The Pharmacist's Role in Anemia Management

For almost 20 years, erythropoiesis-stimulating agents (ESAs) have played a major role in the management of anemia due to chronic renal failure and chemotherapy.

For almost 20 years, erythropoiesis-stimulating agents (ESAs) have played a major role in the management of anemia due to chronic renal failure and chemotherapy.

Although generally thought to be safe,key clinical trialshave recently found a higher-than-anticipated risk of serious and life-threatening side effects, including death. These findings resulted in the FDA requiring additional boxed warnings and label changes for ESAs. The boxed warnings included:

1. Use the lowest dose of ESA that will gradually increase the hemoglobin (Hb) concentration, to avoid the need for a red

blood cell transfusion.

2. ESAs increase the risk for death and serious cardiovascular events when administered to a target Hb>12 g/dl.

3. There is a higher incidence of deep venous thrombosis documented in patients receiving epoetin alfa preoperatively for reduction of allogeneic blood transfusions.

4. In cancer patients with advanced head and neck cancer receiving radiation therapy, ESAs shortened the time to tumor progression when administered to a target Hb≥12 g/dl.

5. ESAs shortened the overall survival and increased deaths attributed to disease progression at four months in cancer

patients with MBC receiving chemotherapy to target a Hb>12 g/dl.

6. There is an increased mortality in patients not receiving chemotherapy or radiation therapy when administered to target of 12 g/dl.

(For the full text of the boxed warning, plus additional important safety information and the full Procrit prescribing information;

In response to the emerging safety concerns and new black box warnings, theCenters for Medicare and Medicaid(CMS). revised its recommendations and reimbursement for the use of these agents in the treatment of

anemia. Specifically, CMS issueda proposal to limit coveragefor ESAs to cancer patients with specific diagnoses. CMS also

outlined several clinical conditions that must be met before the drug can be considered for reimbursement. This included

guidelines that restrict initial ESA therapy to a Hb level of less than 10 g/dl (or the hematocrit is <30%); implementing

maximum starting dosages for both epoetin and darbepoetin to the recommended FDA label starting dose; implementing strict guidelines for dose escalation by 25% after four weeks for patients whose Hb rises <1 g/dl; a requirement to discontinue

therapy when Hb hits 10 g/dl or if Hb increases by more than 1 g/dl at two weeks; and a requirement that duration of therapy

could only continue within eight weeks of myelosuppressive therapy. There is no restriction in MDS patients.

CMS further indicated that the overall goal of therapy is to use the lowest dosage of an ESA that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for a red blood cell transfusion. The impact of these decisions has been the subject of considerable discussion and concern among caregivers. Of particular note is the concern that the CMS decision will have a negative impact on patients’ ability to purchase the medication, and a subsequent increase in blood transfusions.

The Pharmacist’s Role Following the CMS Decisions

Although the implementation of the new ESA guidelines and their effect on patient care has been questioned by some, it is generally felt that this class of drugs has tended to be over- and misused. Used as the standard of anemia treatment in both the inpatient and outpatient settings, erythropoiesisstimulating agents rank among the most costly drugs within the pharmacy department budget. However, pharmacists—through the development and implementation of active institutional protocols that combine good clinical practice with good economic practice—can positively impact overall costs and improve patient outcomes. Pharmacists now find themselves with an opportunity to develop and foster a collaborative relationship with physicians in the management of anemia for cancer patients through the development of pharmacist-managed anemia programs.

Active pharmacist involvement in disease management is not a new concept. The success ofpharmacist-managed diabetes clinics,hypertension programs,anticoagulation clinics, and other programs has been well documented in the literature. The impact of the pharmacist as part of a multidisciplinary effort to improve outcomes in diabetes, hypertension, and dialysis patients could also be applied to anemia due to chemotherapy. Pharmacists can play a major role in the initial screening of patients for anemia, monitoring patients for proper iron stores, and taking the lead in the development of guidelines for proper ESA use.

Pharmacists can also play a major role in patient advocacy by providing direct patient education on proper dose and proper use of therapy to avoid potential complications. Per CMS guidelines, Hb levels must be monitored prior to initiation or maintenance of ESA treatments and must be below 10 g/dl (or the hematocrit is <30%). Treatments must be discontinued when Hb is above 10 g/dl. The pharmacist can therefore play a vital role in monitoring and adjusting ESA dosages on the basis of laboratory findings and can be the key individual in overseeing that laboratory tests are ordered to determine appropriate ESA treatment.

CMS reimbursement guidelines require a 25% dose reduction if there is a greater than 1 g/dl rise in Hb over two weeks of treatment, unless the Hb remains below 10 g/dl. CMS also will allow the starting dose to be increased by 25% one time only if the Hb rise is <1 g/dl over four weeks of treatment. The pharmacist can also play a vital role in ensuring that laboratory tests are ordered according to CMS guidelines and that proper dosing is achieved.

ESAs and Iron

Assessment of iron stores is an important component of ESA therapy. Iron is an essential component of Hb synthesis; as such, it should be monitored in conjunction with Hb to ensure that patients have adequate iron stores when initiating ESA therapy. Serum ferritin and transferrin saturation are used to determine iron stores. Absolute iron deficiency is prevalent in anemic cancer patients and could lead to poor hematopoiesis. By definition, absolute iron deficiency is classified as serum iron <70 mcg/dl, serum ferritin <100 ng/ml, or transferrin saturation (Tsat) <20%. Tsat rate is considered the most sensitive assessment of iron deficiency.

It is widely accepted that iron supplementation will help the anemic cancer patient achieve targeted Hb levels and reduce the overall need for ESA therapy. There are many issues to consider when choosing an iron product. The intravenous or oral route of administration may be used for iron supplementation. Oral agents include ferrous sulfate, ferrous gluconate, and ferrous fumarate.

The consideration to use an oral agent must include absorption and the adverse effects from the agents. The adverse effects of constipation, abdominal pain, and GI upset are often issues to consider, especially with cancer patients. Parenteral supplements include iron sucrose and sodium ferric gluconate. The choice of which parenteral product to use is often dependent on the clinical state of the patient and the adverse profile of the product.

Pharmacists can play an active role in ensuring laboratory monitoring of iron stores and overseeing the selection of the iron preparation. Ensuring proper iron stores will help patients achieve targeted Hb. The combined pharmacist analysis of proper iron and ESA use can lead to improved anemia management.

Pharmacists Can Bolster Role in Anemia Management With GuidelinesPharmacist involvement in the development of use guidelines or protocols can improve patient outcomes, maximize reimbursement, and ensure adherence to the CMS guidelines. Protocols need to conform to CMS guidelines and should

include requirements that initiation of therapy can only occur when Hb is <10 g/dl. Dosing must conform to an approved

FDA label. For darbepoetin, the dose is 2.25 mg/kg/week. For epoetin, the dose is 150 units/kg/TIW or 40,000 units once

weekly. There should be strict criteria for dose escalation and dose reduction. The protocol should require proper iron stores

and list criteria for discontinuation of therapy. Overall, the protocol should reflect the FDA black box warning to use the

lowest dose of ESA that will gradually increase the Hb concentration to avoid the need for a red blood cell transfusion.

The development of a pharmacist-managed anemia program should include the goal of increasing patient awareness and patient education. Additionally, the program should include a process to initially screen patients for the risk of anemia and ensure adequate billing and reimbursement from all insurers, including Medicare and Medicaid. The pharmacist should make certain that all healthcare providers are properly trained and educated on current standards of practice and are compliant with regulatory mandates.

In developing an anemia program, the pharmacist must have knowledge of clinical factors relating to anemia therapies and patient outcomes. There must be a high degree of knowledge regarding patient billing, reimbursement, financial outcomes, and the requirements of CMS and private insurers. This may include a multidisciplinary team approach consisting of pharmacists, physicians, nurses, and financial staff.

Clinical outcomes should address the CMS objective of using the lowest ESA dose that will gradually increase the Hb concentration to the lowest level to avoid blood transfusions. The FDA recently implemented a black box warning

for the use of erythropoiesis-stimulating agents. CMS responded to this black box warning by revising its recommendations

and limiting reimbursement for the treatment of anemia in cancer patients. This is not the first time new clinical evidence has prompted such regulatory actions and changes, nor will it be the last. Pharmacists are uniquely positioned to help overcome these new barriers to treat cancer patients through the development of anemia management programs that are collaborative with

all healthcare providers and are aimed at improving patient outcomes and maximizing reimbursement.

Howard Cohen, RPh, MS, FASHP, is Corporate Director of Pharmacy Services for Universal Health Services, Inc. Universal Health Services (UHS) is one of the nation’s largest healthcare management companies, operating acute care hospitals, behavioral health facilities, and ambulatory centers nationwide.