Clinical Policy Bulletin: Erythropoiesis Stimulating Agents...More recently, the FDA (2011)...

Erythropoiesis Stimulating Agents of 39

http://qawww.aetna.com/cpb/medical/data/100_199/0195_draft.html 11/03/2014

Clinical Policy Bulletin: Erythropoiesis Stimulating Agents

Revised April 2014

Number: 0195 Policy

I. Aetna considers erythropoietin therapy (e.g., EPO, Epogen [epoetin alfa], epoetin beta, Procrit, r-HuEPO) and

darbepoietin alfa therapy (Aranesp) medically necessary when any of the following selection criteria is met

(see Appendix for specific criteria):

A. Anemia from myelodysplastic syndrome; or

B. Anemia of prematurity; or

C. Special circumstance members who will not or cannot receive whole blood or

components as replacement for traumatic or surgical loss; or

D. Treatment of anemic members scheduled to undergo high-risk surgery who are

at increased risk of or intolerant to transfusions; or

E. Treatment of anemia associated with chronic renal failure, whether or not on

dialysis; or

F. Treatment of anemia in members receiving chemotherapy for hepatitis C; or

G. Treatment of anemia of chronic disease other than cancer when an underlying

chronic disease associated with anemia has been identified (see Appendix); or

H. Treatment of anemia secondary to myelosuppressive anticancer chemotherapy

in solid tumors, multiple myeloma, lymphomas and lymphocytic leukemia; or

I. Treatment of anemia due to zidovudine in HIV-infected members.

II. Adults who are on dialysis due to chronic kidney disease (see appendix for specific criteria).

III. 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 chronichemodialysis who are receiving supplemental erythropoietin or darbepoetin therapy.

IV.

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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):

Acute renal injury

Anemia associated only with radiotherapy

Anemia associated with the treatment of acute and chronic myelogenous leukemia

(AML, CML) or erythroid cancers

Anemia due to bleeding (other than indications I.D. (high-risk surgery [e.g.,

colectomy, hip replacement, and knee replacement]) and I.C. (special

circumstance members) above)

Anemia due to cancer treatment in persons with uncontrolled hypertension

Anemia due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, or

bone marrow fibrosis

Anemia in Castleman's disease

Anemia in Gaucher's disease

Anemia in paroxysmal nocturnal hemoglobinuria (PNH)

Anemia in persons with erythropoietin-type resistance due to neutralizing

antibodies

Anemia of cancer not due to cancer treatment

Aplastic anemia

Autonomic dysfunction

Cardiogenic shock-associated anemia

Cerebral hypoxia/ischemia

Cognitive decline in persons with schizophrenia

Congestive heart failure

Ehlers Danlos syndrome

Guillain-Barre syndrome

Heart failure

Hemolytic anemia

Immediate correction of severe anemia

Ischemic heart disease

Multiple sclerosis

Myelofibrosis

Myocardial infarction

Physiologic anemia of pregnancy

Postural tachycardia syndrome

Prophylactic use to prevent anticancer chemotherapy-induced anemia

Prophylactic use to prevent tumor hypoxia

Scoliosis surgery

Sepsis-associated anemia

Sickle cell anemia

Stroke/subarachnoid hemorrhage (except for I.G above)

Thrombocythemia

Traumatic brain injury.




Background

Erythropoietin therapy (e.g., EPO, Epogen [epoetin alfa], epoetin beta, Omontys

(peginesatide), Procrit, r-HuEPO) 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.

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/dl) 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.

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.

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.

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 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, the U.S.

Pharmacopoeial Convention concluded that chemotherapy-induced anemia is an accepted

indication for darbepoetin alpha. 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.

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 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 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. 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.

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 (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 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 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 (i) evaluating safety

of long-term high-dose intravenous rHuEPO treatment in MS, and (ii) 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: (i) the proximal tubular

brush border enzymes gamma-glutamyl transpeptidase, and (ii) 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".

Peginesatide is a new 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 % 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”.

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.

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.

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 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; (i) 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); (ii) 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.

Appendix

Specific Criteria for Erythropoietin and Darbepoietin Therapy:

I. Criteria for Initiation of Therapy:

A. 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:

a. Anemia is secondary to myelosuppressive anticancer

chemotherapy for solid tumors, multiple myeloma, lymphoma and

lymphocytic leukemia; and

b. 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 (Note: For persons with iron deficiency, ESAs

may be initiated simultaneously with iron replacement), and

c. 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

d. ESAs intended to decrease the need for transfusions in

persons who will receive chemotherapy for a minimum of 2

months.

2. Providers must confirm compliance and participation in the REMS

program that has been implemented for ESA being used in cancer; and

3. The starting dose of ESAs are equal to the following, based upon FDA

labeling, or comparable fixed dosing schedules:

a. 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.

b. Darbepoetin: 2.25 mcg/kg per week, or 500 mcg every 3 weeks.

B. 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/dl) or serum transferrin




saturation (TSAT greater than 20%) within the past 12 months (Note: For

persons with iron deficiency, ESAs may be initiated simultaneously with

iron replacement), 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.

A. 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:

a. 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 (Note: For persons with iron deficiency

on dialysis, ESAs may be initiated simultaneously with iron

replacement); and

b. Member is exhibiting symptoms of anemia (such as fatigue,




anemia; and

2. The starting dose is equal to the following, based upon FDA labeling, or

comparable fixed dose schedules:

a. Erythropoietin: 50 to 100 units/kg body weight 3 times per week

for adults; 50 units/kg body weight for children.

b. Darbepoetin: 0.45 mcg/kg body weight once-weekly or 0.75

mcg/kg body weight every 2 weeks.

B. 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:

a. 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

b. Adequate iron stores are demonstrated by means of bone marrow

iron or serum ferritin levels (greater than 100

ng/dl) or serum transferrin saturation (TSAT greater than 20%)




within the past 12 months (Note: For persons with iron deficiency

on dialysis, ESAs may be initiated simultaneously with iron

replacement); and

c. Member is exhibiting symptoms of anemia (such as fatigue,




anemia; and

d. The rate of hemoglobin decline indicates the likelihood of

requiring a red blood cell (RBC) transfusion; and

e. 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:

a. Erythropoietin: 50 to 100 units/kg body weight 3 times per week

for adults; 50 units/kg body weight for children.

b. Darbepoetin: 0.45 mcg/kg body weight once-weekly or 0.75

mcg/kg body weight every 2 weeks.

C. 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:


serum ferritin levels (greater than 100 ng/ml) or serum iron


persons with iron deficiency on dialysis, ESAs may be initiated

simultaneously with iron replacement); 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.

D. 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













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).

E. 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; and









tachycardia from the anemia.

F. 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.

G. 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).

H. 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.

II. Criteria for continuation of chronic ESAs in persons with anemia due to

myelosuppressive anticancer chemotherapy:

A. The maintenance dose of ESAs are equal to the starting dose if: (i) the

hemoglobin remains below 10 g/dL 4 weeks after initiation of therapy; and (ii)

the rise in hemoglobin is greater than or equal to 1 g/dL;

B. 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.

C. 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.




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

A. 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).

B. 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.

C. 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.

D. 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.

E. 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.

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

A. 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.

V. 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).

VI. Discontinuation criteria for ESAs:

A. 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.

B. 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.

C. 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.

VII. Underlying Causes of Anemia of Chronic Disease: The following conditions have been

associated with anemia of chronic disease (Weiss and Goodnough, 2005):

A. Infections (acute and chronic)

1. Bacterial

2. Fungal

3. Parasitic

4. Viral infections, including human immunodeficiency virus infection

B. Autoimmune

1. Inflammatory bowel disease

2. Rheumatoid arthritis

3. Sarcoidosis

4. Systemic lupus erythematosus and connective tissue diseases

5. Vasculitis

C. Cancer

1. Hematologic

2. Solid tumor

D. Chronic rejection after solid-organ transplantation

VIII. 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) is more effective than another brand. In addition, there is a lack of reliable

evidence that darbepoetin is more effective than erythropoietin alpha for darbepoetin's

labeled indications.

FDA-Approved Indications Brands of ESAs

Treatment of anemia of chronic renal failure Epogen, Omontys, Procrit,

Aranesp

Treatment of anemia in zidovudine-treated HIV-

infected patients

Epogen, Procrit

Treatment of anemia in cancer patients on

chemotherapy

Epogen, Procrit, Aranesp

Reduction of allogeneic blood transfusion in surgery

patients

Epogen, Procrit




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

A. 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.

B. Serum Ferritin:

Female: 12 to 150 ng/mL

Male: 12 to 300 ng/mL

Source: Gersten, 2009.

CPT Codes / HCPCS Codes / ICD-9 Codes

Erythropoietin or darbepoetin therapy:

Other CPT codes related to the CPB:

96401 - 96417

99601 - 99602

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

J0886 Injection, epoetin alfa, 1000 units (for ESRD on dialysis)

Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis)

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 :

Modifier EB Erythropoetic stimulating agent (ESA) administered to treat anemia due

to anticancer radiotherapy

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-9 codes covered if selection criteria are met:

042 Human immunodeficiency virus [HIV] disease

079.53 Human immunodeficiency virus, type 2 [HIV-2]

140.0 - 204.92 Malignant neoplasm

238.72 - 238.75 Myelodysplastic syndrome

285.3 Antineoplastic chemotherapy induced anemia

285.21 - 285.29 Anemia of chronic disease [not covered for breast cancer]

585.1 - 585.9 Chronic kidney disease (CKD)

776.6 Anemia of prematurity

ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):

205.00 - 208.92 Myeloid leukemia, monocytic leukemia, and other specified leukemia

238.71 Essential thrombocythemia

238.76 Myelofibrosis with myeloid metaplasia

272.7 Lipidoses [Gaucher's disease]

280.0 - 280.9 Iron deficiency anemias

281.1 - 281.2 Other vitamin B12 deficiency anemia

282.0 - 282.9 Hereditary hemolytic anemias

283.0 - 283.9 Acquired hemolytic anemias

284.0 - 284.9 Aplastic anemia and other bone marrow failure syndromes

285.1 Acute posthemorrhagic anemia

286.6 Defibrination syndrome

289.83 Myelofibrosis

295.00 - 295.95 Schizophrenic disorders

310.2 Postconcussion syndrome

337.00 - 337.9 Disorders of the autonomic nervous system

340 Multiple sclerosis




348.1 Anoxic brain damage

357.0 Acute infective polyneuritis [Guillain-Barre syndrome]

362.20 - 362.29 Retinopathy of prematurity

410.00 - 414.9 Ischemic heart disease

427.89 Other specified cardiac dysrhythmias

428.0 - 428.9 Heart failure

433.00 - 434.91,

436 - 438.9

Occlusion and stenosis of precerebral arteries, cerebral arteries, acute,

but ill-defined, cerebrovascular disease, other and ill-defined,

cerebrovascular disease, and late effects of cerebrovascular disease

[except transient ischemic attacks]

584.5 - 584.9 Acute kidney failure

648.20 - 648.24 Anemia complicating pregnancy, childbirth, or the puerperium

737.30 - 737.39 Kyphoscoliosis and scoliosis

737.43 Scoliosis associated with other conditions

756.83 Ehlers-Danlos syndrome

772.4 Fetal and neonatal gastrointestinal hemorrhage

785.51 Cardiogenic shock

785.6 Enlargement of lymph nodes [Castleman's disease]

850.0 - 854.19 Intracranial injury

905.0 Late effect of fracture of skull and face bones

907.0 Late effect of intracranial injury without mention of skull fracture

990 Effects of radiation, unspecified

Other ICD-9 codes related to the CPB:

001.0 - 139.8 Infectious and parasitic diseases [acute and chronic viral, bacterial,

parasitic, and fungal]

230.0 - 234.9 Carcinoma in situ

401.0 - 405.99 Hypertensive disease

411.1 Intermediate coronary syndrome [unstable angina]

413.9 Other and unspecified angina pectoris

447.6 Arteritis, unspecified

447.7 Other specified disorders of arteries and arterioles




458.0 Orthostatic hypotension

555.0 - 556.9 Regional enteritis and ulcerative colitis

564.1 Irritable bowel syndrome

585.1 - 585.9 Chronic kidney disease

710.0 Systemic lupus erythematosus

714.0 - 714.33 Rheumatoid arthritis

780.2 Syncope and collapse

780.4 Dizziness and giddiness [light-headedness]

780.79 Other malaise and fatigue

785.0 Tachycardia, unspecified

786.05 Shortness of breath

993.2 Other and unspecified effects of high altitude [living at an elevation of

greater than 6000 feet]

996.80 - 996.89 Complications of transplanted organ

E930.7 Adverse effects of antineoplastic antibiotics

E933.1 Adverse effects of antineoplastic and immunosuppressive drugs

V45.11 Renal dialysis status

V56.0 Encounter for extracorporeal dialysis

V56.8 Encounter for other dialysis

V58.11 - V58.12 Encounter for antineoplastic chemotherapy and immunotherapy

V62.6 Refusal of treatment for reasons of religion or conscience

Peginesatide (Omontys):


J0890 Injection, Peginesatide 0.1 MG (for ESRD on dialysis)


285.21 Anemia in chronic kidney disease

Sodium Ferric Gluconate:


J2916 Injection, sodium ferric gluconate complex in sucrose injection, 12.5 mg





280.0 - 280.9 Iron deficiency anemias

Other ICD-9 codes related to the CPB:

V45.11 Renal dialysis status

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benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in

private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible

for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to

change.

CPT only copyright 2008 American Medical Association. All Rights Reserved.


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Transcript of Clinical Policy Bulletin: Erythropoiesis Stimulating Agents...More recently, the FDA (2011)...