and requires more intensive investigations.

Kelada and Marignol (2014) stated that ESAs are used in breast cancer patients with chemotherapy-induced anemia to alleviate anemia and in turn, reduce fatigue.  These drugs may also decrease overall survival and increase the incidence of serious adverse effects such as thrombo-vascular events (TVEs).  These investigators evaluated the evidence to-date on administering ESAs to breast cancer patients with chemotherapy-induced anemia.  The authors concluded that these findings suggested a clear need for well-designed clinical trials that follow current FDA ESA label changes to guide clinical practice in an effort to reduce harm to these patients.

Fokkema et al (2014) stated that ESAs have been investigated in small studies in patients with STEMI undergoing PCI.  Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events.  These researchers performed a systematic literature search in MEDLINE, until December 2012.  They included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with greater than or equal to 30 days of follow-up.  The primary end-point was a composite of all-cause mortality, MI, and stent thrombosis after PCI; secondary end-point was all-cause mortality.  Individual patient data were obtained from 10 of 11 trials, including 97.3 % (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642).  Baseline characteristics were well-balanced between the treatment allocations.  Mean follow-up time was 248 (±131) days.  The primary end-point occurred in 3.5 % (20/577) in the control group and in 2.1 % (13/610) in the ESA group (hazard ratio [HR] for ESAs, 0.63; 95 % CI: 0.31 to 1.27]; p = 0.20).  Mortality occurred in 13 (2.3 %) in the control group and 5 (0.8 %) in the ESA group (HR for ESAs, 0.38; 95 % CI: 0.13 to 1.06]; p = 0.06).  The authors concluded that ESA administration did not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI.  They stated that results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients.

Robertson et al (2014) compared the effects of erythropoietin and 2 Hb transfusion thresholds (7 and 10 g/dL) on neurological recovery after TBI.  Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 U.S. level I trauma centers between May 2006 and August 2012 were included in this study, which used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20 % and whether a Hb transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications.  Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126).  There were 99 patients assigned to a Hb transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL.  Interventions included intravenous erythropoietin (500 IU/kg per dose) or saline; transfusion threshold was maintained with packed red blood cells.  Main outcome measure was Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months post-injury.  There was no interaction between erythropoietin and Hb transfusion threshold.  Compared with placebo (favorable outcome rate: 34/89 [38.2 %; 95 % CI: 28.1 % to 49.1 %]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6 %; 95 % CI: 31.4 % to 66.0 %], p = 0.13; second dosing regimen: 17/57 [29.8 %; 95 % CI: 18.4 % to 43.4 %], p < 0.001).  Favorable outcome rates were 37/87 (42.5 %) for the Hb transfusion threshold of 7 g/dL and 31/94 (33.0 %) for 10 g/dL (95 % CI: for the difference, -0.06 to 0.25, p = 0.28).  There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8 %] versus 8/99 [8.1 %] for the threshold of 7 g/dL, OR, 0.32 [95 % CI: 0.12 to 0.79], p = 0.009).  The authors concluded that in patients with closed head injury, neither the administration of erythropoietin nor maintaining Hb concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months.  The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events.  They stated that these findings did not support either approach in this setting.

Lindquist et al (2015) determined the safety and effectiveness of ESAs for the treatment of anemia in patients with systolic heart failure.  A search of MEDLINE (1946 to January 2014) and EMBASE (1947 to January 2014) was conducted using the search terms erythropoietin and systolic heart failure.  In addition, bibliographies of relevant articles were reviewed for additional citations.  All English language RCTs evaluating clinical outcomes or adverse events when using ESAs in the setting of systolic heart failure were included.  A total of 9 studies were reviewed.  All studies examining hematological parameters found a statistically significant increase in Hb levels with active treatment versus placebo.  Of the 7 trials evaluating exercise tolerance or capacity, only 4 demonstrated statistically significant improvement in these measures in patients receiving ESAs, whereas the remainder showed no clinical benefit.  Four studies examined quality-of-life measures.  Although numerical improvements were observed in most trials, statistical significance was reached in only 2 trials.  A non-significant trend for decreased mortality in patients treated with darbepoetin with a similar adverse event profile compared to placebo was shown in 1 study; however, the largest trial to-date showed no benefit in all-cause mortality or heart failure-related hospitalizations with the use of ESAs.  Additionally, a statistically significant increase in the number of cerebrovascular events and thrombotic events was found.  The authors concluded that there was inconclusive evidence to suggest that the use of ESAs in treating anemia in patients with heart failure is beneficial.  They noted that although ESAs demonstrated a clear ability for increasing Hb levels, the data regarding clinical outcomes such as exercise parameters, quality of life, and hospitalizations are conflicting.  In addition, a mortality benefit has not been shown; therefore, the potential for improved symptomatology must be weighed against the potential for adverse events.

Silverberg et al (2014) noted that little is known about iron deficiency (ID) and anemia in chronic obstructive pulmonary disease (COPD).  The purposes of this study were:

1. to study the prevalence and treatment of anemia and ID in patients hospitalized with an exacerbation of COPD, and
2. to study the hematological responses and degree of dyspnea before and after correction of anemia with subcutaneous ESAs and intravenous (IV) iron therapy, in ambulatory anemic patients with both COPD and CKD. 

These investigators examined the hospital records of all patients with an acute exacerbation of COPD (AECOPD) to assess the investigation, prevalence, and treatment of anemia and ID.  They treated 12 anemic COPD outpatients with the combination of ESAs and IV-iron, given once-weekly for 5 weeks.  One week later they measured the hematological response and the severity of dyspnea by VAS.  Of 107 consecutive patients hospitalized with an AECOPD, 47 (43.9 %) were found to be anemic on admission.  Two (3.3 %) of the 60 non-anemic patients and 18 (38.3 %) of the 47 anemic patients had serum iron, percent transferrin saturation (%Tsat) and serum ferritin measured.  All 18 (100 %) anemic patients had ID, yet none had oral or IV iron subscribed before or during hospitalization, or at discharge.  Iron deficiency was found in 11 (91.7 %) of the 12 anemic ambulatory patients.  Hemoglobin, hematocrit (Hct) and the VAS scores increased significantly with the ESAs and IV-iron treatment.  There was a highly significant correlation between the ∆Hb and ∆VAS; rs = 0.71 p = 0.009 and between the ∆Hct and ∆VAS; rs = 0.8 p = 0.0014.  The authors concluded that ID is common in COPD patients but is rarely looked for or treated.  Yet correction of the ID in COPD patients with ESAs and IV iron can improve the anemia, the ID, and may improve the dyspnea.  These findings need to be validated by well-designed studies.

Furthermore, current COPD guidelines (GOLD, 2015; NICE, 2010; Qaseem, et al., 2011) do not mention the use of erythropoietin/erythropoesis stimulating agents as management tools. UpToDate reviews on “Management of stable chronic obstructive pulmonary disease” (Ferguson and Make, 2014) and “Management of exacerbations of chronic obstructive pulmonary disease” (Stoller, 2014) do not mention the use of erythropoietin/erythropoiesis stimulating agents as therapeutic options.

Messier and Ohls (2014) noted that the use of ESAs such as erythropoietin and darbepoetin in preterm and term infants has been studied for over 20 years.  Recent investigations have explored the potential neuroprotective effects of ESAs.  These investigators reviewed the recent clinical trials and experimental animal models that provide evidence in support of using ESA to improve the neurodevelopmental outcomes in term and preterm infants.  Continued work using animal models have confirmed the neuroprotective properties of ESAs, including promotion of oligodendrocyte development in the face of neuronal injury.  Clinical studies in term and preterm infants have reported the neuroprotective effects following ESA administration, and improved neurodevelopmental outcomes have been reported in the studies of preterm infants.  The authors concluded that ESAs show great promise in preventing and treating brain injury in term and preterm infants.

Also, an UpToDate review on “Late preterm infants” (Barfield and Lee, 2014) does not mention the use of erythropoietin/erythropoiesis stimulating agents as management tools.

Martino et al (2015) stated that ESAs are used in treating cancer- and chemotherapy-induced anemia with the aim of accelerating the recovery of RBCs, reduce the risks associated with RBC transfusions and improve quality of life.  These researchers performed a systematic review to examine the current evidence for the safety and effectiveness of using ESAs in hematopoietic stem cell transplants (HSCTs).  These investigators noted that despite the international recommendations for the use of ESAs in treating different malignancies, there is a lack of guidelines for their use in patients undergoing HSCT.  An evaluation of published clinical trials showed that there are no available powerful studies concerning the use of ESAs in this setting, with only heterogeneous and small numbers of patients reported so far.  Nevertheless, the more robust and intriguing of these data suggested that the ESA's administration at an appropriate time after the infusion of stem cells may be effective both in autologous and allogeneic HSCTs.  The authors concluded that new guidelines are needed, overseen by an expert in the in the field of stem cell transplantation.

Myelodysplastic Syndromes (MDS)

The British Committee for Standards in Haematology’s guidelines on “The diagnosis and management of adult myelodysplastic syndromes” (Killick et al, 2014) provided the following recommendations:

• Patients with International Prognostic Scoring System (IPSS) low and intermediate-1 (INT-1) MDS, symptomatic anemia and who fulfil the criteria for a high or intermediate predictive score for response should be considered for a trial of therapy with an ESA (Grade 1B).
• Patients with non-sideroblastic phenotypes should be offered a trial of therapy with an ESA (Grade 1B).
• Patients with sideroblastic phenotypes should be offered a trial of therapy with an ESA plus G-CSF (Grade 1B).
• Patients should receive a maximum trial period of 16 weeks of therapy.  This should comprise 8 weeks at the starting dose of ESA ± G-CSF and a further 8 weeks at the higher doses, if required (Grade 2B).
• Patients achieving a complete or partial erythroid response by accepted criteria should continue on long-term therapy until the response is lost and at the minimum dose of ESAs required to maintain the response.

Seastone and Gerds (2015) stated that MDS are characterized by refractory cytopenias that lead to symptomatic anemia, bleeding, and increased risk for infections.  For the past 20 years, the use of darbepoetin and other ESAs to treat symptomatic anemia in lower-risk MDS has been a standard of care.  This practice is supported by numerous phase I/II studies and 1 phase III study demonstrating the benefit of using ESAs alone, or in combination with G-CSF, for treatment of symptomatic anemia with the goal of decreasing RBC transfusion requirements.  The authors summarized the published experience regarding the use of ESAs, with a special focus on darbepoetin, in patients with MDS and symptomatic anemia.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2016) lists MDS as a recommended indication of darbepoetin alfa (2A recommendation).  It is indicated as initial treatment of lower risk disease associated with symptomatic anemia, no del(5q) with or without other cytogenetic abnormalities, serum erythropoietin levels less than or equal to 500 mU/ml, and

• Ring sideroblasts less than 15 % as a single agent
• Ring sideroblasts greater than or equal to 15 % in combination with filgrastim

Preterm Infants

Natalucci and colleagues (2016) examined if prophylactic early high-dose recombinant human erythropoietin (rhEPO) in preterm infants improves neurodevelopmental outcome at 2 years' corrected age.  Preterm infants born between 26 weeks 0 days' and 31 weeks 6 days' gestation were enrolled in a randomized, double-blind, placebo-controlled, multi-center trial in Switzerland between 2005 and 2012.  Neurodevelopmental assessments at age 2 years were completed in 2014.  Participants were randomly assigned to receive either rhEPO (3,000 IU/kg) or placebo (isotonic saline, 0.9 %) intravenously within 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth.  Primary outcome was cognitive development assessed with the Mental Development Index (MDI; norm, 100 [SD, 15]; higher values indicate better function) of the Bayley Scales of Infant Development, second edition (BSID-II) at 2 years corrected age.  The minimal clinically important difference between groups was 5 points (0.3 SD).  Secondary outcomes were motor development (assessed with the Psychomotor Development Index), cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.  Among 448 preterm infants randomized (mean gestational age of 29.0 [range of 26.0 to 30.9] weeks; 264 [59 %] female; mean birth weight of 1,210 [range of 490 to 2,290] g), 228 were randomized to rhEPO and 220 to placebo.  Neurodevelopmental outcome data were available for 365 (81 %) at a mean age of 23.6 months.  In an intention-to-treat analysis, mean MDI was not statistically significantly different between the rhEPO group (93.5 [SD, 16.0] [95 % CI: 91.2 to 95.8]) and the placebo group (94.5 [SD, 17.8] [95 % CI, 90.8 to 98.5]) (difference, -1.0 [95 % CI: -4.5 to 2.5]; p = 0.56).  No differences were found between groups in the secondary outcomes.  The authors concluded that among very preterm infants who received prophylactic early high-dose rhEPO for neuroprotection, compared with infants who received placebo, there were no statistically significant differences in neurodevelopmental outcomes at 2 years.  Moreover, they stated that follow-up for cognitive and physical problems that may not become evident until later in life is required.

Beta Thalassemia

An UpToDate review on “Treatment of beta thalassemia” (Benz, 2016) states that “Addition of erythropoietin -- The myelosuppressive effect of HU [hydroxyurea] may compromise its therapeutic efficacy, suggesting the use of erythropoietin to support red cell production when HU is used in the treatment of beta thalassemia.  This was tested in a randomized trial in 80 transfusion-dependent subjects ≤ 18 years of age with thalassemia intermedia (TI).  All received HU (25 mg/kg per day by mouth) and were randomly assigned to receive (Group A) or not receive (Group B) recombinant human erythropoietin (EPO, total dose of 1,000 international units/kg per week subcutaneously, divided into 3 doses per week).  After a mean follow-up period of 1 year, the following results were obtained:

• Subjects receiving both HU and EPO (Group A) had significantly greater increases in hemoglobin (1.6 versus 0.7 g/dL) and HbF (17.0 versus 10.8 %) over baseline than those receiving HU alone (Group B).
• While all 80 subjects were initially transfusion-dependent, 15 of 40 in Group A (37.5 %) became transfusion-independent, whereas only 6 of 40 in Group B (15 %) reached this status.
• No serious adverse events necessitating discontinuation of therapy were seen in either group.

While this proof-of-principle study reported better responses to HU plus EPO in patients with lower initial blood EPO levels, HbF levels > 40 %, or prior splenectomy, larger clinical trials with longer follow-up are needed.  Questions to be addressed before recommending use of this regimen include determining those who are most likely to respond as well as overall costs and safety of long-term treatment, such as the side effects of high-dose EPO (e.g., thrombosis, reduced survival, bone remodeling) and the development of complications (e.g., myelodysplasia, acute leukemia) when HU is given in concert with EPO.

Friedreich's Ataxia

Sacca and colleagues (2016) stated that Friedreich's ataxia (FRDA) is an autosomal recessive disease with no available therapy.  Clinical trials with EPO in FRDA patients have yielded conflicting results, and the long-term effect of the drug remains unknown.  These researchers designed a double-blind, placebo-controlled, multi-center study to examine the effectiveness of epoetin alfa on 56 patients with FRDA.  The primary end-point of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test.  Secondary end-points were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life.  Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1,200 IU/Kg of body weight every 12 weeks for 48 weeks.  A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group [KG1]; VO2 max was not modified after treatment (0.01 [-0.04 to 0.05]; p = 0.749), as well as most of the secondary end-point measures, including frataxin.  The 9-hole peg test showed a significant amelioration in the treatment group (-17.24 sec. [-31.5 to -3.0]; p = 0.018).  The treatment was safe and well-tolerated.  The authors concluded that although results were not in favor of an effect of epoetin alfa in FRDA, this was the largest study examining its effect.  These investigators stated that it is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance.  This study provided class I evidence that EPO did not ameliorate VO2 max in patients with FRDA.

Aranca and associates (2016) noted that FRDA is an inherited, progressive neurodegenerative disease that typically affects teenagers and young adults.  Therapeutic strategies and disease insight have expanded rapidly over recent years, leading to hope for the FRDA population.  There is currently no FDA-approved treatment for FRDA, but advances in research of its pathogenesis have led to clinical trials of potential treatments.  The authors reviewed emerging therapies and discussed future perspectives, including the need for more precise measures for detecting changes in neurologic symptoms as well as a disease-modifying agent; and EPO is one of the keywords listed in this review.

Hairy Cell Leukemia

Naika and Saven (2012) stated that neutrophil growth factors have been applied to reduce complications from cladribine-induced severe neutropenia because it occurs in 30 % to 40 % of patients. At Scripps Clinic, the authors performed a phase-II clinical trial investigating filgrastim at a dose of 5 μg/kg per day subcutaneously for 3 consecutive days before cladribine administration, then daily after cladribine was finished until resolution of neutropenia.  These researchers treated 35 patients with hairy cell leukemia and compared them with historical controls.  The median nadir neutrophil count was roughly 0.5 × 109/L compared with 0.3 × 109/L in patients not receiving filgrastim (p = 0.04).  After a median of 10 days of filgrastim, the time for neutrophils to recover to greater than 1.0 × 109/L was shortened from 22 days in the historical control arm to 9 days.  However, these investigators noted no differences with regard to the number of febrile days or hospitalization rates.  The authors concluded that routine use of filgrastim is not recommended.  Because the rates of severe anemia from cladribine are low, these investigators similarly do not recommend prophylactic erythropoietin-stimulating agents, although this has never been prospectively studied.

Maevis et al. (2014) conducted a short review of current recommendations for hairy cell leukemia. Their review did not recommend epoetin as a therapeutic option. The authors referenced Saven et al. who neither  recommend a routine use of granulocyte-colony-stimulating factor based on their findings in a  phase II study investigating the influence of filgrastim on cladribine-induced severe neutropenia nor prophylactic erythropoietin-stimulating agents because of the rareness of severe cladribine-induced anemia.

An UpToDate review on “Treatment of hairy cell leukemia” (Tallman, 2017) does not mention epoetin as a therapeutic option.

Furthermore, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines on “hairy cell leukemia” (Version 2.2018) and "cancer- and chemotherapy-induced anemia" (Version 2.2018) do not make a recommendation for ESAs or epoetin as a therapeutic intervention.

Hemolytic Anemia

Zuppa et al (2012) investigated a cohort of 14 neonates to compare the effectiveness of recombinant human erythropoietin (rHuEPO) in two care protocols that differ for doses of rHuEPO administrated and for timing of administration. Protocol A: a dose of 200 U/kg/day of rHuEpo administered subcutaneously starting from the end of the second week of life; Protocol B: a dose of 400 U/kg/day of rHuEpo administered subcutaneously starting from the end of the first week of life. The hematocrit values in the protocol A group decreased during treatment (32,5% vs 25,2%), whereas the hematocrit value in protocol B group remained almost stable (38,7% vs 42,8%). The mean numbers of platelets remained stable in both groups while neutrophils increased in protocol A group and decreased in protocol B (p<0,05). Reticulocyte count increased during treatment in both groups, although only in protocol B group it was statistically significative (p<0,05). The authors concluded that their results suggest similar efficacy between the two treatment protocols. Increasing doses of rHuEPO does not seem to enhance their effectiveness.

Donato et al. (2009) discussed recombinant erythropoietin as treatment for hyporegenerative anemia following hemolytic disease of the newborn. The authors study consisted of a case series report on 50 neonates with hemolytic disease of the newborn (HDN) due to Rh, ABO or KpA antigens. The neonates were 7 days or older. Treatment with erythropoietin was started when hematocrit dropped to levels requiring a transfusion, and inappropriate reticulocyte response Reticulocyte Production Index <1). At start of treatment mean age was 24.3 +/- 12.0 days (range 8-65 days), hematocrit 24.1 +/- 2.8% (range 18-30%), and Reticulocyte Production Index 0.34 +/- 0.25 (range 0.05-0.98). The authors stated that the Hematocrit and Reticulocyte Production Index showed significant increases after 7 and 14 days of treatment (p <0.001). No difference was observed either between infants with Rh-HDN and ABO-HDN or between Rh-HDN patients with or without intrauterine transfusions. Seven infants (14%) required one packed RBC transfusion during erythropoietin therapy, 2 of them within 72 hours from starting treatment. The percentage of transfused infants showed no difference either between ABO-HDN and Rh-HDN or between Rh-HDN with and without intrauterine transfusions. Moderate, short-lasting neutropenia, not associated to infections, was observed in 11 patients. No other adverse effect was observed. They concluded that the administration of erythropoietin appears to be a safe and useful therapy; however, Its efficacy should be confirmed by randomized studies.

Dominquez et al (2010) conducted an observational study in 13 newborns with late anemia due to a hemolytic disease caused by Rh isoimmunization (9 cases), ABO isoimmunication (2 cases), glucose-6-P-dehydrogenase deficiency (1 case) or idiopathic (1 case). The newborns began EPO treatment when they reached the haematocrit level for a blood transfusion. EPO treatment was started at 26±7 days of life (15-46), with a haematocrit value of 21.7±3% (18-27) and a reticulocyte count of 3.8±2.2%. Blood transfusion was not necessary in 11 newborns (haematocrit of 30.7±4.4% and reticulocytes of 5.9±1.4%), and only 2 newborns were admitted for a blood transfusion (haematocrit 18±4.4% and reticulocytes 0.6%). Significant increases in haemoglobin and reticulocyte figures were seen after EPO treatment. Although the authors concluded that EPO administration proved useful to avoid blood transfusion in 84% of treated newborns, sample size was small.

Rath et al. (2011) discussed hematological morbidity and management in neonates with hemolytic disease due to red cell alloimmunization. The authors state that treatment of severe anemia with intrauterine red cell transfusions in fetuses with red cell alloimmunization, has led to an increase in perinatal survival, creating a shift towards improving postnatal treatment options. They state that postnatal treatment of anemia consists of top-up transfusions and supplements to support erythropoiesis such as folic acid and iron, and occasionally erythropoietin treatment.

An American Society for Hematology education module (2015) uses the reference to Zuppa et al. (2010) to support the point that low erythropoietin levels may contribute to anemia; however, there is no recommendation for administration of erythropoietin for hemolytic anemia due to Rh sensitization in newborn (Delaney and Matthews, 2015).

Hereditary Hemochromatosis

Bruckl and colleagues (2017) examined retrospectively the effectiveness of combined therapy using EPO and erythrocytapheresis (EA) in patients with hereditary hemochromatosis (HH) who did not tolerate phlebotomy.  A total of 20 patients (age range of 43 to 74 years) with genetically confirmed HH had received low-dose EPO (4,000 IU) in accordance to the patient's hemoglobin levels between each EA session.  Laboratory parameters including hemoglobin, ferritin, transferrin, and iron were measured at regular intervals.  Anemia did not occur in a single patient and no serious adverse events (AEs) were observed.  Combined treatment with EPO and EA was well-tolerated, and all 18 patients who suffered from fatigue prior to therapy recovered.  Median ferritin values were 678.5 ng/L before treatment and 145 ng/L after treatment.  The authors concluded that EA in combination with EPO is safe and effective in treating patients with HH.  Moreover, they stated that prospective studies comparing this therapeutic option to phlebotomy are needed.

Myelofibrosis

Huang et al (2008) conducted a retrospective study to examine the risk factors for leukemic transformation in patients with primary myelofibrosis. The study that examined clinical variables at the time of diagnosis and specific treatment modalities for their effect on leukemic transformation in 311 patients with primary myelofibrosis  (PMF) who were seen at the Mayo Clinic. Analysis of parameters at the time of diagnosis revealed a significant association between inferior leukemia-free survival and a peripheral blood blast percentage>or=3 (P<.0001), a platelet count<100x10(9)/L (P=.004), a monocyte count>or=1x10(9)/L (P=.02), the presence of hypercatabolic symptoms (P=.03), a low hemoglobin level (P=.04), and a high leukocyte count (P=.04). Neither leukemia-free nor overall survival was found to be affected by the presence of <3% peripheral blood blasts or JAK2V617F mutation. The evaluation of treatment effect on leukemic transformation unexpectedly revealed a significant and independent association with previous therapy with either erythropoiesis-stimulating agents (ESA) (P=.004) or danazol (P=.007), even when the aforementioned prognostic indicators at the time of diagnosis were added as covariates to the multivariate model. In contrast, leukemia-free survival was not found to be affected by a treatment history with hydroxyurea, thalidomide, or other drugs. The authors concluded that peripheral blood blast percentage>or=3 and/or a platelet count<100x10(9)/L at the time of diagnosis were found to be strong and independent predictors of leukemic transformation in patients with PMF. The unexpected association between leukemic transformation and a history of treatment with ESA or danazol requires validation by prospective studies.

Huang et al (2009) discussed ESA having limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis (PMF) regardless of serum erythropoietin level. The authors reviewed a master database of patients diagnosed with PMF from 1976 through 2006, and seen at the Mayo Clinic. They identified 43 patients (median age 67 yrs old) treated with ESA. Study inclusion required documentation of a complete blood count prior to therapy and follow-up that was adequate enough to assess response. They excluded patients who were receiving other anemia-improving agents concomitantly with an ESA, such as prednisone, androgens, danazol, or thalidomide. Response was defined as a minimum 2.0 g ⁄dL increase in hemoglobin level or becoming transfusion-independent over a minimum of 1-month period. ESA was administered for a median of 4.3 months (range 0.5–54.0). Prior to ESA treatment, 16 (37%) patients were red blood cell transfusion-dependent and the median hemoglobin level in transfusion-independent patients at start of therapy was 9.4 g/dL. Pretreatment serum Epo level was documented in 25 patients (median 34 U⁄ L range 2-323). Overall response rate to ESA was 23% among transfusion-dependent patients, and 37% (10 out of 27) among transfusion-independent patients (p = 0.007). ESA response was not correlated with baseline serum Epo level in all 43 study patients (P = 0.68) or the subset of 27 transfusion-independent patients (P = 0.39), PMF-specific treatment history, use of concurrent cytoreductive therapy, cytogenetic findings, or JAK2V617F presence. The authors concluded that ESA, if at all used in PMF, should be avoided in those patients who are either transfusion-dependent or have a baseline hemoglobin of ≥ 10 g/dL.

Based on the experience and knowledge of experts in the field, Barbui and colleagues (2011) presented a review of critical concepts and developed recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. The authors noted a consensus on primary myelofibrosis (PMF) in that corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF; however, all of these agents have limitations, and there are no comparative trials, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly.

Hernandez-Boluda et al (2017) discussed predictive factors for anemia response to erythropoiesis-stimulating agents (ESA) in myelofibrosis. The authors analyzed ESA therapy in 163 myelofibrosis patients with severe anemia, of which, most of had inadequate EPO levels (< 125 U/L) at start of treatment. The revised criteria of the International Working Group for Myelofibrosis Treatment and Research were used in evaluating anemia response. The authors noted that 86 patients (53%) achieved an anemia response. Median response duration was 19.3 months. In multivariate analysis, baseline factors associated with a higher response rate were female sex (P=.007), leukocyte count ≥10×109 /L (P=.033), and serum ferritin <200 ng/mL (P=.002). Patients with 2 or 3 of the above features had a significantly higher response rate than the remainder (73% vs 28%, respectively; P<.001). Over the 373 patient-years of follow-up on ESA treatment, nine patients developed thrombotic complications (six arterial, three venous), accounting for 2.41 events per 100 patient-years. Survival time from ESA start was longer in anemia responders than in non-responders (P=.011). Hernandez-Boluda and colleagues concluded that the data obtained can help to identify which myelofibrosis patients are more likely to benefit from ESA treatment.

An UpToDate review on “Management of primary myelofibrosis” (Tefferi, 2017), states that “erythropoietin or darbepoetin have generally not been successful in alleviating the anemia associated with PMF, although others have reported responses, most often in patients not requiring transfusional support and/or those with inappropriately low serum erythropoietin levels.”

Per the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2018) and Drugs and Biologics Compendium (2018) on "Myeloproliferative neoplasms", ESAs such as darbepoetin alfa and epoetin alfa have a category 2A recommendation for managment of myelofibrosis-associated anemia with serum EPO less than 500 mU/mL. ESAs are "not effective for patients with transfusion-dependent anemia".

Neonatal Encephalopathy

Rogers and colleagues (2014) stated that EPO is neuro-protective in animal models of neonatal hypoxic-ischemic encephalopathy (HIE).  These researchers previously reported a phase I safety and pharmacokinetic study of EPO in neonates.  This article presented the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial.  These investigators enrolled 24 newborns with HIE in a dose-escalation study.  Patients received up to 6 doses of EPO in addition to therapeutic hypothermia (TH).  All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuro-radiologist.  Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy (CP) with Gross Motor Function Classification System levels III to V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score.  Outcomes were available for 22 of 24 infants, at mean age of 22 months (range of 8 to 34).  There were no deaths; 8 (36 %) had moderate-to-severe brain injury on neonatal MRI.  Moderate-to-severe disability occurred in 1 child (4.5 %), in the setting of moderate-to-severe basal ganglia and/or thalamic injury; 7 infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (n = 3), mild language delay (n = 2), mild hemiplegic CP (n = 1), and epilepsy (n = 1).  All 11 patients with a normal brain MRI had a normal outcome.  The authors concluded that this study was the first to describe neurodevelopmental outcomes in infants who received high doses of EPO and TH during the neonatal period.  The findings suggested that future studies are needed to evaluate the effectiveness of this new potential neuro-protective therapy.

McAdams and Juul (2016) stated that neonatal encephalopathy (NE) is a major cause of neonatal mortality and morbidity; and TH is standard treatment for newborns at 36 weeks of gestation or greater with intra-partum hypoxia-related NE.  Term and late preterm infants with moderate to severe NE show improved survival and neurodevelopmental outcomes at 18 months of age after TH.  Therapeutic hypothermia can increase survival without increasing major disability, rates of an IQ less than 70, or CP.  Neonates with severe NE remain at risk of death or severe neurodevelopmental impairment.  The authors discussed the evidence supporting TH and other novel therapeutics for term or near term neonates with NE; EPO is one of the keywords listed in this review.

Juul and colleagues (2018) noted that HIE remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors.  Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities.  Adjunctive therapies are needed, and EPO has the potential to provide additional neuroprotection.  These investigators reviewed the current incidence, mechanism of injury, and sequelae of HIE, and described a new phase-III randomized, placebo-controlled clinical trial of EPO neuro-protection in term and near-term infants with moderate-to-severe HIE treated with therapeutic hypothermia.  They presented an overview of HIE, neuro-protective functions of EPO, and the design of a double-blind, placebo-controlled, multi-center clinical trial of high-dose EPO administration, enrolling 500 neonates of greater than or equal to 36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria.  The authors stated that EPO has robust neuro-protective effects in pre-clinical studies, and phase-I/phase-II clinical trials suggesting that multiple high-doses of EPO may provide neuro-protection against brain injury in term infants.  The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will examine if high-dose EPO reduces the combined outcome of death or neuro-developmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

Optic Neuritis

Diem and associates (2016) stated that optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve.  The standard treatment is a methylprednisolone pulse therapy.  This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment.  In a phase II clinical  trial performed in preparation of this study, these researchers have shown that EPO protects global retinal nerve fiber layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function.  These researchers noted that “Treatment of Optic Neuritis with Erythropoietin (TONE)” is a national, randomized, double-blind, placebo-controlled, multi-center trial with 2 parallel arms.  The primary objective is to determine the effectiveness of EPO compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomization.  Inclusion criteria were a first episode of optic neuritis with decreased visual acuity to less than or equal to 0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion.  The most important exclusion criteria were history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy.  After randomization, patients either receive 33,000 IU rhEPO intravenously for 3 consecutive days or placebo (0.9 % saline) administered intravenously.  With an estimated power of 80 %, the calculated sample size is 1,00 patients.  The authors noted that the trial started in September 2014 with a planned recruitment period of 30 months.

Out-of-Hospital Cardiac Arrest

Cariou and colleagues (2016) stated that preliminary data suggested a clinical benefit in treating out-of-hospital cardiac arrest (OHCA) patients with a high dose of EPO analogs.  These researchers evaluated the effectiveness of epoetin alfa treatment on the outcome of OHCA patients in a phase III clinical trial.  These researchers performed a multi-center, single-blind, RCT.  Patients still comatose after a witnessed OHCA of presumed cardiac origin were eligible.  In the intervention group, patients received 5 intravenous injections spaced 12 hours apart during the first 48 hours (40,000 units each, resulting in a maximal dose of 200,000 total units), started as soon as possible after resuscitation.  In the control group, patients received standard care without EPO.  The main end-point was the proportion of patients in each group reaching level 1 on the Cerebral Performance Category (CPC) scale (survival with no or minor neurological sequelae) at day 60.  Secondary end-points included all-cause mortality rate, distribution of patients in CPC levels at different time-points, and side effects.  In total, 476 patients were included in the primary analysis.  Baseline characteristics were similar in the 2 groups.  At day 60, 32.4 % of patients (76 of 234) in the intervention group reached a CPC 1 level, as compared with 32.1 % of patients (78 of 242) in the control group (OR: 1.01; 95 % CI: 0.68 to 1.48).  The mortality rate and proportion of patients in each CPC level did not differ at any time points.  Serious AEs were more frequent in EPO-treated patients as compared with controls (22.6 % versus 14.9 %; p = 0.03), particularly thrombotic complications (12.4 % versus 5.8 %; p = 0.01).  The authors concluded that in patients resuscitated from an OHCA of presumed cardiac cause, early administration of EPO plus standard therapy did not confer a benefit, and was associated with a higher complication rate.

Cognitive Deficits Associated with Bipolar Disorder, Depression and Schizophrenia

Li and associates (2018) reviewed the safety and efficacy of adjunctive EPO in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression based on RCTs.  Two evaluators independently and systematically searched and selected studies, extracted data, and conducted quality assessment.  A total of 4 RCTs with 144 patients (71 in the EPO group and 73 in the placebo group) met the study entry criteria.  Adjunctive EPO could improve schizophrenia-related cognitive performance.  In patients with bipolar disorder, EPO could also enhance sustained attention, recognition of happy faces, and speed of complex information processing across learning, attention, and executive function when compared with placebo.  In addition, EPO could enhance verbal recall, recognition, and memory in patients with major depression.  The authors concluded that this preliminary study found that adjunctive EPO appeared to be effective in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression without major AEs observed.  Moreover, these researchers stated that further higher quality RCTs with larger samples are needed to confirm these findings.

Traumatic Brain Injury

In a matched case control study, Talving and co-workers (2010) examined if administration of ESA would improve survival following severe traumatic brain injury (sTBI).  Patients with sTBI [head Abbreviated Injury Scale (AIS), greater than or equal to 3] receiving ESA while in the surgical intensive care unit (n = 89) were matched 1 to 2 (n = 178) by age, gender, mechanism of injury, Glasgow Coma Scale, presence of hypotension on admission, Injury Severity Score, AIS for all body regions, and presence of anemia with patients who did not receive the agent.  Each case's controls were chosen to have surgical intensive care unit length of stay more than or equal to the time from admission to first dose of ESA.  The primary outcome measure in this study was mortality.  Cases and controls had similar age, gender, mechanisms of injury, incidence of hypotension, Glasgow Coma Scale on admission, Injury Severity Score, and AIS for all body regions.  Although the ESA-treated patients experienced protracted hospital length of stay and comparable surgical intensive care unit free days, they demonstrated a significantly lower in-hospital mortality in comparison to controls at 7.9 % versus 24.2 %, respectively (OR: 0.27; 95 % CI: 0.12 to 0.62; p = 0.001).  The authors concluded that administration of ESA in sTBI is associated with a significant in-hospital survival advantage without increase in morbidity. They stated that prospective, large, randomized controlled trials are needed to validate these findings.

In a systematic review and meta-analysis, Lee and colleagues (2018) examined the effects of EPO on mortality and neurological outcomes in patients with TBI.  Electronic databases of studies published up to January 5, 2017 were searched to retrieve relevant investigations comparing the outcomes of EPO-treated patients and untreated patients following TBI.  These investigators calculated the relative risk (RR) of mortality, neurologic outcomes, and DVT with corresponding 95 % CI using meta-analysis.  A total of 6 RCTs (1,041 patients) met the eligibility criteria; EPO was found to significantly reduce the occurrence of mortality (RR 0.68 [95 % CI: 0.50 to 0.95]; p = 0.02), but did not significantly reduce poor functional outcome (RR 1.22 [95 %: CI 0.82 to 1.81]; p = 0.33).  There were no significant differences in the occurrence of complications, such as DVT, between the treatment groups (RR -0.02 [95 % CI: -0.06 to 0.02]; p = 0.81).  The authors concluded that findings of this meta-analysis suggest that the use of EPO may prevent death following TBI without causing AEs, such as DVT.  However, these researchers stated that the role of EPO in improving neurological outcome(s) remains unclear, and further well-designed RCTs using modified protocols and involving specific patient populations are needed to clarify this issue, and to verify the findings.

Erythropoietin for Hypoxic-Ischemic Encephalopathy

Nair and Kumar (2018) noted that clinical trials evaluating erythropoietin in infants with hypoxic ischemic encephalopathy (HIE) have shown promising results. The authors commented that, since hypothermia has become standard of care therapy for HIE, larger trials are currently on going evaluating erythropoietin as a complement to cooling therapy. The authors stated that a phase III trial evaluating the effect of erythropoeitin with hypothermia on the combined outcome of death or neurodevelopmental disability is currently underway. They also reported that a large multicenter randomized controlled trial evaluating use of darbepoetin in mild HIE is currently underway (MEND study).

In an open-label pilot study, Nonomura and colleagues (2019) examined the safety and feasibility of the combination therapy with erythropoietin (Epo), magnesium sulfate and hypothermia in neonates with hypoxic-ischemic encephalopathy (HIE).  A combination therapy with Epo (300 U/kg every other day for 2 weeks), magnesium sulfate (250 mg/kg for 3 days) and hypothermia was started within 6 hours of birth in neonates who met the institutional criteria for hypothermia therapy was carried out.  All patients received continuous infusion of dopamine.  Vital signs and AEs were recorded during the therapy.  Short-term and long-term developmental outcomes were also evaluated.  A total of 9 patients were included in the study.  The mean age at first intervention was 3.9 hours (SD, 0.5).  Death, serious AEs or changes in vital signs likely due to intervention were not observed during hospital care.  All 9 patients completed the therapy.  At the time of hospital discharge, 8 patients had established oral feeding and did not require ventilation support; 2 patients had abnormal MRI findings.  At 18 months of age, 8 patients received a follow-up evaluation, and 3 of them showed signs of severe neurodevelopmental disability.  The authors concluded that the this pilot study showed that combination therapy with 300 U/kg Epo every other day for 2 weeks, 250 mg/kg magnesium sulphate for 3 days and therapeutic hypothermia was feasible in newborn patients with HIE.  Moreover, these researchers stated that to demonstrate the long-term neuroprotective safety and efficacy of this therapy, phase-II and phase-III clinical trials with an adequate sample size are needed.

The authors stated that this study had several limitations.  First, it was conducted in a small number of patients (n = 9) without a control treatment and was not designed to evaluate efficacy.  However, all 9 patients included in the study completed the therapy without developing AEs.  Death or serious AEs were not observed.  Second, these investigators chose the low-dose of Epo.  Thus, the safety data would not be applicable to future studies using higher doses.

Erythropoietin for the Treatment of Diabetic Neuropathy

Suarez-Mendez and colleagues (2018) noted that EPO is needed for promoting the progress of erythroid differentiation.  However, the discovery of EPO and the EPO receptor (EPOR) in the nervous system may contribute to new treatment strategies for the use of EPO in neurodegenerative disorders.  Diabetic neuropathy (DN) is a neurodegenerative disease that affects a large proportion of diabetic patients and results in alterations in functionality, mood and sleep.  The pathogenic mechanisms generating DN involve: Schwannopathy, polyol pathway activity, advanced glycation end-products (AGEs) accumulation, protein kinase C (PKC) activity, increased hexosamine pathway flux, oxidative stress, nitric oxide and inflammation.  In this sense, evidence from both clinical and experimental studies indicated that EPO may reverse DN via an anti-oxidant action by decreasing pro-inflammatory cytokines, restoring Na+/K+-ATPase activity, and blocking the generation of pro-apoptotic proteins.  In this review, the authors discussed the potential neuro-protective effect of EPO on the pathogenesis of DN; and suggested a possible therapeutic use of EPO for DN.

Erythropoietin for the Treatment of Oral Mucositis

Rezazadeh and colleagues (2018) noted that oral mucositis (OM) represents a therapeutic challenge frequently encountered in cancer patients undergoing chemotherapy or radiotherapy; and EPO has anti-inflammatory, anti-oxidant, and wound-healing properties and thus has important roles in the prevention and treatment of OM.  In the current study, these researchers developed a thermally sensitive muco-adhesive gel based on tri-methyl chitosan (TMC) containing EPO for the treatment of OM.  TMCs with various degrees of substitution (DS) were synthesized and mixed with β-glycero-phosphate (GP) and characterized for gelation properties by means of rheological analysis.  The effects of DS of TMCs and different concentrations of GP on gelation temperature and time were examined.  The muco-adhesive property of the mixtures was also assessed using cattle buccal mucosa.  The optimized mixture was loaded with EPO and subjected to in-vitro drug release, wash-away, in-vitro anti-microbial, and wound-healing tests.  The effect of EPO-loaded formulation was also examined in-vivo in Sprague-Dawley rats with chemotherapy-induced mucositis.  The best properties were obtained with the blend of TMC of 9.8 % DS (5 %) and GP (20 %).  EPO was released from the hydrogel during 8 hours, and more than 30 % of the drug still remained on the mucosa after 3 hours of washing the buccal mucosa with phosphate buffer.  TMC/GP mixture was characterized by anti-microbial properties.  The authors concluded that the EPO hydrogel demonstrated in-vitro/in-vivo wound-healing properties; thus, EPO-loaded hydrogel has the potential to be used in the treatment of OM and other oral or subcutaneous wounds.

Appendix

Specific Criteria for Erythropoiesis Stimulating Agents

Note: For persons with iron deficiency, ESAs may be initiated simultaneously with iron replacement.

1. 1. Criteria for Initiation of Therapy:

      1. For treatment of anemia associated with myelosuppressive anticancer chemotherapy:

         1. Erythropoiesis stimulating agents (ESAs) are considered medically necessary where hemoglobin (Hgb) has fallen below 10g/dL and the following criteria are met:

            1. Anemia is secondary to myelosuppressive anticancer chemotherapy for solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia; and
            2. Adequate iron stores have been demonstrated by means of bone marrow iron or serum ferrtin levels (greater than 100 ng/ml) or serum transferrin saturation (TSAT greater than 20%) within the prior 12 months, and 
            3. Member is exhibiting symptoms of anemia (such as fatigue, weakness, shortness of breath, or lightheadedness) affecting their ability to perform activities of daily living, or the member exhibits angina, syncope, or tachycardia from the anemia; and
            4. ESAs intended to decrease the need for transfusions in persons who will receive chemotherapy for a minimum of 2 months.

         2. The starting dose of ESAs are equal to the following, based upon FDA labeling, or comparable fixed dosing schedules:

            1. Erythropoietin: 150 units/kg 3 times per week, or 40,000 units weekly in adults; 600 units/kg (maximum 40,000 units) weekly for children.
            2. Darbepoetin: 2.25 mcg/kg per week, or 500 mcg every 3 weeks.
                

      2. For treatment of anemia associated with myelodysplastic syndrome, ESAs are considered medically necessary where hemoglobin (Hgb) has fallend below 10g/dL, and the following criteria are met:

         1. Adequate iron stores are demonstrated by means of bone marrow iron or serum ferritin levels (greater than 100 ng/ml) or serum transferrin saturation (TSAT greater than 20%) within the past 12 months, and
         2. Member is exhibiting symptoms of anemia (such as fatigue, weakness, shortness of breath, or lightheadedness) affecting their ability to perform activities of daily living, or the member exhibits angina, syncope, or tachycardia from the anemia; and
         3. Bone marrow has less than 15% blasts, and
         4. Member has required transfusion of 2 or fewer units of blood per month, and
         5. Endogenous serum erythropoietin (EPO) levels are less than or equal to 500 IU/L.
             
      3. For treatment of anemia associated chronic renal failure on dialysis:
          
         1. ESAs are considered medically necessary where hemoglobin (Hgb) is less than 10 g/dL, and the following criteria are met:
             
            1. Adequate iron stores are demonstrated by means of bone marrow iron or serum ferritin levels (greater than 100 ng/ml) or serum transferrin saturation (TSAT greater than 20%) within the past 12 months; and
            2. Member is exhibiting symptoms of anemia (such as fatigue, weakness, shortness of breath, or lightheadedness) affecting their ability to perform activities of daily living, or the member exhibits angina, syncope, or tachycardia from the anemia; and 
                
         2. The starting dose is equal to the following, based upon FDA labeling, or comparable fixed dose schedules:
            

            1. Erythropoietin: 50 to 100 units/kg body weight 3 times per week for adults; 50 units/kg body weight for children.

            2. Darbepoetin: 0.45 mcg/kg body weight once-weekly or 0.75 mcg/kg body weight every 2 weeks.  

            3. Mircera: 0.6 mcg/kg body weight administered once every 2 weeks.
               
               
      4. For treatment of anemia associated chronic renal failure not on dialysis:
          
         
         1. ESAs are considered medically necessary where hemoglobin (Hgb) is less than 10 g/dL, and the following criteria are met:
             
            1. Member has chronic kidney failure (defined as creatinine clearance less than 60 ml/min, or glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2);
               and
            2. Adequate iron stores are demonstrated by means of bone marrow iron or serum ferritin levels (greater than 100 ng/ml) or serum transferrin saturation (TSAT greater than 20%) within the past 12 months; and
            3. Member is exhibiting symptoms of anemia (such as fatigue, weakness, shortness of breath, or lightheadedness) affecting their ability to perform activities of daily living, or the member exhibits angina, syncope, or tachycardia from the anemia; and
            4. The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell (RBC) transfusion; and
            5. Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
                
         2. The starting dose is equal to the following, based upon FDA labeling, or comparable fixed dose schedules:
            
            

            1. Erythropoietin: 50 to 100 units/kg body weight 3 times per week for adults; 50 units/kg body weight for children.

            2. Darbepoetin: 0.45 mcg/kg body weight once-weekly or 0.75 mcg/kg body weight every 2 weeks.

            3. Mircera: 0.6 mcg/kg body weight administered once every 2 weeks.  

      5. For treatment of anemia related to zidovudine in HIV-infected persons, ESAs are considered medically necessary where hemoglobin (Hgb) is less than 10 g/dL, and the following criteria are met:
          
         
         1. Adequate iron stores are demonstrated by means of bone marrow iron or serum ferritin levels (greater than 100 ng/ml) or serum iron saturation (TSAT greater than 20%) within the past 12 months; and
         2. Member is exhibiting symptoms of anemia (such as fatigue, weakness, shortness of breath, or lightheadedness) affecting their ability to perform activities of daily living, or the member exhibits angina, syncope, or tachycardia from the anemia; and
         3. Endogenous EPO level is less than or equal to 500 IU/L; and
         4. Dose of zidovudine is less than or equal to 4200 mg/week.
             
      6. For treatment of anemia due to chemotherapy (e.g., ribavirin) in persons with hepatitis C, ESAs are considered medically necessary where the Hgb is less than 10 g/dL and the following criteria are met:
          
         
         1. Member is receiving interferon or pegylated interferon plus ribavirin; and
         2. Adequate iron stores are demonstrated by means of bone marrow iron or serum ferritin levels (greater than 100 ng/ml) or serum transferrin saturation (TSAT greater than 20%) within the past 12 months; and
         3. Member is exhibiting symptoms of anemia (such as fatigue, weakness, shortness of breath, or lightheadedness) affecting their ability to perform activities of daily living, or the member exhibits angina, syncope, or tachycardia from the anemia; and
         4. Hgb remains below 10 g/dl despite reduction of dose or ribavirin (dose of ribavirin can be decreased by 80 percent of target dose; daily ribavirin dose should not be less than 800 mg).
             
      7. For treatment of anemia of chronic disease other than cancer, ESAs are considered medically necessary where Hgb is less than 10 g/dL and the following criteria are met:
          
         
         1. An underlying chronic disease has been identified (see table "Underlying Causes of Anemia of Chronic Disease" below); and
         2. Adequate iron stores are demonstrated by means of bone marrow iron or serum ferritin levels (greater than 100 ng/ml) or serum transferrin saturation (TSAT greater than 20%) within the past 12 months; and
         3. Member is exhibiting symptoms of anemia (such as fatigue, weakness, shortness of breath, or lightheadedness) affecting their ability to perform activities of daily living, or the member exhibits angina, syncope, or tachycardia from the anemia.
             
      8. For treatment of anemic members scheduled to undergo high-risk surgery at increased risk of or intolerant to transfusions, ESAs are considered medically necessary in persons with a Hgb less than 13 g/dL. 
      9. For treatment of anemia of prematurity, ESAs are considered medically necessary when the member has either a birth weight of less than 1,500 grams or a gestational age of less than 33 weeks (medically necessary duration of therapy limited to 6 weeks).
      10. For special circumstance members who will not or can not receive whole blood or components as replacement for traumatic or surgical loss, ESAs are considered medically necessary in persons with a Hgb less than 12 g/dL.

   2. Criteria for continuation of chronic ESAs in persons with anemia due to myelosuppressive anticancer chemotherapy:

      1. The maintenance dose of ESAs are equal to the starting dose if:
          
         1. the hemoglobin remains below 10 g/dL 4 weeks after initiation of therapy; and
         2. the rise in hemoglobin is greater than or equal to 1 g/dL;
             
      2. Continued administration of ESAs are considered not medically necessary if there is a rapid rise in hemoglobin greater than 1 g/dl over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to less than 10 g/dL. Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.
      3. For persons whose hemoglobin rises less than 1 g/dl compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains less than 10 g/dL after the 4 weeks of treatment, the recommended FDA label starting dose of ESAs may be increased once by 25%. Continued use of ESAs are considered not medically necessary if the hemoglobin rises less than 1 g/dl compared to pretreatment baseline by 8 weeks of treatment.

   3. Criteria for continuation of chronic ESAs for chronic renal failure on dialysis:

      1. ESAs should be administered with a Hgb range of 10 g/dL to 11 g/dL (Note: maintenance at a higher Hgb level may be necessary for persons with acute myocardial infarction, angina, orthostatic hypotension, living at an elevation of greater than 6000 feet, or anemia with Hgb below 11 g/dL has significantly interfered with activities of daily living).
      2. For hemoglobin less than 10 g/dL, dose may be increased by up to 50 % over the previously administered dose, until the hemoglobin is between 10 g/dL and less than or equal to 11 g/dL.  Dosage adjustments may be made as frequently as twice monthly.  Exception: If, after increasing the ESA dose, the hemoglobin has risen more than 0.5 g/dL in the past 2 weeks or more than 1 g/dL in the past 4 weeks, decrease dose by 25 % over the previously administered dose.
      3. For hemoglobin greater than 11 g/dL and less than or equal to 14 g/dL, the dose should be decreased by 10 % over the previously administered dose.  Dose decreases should be made twice-monthly until the hemoglobin is less than or equal to 11 g/dL.
      4. For hemoglobin greater than 14 g/dL and less than or equal to 15 g/dL, the dose should be decreased by 25 % over the previously administered dose.  Dose decreases can be made twice-monthly or monthly until the hemoglobin falls to less than 11 g/dL.
      5. For hemoglobin greater than 15 g/dL, the dose of ESAs should be held and should be restarted at 50 % of the previously administered dose when the hemoglobin is less than or equal to 11 g/dL.

   4. Criteria for continuation of chronic ESAs for chronic renal failure not on dialysis:

      1. If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of ESAs, and use the lowest dose of ESAs sufficient to reduce the need for RBC transfusions.

   5. Criteria for continuation of chronic ESAs for other indications:

      For persons who meet medical necessity criteria for ESAs, continued ESAs are considered medically necessary for persons with a Hgb less than 11g/dL.  (For anemic members scheduled to undergo high-risk surgery, continued ESAs are considered medically necessary where Hgb is less than 13 g/dL).

   6. Discontinuation criteria for ESAs:

      1. For indications other than end-stage renal disease, continued ESAs are considered not medically necessary if the member's Hgb has failed to rise by 1 g/dL compared to pre-treatment baseline within 8 weeks of therapy despite appropriate dose escalation.
      2. Continued ESAs are considered not medically necessary for myelodysplastic syndrome if transfusion requirements have been reduced by less than 50% after 6 months of therapy.
      3. ESAs for each course of chemotherapy for anemic persons with cancer or hepatitis C includes the 8 weeks following the final dose of chemotherapy in a chemotherapy regimen.

   7. Underlying Causes of Anemia of Chronic Disease:

       The following conditions have been associated with anemia of chronic disease (Weiss and Goodnough, 2005):

      1. Infections (acute and chronic) 

         1. Bacterial
         2. Fungal
         3. Parasitic
         4. Viral infections, including human immunodeficiency virus infection

      2. Autoimmune

         1. Inflammatory bowel disease
         2. Rheumatoid arthritis
         3. Sarcoidosis
         4. Systemic lupus erythematosus and connective tissue diseases
         5. Vasculitis

      3. Cancer

         1. Hematologic
         2. Solid tumor
             

      4. Chronic rejection after solid-organ transplantation

   8. FDA-Approved Indications and Brands of Erythropoiesis-Stimulating Agents

      Note: There is a lack of evidence that one brand of erythropoietin alpha (i.e., Procrit, Epogen, Retacrit) is more effective than another brand. In addition, there is a lack of reliable evidence that darbepoetin is more effective than erythropoietin alpha or Mircera for darbepoetin's labeled indications. 

      Table:FDA-Approved Indications and Brands of Erythropoiesis-Stimulating Agents

      FDA-Approved Indications	Brands of ESAs
      Treatment of anemia of chronic renal failure	Epogen, Procrit, Aranesp, Retacrit, Mircera
      Treatment of anemia in zidovudine-treated HIV-infected patients	Epogen, Procrit, Retacrit
      Treatment of anemia in cancer patients on chemotherapy	Epogen, Procrit, Aranesp, Retacrit
      Reduction of allogeneic blood transfusion in surgery patients	Epogen, Procrit, Retacrit

       

   9. Normal Reference Range of Serum Iron and Serum Ferritin:

      1. Serum Iron:

         • Children: 50 to 120 µg/dL
         • Men: 65 to 176 µg/dL
         • Newborns: 100 to 250 µg/dL
         • Women: 50 to 170 µg/dL

         Source: Slon, 2006.

      2. Serum Ferritin:

         • Female: 12 to 150 ng/mL
         • Male: 12 to 300 ng/mL

         Source: Gersten, 2009.

   10. Conversion of Epoetin alpha to Darbepoetin

       For adult patients already receiving either IV or SQ epoetin alfa, the manufacturer recommends the conversion in the following table:
       
       

       Table:Conversion of Epoetin alpha to Darbepoetin

       Previous weekly epogen alfa dose (units/week)	Weekly darbepoetin alfa dose (micrograms/week)
       less than 1500	6.25
       1500 to 2499	6.25
       2500 to 4999	12.5
       5000 to 10,999	25
       11,000 to 17,999	40
       18,000 to 33,999	60
       34,000 to 89,999	100
       90,000 or greater	200

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Erythropoietin or darbepoetin therapy:
CPT not covered for indications listed in the CPB:
38204 - 38232	Bone Marrow or Stem Cell Services/Procedures
38240 - 38243	Transplantation and Post- Transplantation Cellular Infusions
Other CPT codes related to the CPB:
96372, 96374 - 96376	Therapeutic, prophylactic, or diagnostic injection
96401 - 96417	Chemotherapy administration
99601 - 99602	Home infusion/specialty drug administration
HCPCS codes covered if selection criteria are met:
J0881	Injection, darbepoetin alfa, 1 mcg (non-ESRD use)
J0882	Injection, darbepoetin alfa, 1 mcg (for ESRD on dialysis)
J0885	Injection, epoetin alfa, (for non-ESRD use), 1,000 units
J0887	Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)
J0888	Injection, epoetin beta, 1 microgram, (for non-ESRD use)
Q4081	Injection, epoetin alfa, 100 units (for ESRD on dialysis)
Q5105	Injection, epoetin alfa, biosimilar, (Retacrit) (for ESRD on dialysis), 100 units
Q5106	Injection, epoetin alfa, biosimilar, (Retacrit) (for non-esrd use), 1000 units
S9537	Home therapy; hematopoietic hormone injection therapy (e.g., erythropoietin, G-CSF, GM-CSF); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
HCPCS codes not covered for indications listed in the CPB :
S2140	Cord blood harvesting for transplantation, allogeneic
S2142	Cord blood-derived stem-cell transplantation allogeneic
S2150	Bone marrow or blood-derives stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including : pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical ,diagnostic ,emergency, and rehabilitative services; and the number of days pre and post-transplant care in the global definition
Other HCPC codes related to the CPB:
J9213	Injection, interferon, alfa-2a, recombinant, 3 million units
J9214	Injection, interferon, alfa-2b, recombinant, 1 million units
S0145	Injection, pegylated interferon alfa-2a, 180 mcg per ml
S0148	Injection, pegylated interferon alfa-2B, 10 mcg
ICD-10 codes covered if selection criteria are met:
B20	Human immunodeficiency virus [HIV] disease
B97.35	Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere
C00.0 - C43.9, C44.0 - C75.9, C76.0 - C86.6, C88.4 - C91.32, C91.50 - C91.92, C96.0 - C96.4, C96.6 - C96.9	Malignant neoplasm
C4A.0 - C4A.9	Merkel cell carcinoma
C7A.00 - C7A.8	Malignant neuroedocrine tumors
C7B.00 - C7B.8	Secondary neuroendocrine tumors
D03.0 - D03.9	Melanoma in situ
D46.0 - D46.9	Myelodysplastic syndrome
D47.4	Osteomyelofibrosis
D63.0 - D63.8	Anemia in chronic diseases classified elsewhere [not covered for anemia associated with COPD]
D64.81	Anemia due to antineoplastic chemotherapy
D75.81	Myelofibrosis
J40 - J47	Chronic lower respiratory diseases
N18.1 - N18.9	Chronic kidney disease (CKD)
P15.9	Birth injury, unspecified [brain injury]
P61.2	Anemia of prematurity
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C92.00 - C94.32 C94.80 - C95.92	Myeloid leukemia, monocytic leukemia, other leukemias of specified cell type and leukemia of unspecified cell type
D45	Polycythemia vera [Heilmeyer-Schoner disease]
D47.3	Essential (hemorrhagic) thrombocythemia
D47.Z2	Castleman disease
D50.0 - D50.9	Iron deficiency anemia
D51.1 - D52.9	Vitamin B12 deficiency anemia and folate deficiency anemia
D55.0 - D59.9	Hemolytic anemias [hereditary and aquired]
D60.0 - D61.9	Aplastic anemia and other bone marrow failure syndromes
D62	Acute posthemorrhagic anemia
D65	Disseminated intravascular coagulation [defibrination syndrome]
E08.40 - E08.42	Diabetes mellitus due to underlying condition with diabetic neuropathy/ mononeuropathy/polyneuropathy
E09.40 - E09.42	Drug or chemical induced diabetes mellitus with neurological complications with diabetic neuropathy/mononeuropathy/polyneuropathy
E10.40 - E10.42	Type 1 diabetes mellitus with diabetic neuropathy/mononeuropathy /polyneuropathy
E11.40 - E11.42	Type 2 diabetes mellitus with diabetic neuropathy/mononeuropathy /polyneuropathy
E13.40 - E13.42	Other specified diabetes mellitus with diabetic neuropathy/mononeuropathy /polyneuropathy
E75.22	Gaucher disease
E83.110	Hereditary hemochromatosis
F07.81	Postconcussional syndrome
F20.0 - F20.9, F25.0 - F25.9	Schizophrenia and Schizoaffective disorders
F31.10 - F31.9	Bipolar disorder
F32.0 - F33.9	Major depressive disorder
G11.1	Early-onset cerebellar ataxia [Friedreich's ataxia]
G35	Multiple sclerosis
G45.4	Transient global amnesia
G61.0	Guillain-Barre syndrome
G90.01 - G90.09, G90.4 - G90.9 G99.0	Disorders of the autonomic nervous system
G93.1	Anoxic brain damage, not elsewhere classified
H35.10 - H35.109	Retinopathy of prematurity
H46.00 - H46.9	Optic neuritis
I21.0 - I25.9	Ischemic heart disease
I46.2 - I46.9	Cardiac arrest [out-of-hospital]
I50.1 - I50.9	Heart failure
I63.00 - I66.9, I67.1 - I67.2 I67.4 - I67.9, I68.0 - I68.8 I69.00 - I69.998	Cerebrovascular diseases [except transient ischemic attacks]
K12.30 - K12.39	Oral mucositis (ulcerative)
M41.00 - M41.35 M41.80 - M41.9	Scoliosis
M41.40 - M41.57	Neuromuscular and other secondary scoliosis
M96.5	Postradiation scoliosis
N17.0 - N17.9	Acute kidney failure
O99.011 - O99.03	Anemia complicating pregnancy, childbirth and the puerperium
P54.3	Other neonatal gastrointestinal hemorrhage
P91.60 - P91.63	Hypoxic ischemic encephalopathy (HIE)
P91.811 - P91.819	Neonatal encephalopathy
Q79.6	Ehlers-Danlos syndrome
R57.0	Cardiogenic shock
S06.0x0+ - S06.9x9+	Intracranial injury
S06.9x0S - S06.9x9S	Unspecified intracranial injury, sequela
T66.xxx+	Radiation sickness, unspecified
Numerous options	Fracture of skull and facial bones, sequela [Codes not listed due to expanded specificity]
Peginesatide (Omontys):
HCPCS codes not covered for indications listed in the CPB:
J0890	Injection, peginesatide, 0.1 mg (for ESRD on dialysis)
ICD-10 codes covered if selection criteria are met:
D63.1	Anemia in chronic kidney disease
Sodium Ferric Gluconate:
HCPCS codes covered if selection criteria are met:
J2916	Injection, sodium ferric gluconate complex in sucrose injection, 12.5 mg
ICD-10 codes covered if selection criteria are met:
D50.0 - D50.9	Iron deficiency anemia

The above policy is based on the following references: