Feature Article
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Diagnosis and Management of Anemia in Long-Term Care Authors
Council Chair
John E. Morley, MB, BCh
Dammert Professor of Gerontology
Director, Division of Geriatric Medicine
St. Louis University Health Sciences Center
Director, GRECC, St. Louis Medical Center St. Louis, Missouri
Consensus Committee Publication Chair
David R. Thomas, MD, CMD, FACP, AGSF
Professor of Medicine
Division of Geriatric Medicine
St. Louis University Health Sciences Center
St. Louis, Missouri
Council Consensus Committee
Robert P. Geronemus, MD
President
South Florida Nephrology Associates Private Practice
Ft. Lauderdale, Florida
Jeffrey Hoggard, MD
Medical Director
Greenville Dialysis Center
Greenville, North Carolina
Anne M. Murray, MD, MSc
Assistant Professor of Medicine
University of Minnesota
Hennepin County Medical Center, Geriatrics
Minneapolis, Minnesota
Armon B. Neel, Jr., PharmD, CGP, FASCP
President
MedicationXpert, LLC
Griffin, Georgia
Miriam B. Rodin, MD, PhD, CMD
Assistant Professor of Clinical Medicine
The University of Chicago
Chicago, Illinois
Laurence Z. Rubenstein, MD, MPH, FACP
Professor of Geriatric Medicine
UCLA School of Medicine
Director, Sepulveda VA GRECC
Los Angeles, California
Michael W. Schuster, MD
Professor of Clinical Medicine at the Weill Medical College of Cornell University
Director of Bone Marrow Transplantation
and Clinical Research
Hematology/Oncology Division
New York Presbyterian Hospital
New York, New York
Eric G. Tangalos, MD, CMD
Chair, Division of Community Internal Medicine
Professor of Medicine
Mayo Medical School
Rochester, Minnesota
Lynn Williams Shipp, RPh, FASCP
President of
Senior Care Pharmacy
Boulder, Colorado
Shing-shing Yeh, PhD, MD
Associate Professor in Medicine
University Hospital SUNY at Stony Brook
Geriatric Division Department of Medicine
VA Medical Center at Northport
Northport, New York
Methods
This expert panel of interdisciplinary thought leaders representing academia and the medical community was assembled by Medical Education Resources (MER), a nonprofit medical education company, to review the existing literature and author this publication on the diagnosis and management of anemia in long-term care. Where evidence existed, it served as the basis for specific recommendations. In the absence of evidence, consensus was obtained. Programs in Medicine was selected to facilitate a summit meeting and a closed Internet discussion forum to obtain consensus agreement by the members of the Council on the information presented within this publication.
Sponsorship and Accreditation Information
Target Audience
This program is intended for long-term care physicians, pharmacists, and nurses who diagnose and treat elderly patients with anemia.
Educational Objectives
Upon completion of this program, participants should be able to:
• Describe the epidemiology of anemia in long-term care.
• Define the differential diagnosis of anemia in long-term care.
• Discuss the management options for anemia in long-term care.
Program Completion Time
Based upon trials, the estimated time to complete this program is 1 hour.
Educational Grant
This program is made possible by an unrestricted educational grant from Amgen, Inc.
Sponsorship
This activity is sponsored by Medical Education Resources Inc., a nonprofit medical education company. Programs in Medicine was selected to manage program logistics.
Physician Accreditation
Medical Education Resources is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians.
Credit Designation
Medical Education Resources designates this continuing medical education activity for up to 1 credit hour in category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the activity.
This CME activity was planned and produced in accordance with the ACCME Essentials.
Nursing Accreditation
This program qualifies for 1.25 contact hours. Medical Education Resources is approved as a provider of continuing education in nursing (CNE) by the Colorado Nurses’ Association, which is accredited as an approver of CNE by the American Nurses Credentialing Center’s Commission on Accreditation.
Provider approved by the California Board of Registered Nursing, Provider CEP # 12299, 1.25 contact hours.
Each participant should claim only those hours of credit that he/she actually spent in the educational activity.
Pharmacy Accreditation
Medical Education Resources (MER) is approved by the American Council of Pharmaceutical Education as a provider of continuing pharmaceutical education. MER designates this continuing education activity for 1.0 contact hour (0.1 CEUs) in states that recognize ACPE. Universal Program Number: 816-000-03-043-H04.
Disclaimer
The content and views presented in this educational program are those of the faculty and do not necessarily reflect those of Medical Education Resources, Amgen, Inc., or MultiMedia HealthCare/Freedom, LLC. The authors have disclosed if any unlabeled use of products is mentioned in the material. Before prescribing any medicine, primary references and full prescribing information should be consulted.
Faculty Disclosure Policy
Faculty Disclosure Policy
It is the policy of Medical Education Resources (MER) to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. All faculty participating in our programs are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned so that participants may evaluate the objectivity of the presentations.
Dr. Robert P. Geronemus reported that he serves on the Speakers’ Bureau for Amgen, Inc., Ortho Biotech Products, and Watson Laboratories.
Dr. Jeffrey Hoggard reported that he serves on the Speakers’ Bureau for Amgen, Inc.
Dr. John Morley reported that he receives Grant/Research support from Organon Inc., Merck & Co. Inc, Nestec Ltd, Bayer Corporation, and B. Braun McGaw. He serves on the Speakers’ Bureau for LXN, Organon Inc., GeriMed of America, UniMed Pharmaceuticals Inc., Solvay Pharmaceuticals, Essentia, Alza Pharmaceuticals, Pharmacia & Upjohn, Glaxo Wellcome, B. Braun McGaw, Bristol-Myers Squibb, Novartis, Pfizer Inc/Parke-Davis and GlaxoSmithKline. He receives grant support from Solvay Pharmaceuticals to undertake a study on testosterone and renal failure. He is also an 8% shareholder of CUM Pharmaceuticals, which is developing an inhalation form of testosterone.
Dr. Anne M. Murray reported that she is a consultant for Amgen, Inc.
Dr. Miriam B. Rodin reported that she is a consultant for Amgen, Inc.
Dr. Michael W. Schuster reported that he receives Grant/Research support from Amgen, Inc. He serves on the Speakers' Bureau for Amgen, Inc. and Ortho Biotech Products.
Dr. Eric G. Tangalos reported that he is a consultant for Omnicare, Eli Lilly and Company, Janssen Pharmaceutica, and Abbott Laboratories.
Dr. David Thomas reported that he is a consultant for Amgen, Inc.
Dr. Armon B. Neel, Dr. Lawrence Z. Rubenstein, Dr. Lynn Williams Shipp, and Dr. Shing-shing Yeh reported that they do not have a financial arrangement or affiliation with commercial companies whose products may be mentioned in this program.
Obtaining Continuing Education Credit
To receive credit, participants must complete the CME/CE Test Questionnaire that appears at the end of this program and fax or mail it to:
Medical Education Resources 1500 West Canal Court Littleton, CO 80120 Fax: 303-798-5731
A minimum score of 70% on the Continuing Pharmaceutical Education Test is required for credit. A certificate of completion will be mailed within 4 weeks of receipt of the completed answer sheet.
Program Release Date: August 2003 Program Expiration Date: August 2005
Anemia is very common in nursing home residents and is associated with increased morbidity and mortality. While some of this anemia is due to deficiencies in iron, folate, or vitamin B12ý the most common cause is anemia of chronic disease. Much of the anemia of chronic disease is associated with chronic kidney disease. Erythropoietin, or epoetin alfa, has been demonstrated to restore hemoglobin concentrations approaching normal in these persons. Darbepoetin alfa has a longer half-life than that of epoetin alfa, and can thus be administered every other week. Studies are in progress on less frequent dosing. The Council for Anemia Clinical Strategies in Long-Term Care recommends that the causes of anemia should be aggressively sought and that appropriate treatment should be given to correct underlying causes and restore hemoglobin concentrations to normal.
Anemia is not a normal finding in older persons, and hemoglobin concentration should not be adjusted downward in older persons.1,2 Hemoglobin and hematocrit values differ little between the healthy elderly population and the younger population. A hemoglobin concentration of less than 13 g/dL in men and less than 12 g/dL in women defines anemia, according to World Health Organization standards. While the World Health Organization cutoffs for anemia may be reasonable, they should not be considered optimal hemoglobin concentration. For example, women with a hemoglobin concentration between 13-14 g/dL have better mobility and lower mortality compared to those with a hemoglobin concentration of less than 12 g/dL.3
We know from the third National Health and Nutrition Examination Survey (NHANES II) that there is a significant increase in anemia with each decade of life over the age of 70. The prevalence jumps from 10.6% in males aged 70-79 years to 22% in males aged 80-89 years. For each decade of life over the age of 70 years, the percentage of anemic patients is consistently higher in men than in women, probably in part due to falling androgen levels. Sex differences in hemoglobin concentration result chiefly froª differences in testosterone concentration. Hypogonadism in older males (andropause) is commonly associated with approximately a 1 g/dL fall in hemoglobin concentration.4VFurthermore, men who have functional hypogonadism from pituitary adenomas are anemic,5 and men with prostate cancer who are undergoing therapy with total androgen blockade are anemic.6
Anemia is as abnormal in the elderly as it is in the young. It should be investigated and treated appropriately, irrespective of age.
A Brief History of Blood
As long ago as 2500 BCE, Egyptians induced anemia to cure disease by bleeding from the foot and neck. In 350 BCE, Aristotle considered blood to be the mirror of the soul. However, it was not until 1628 that William Harvey demonstrated that blood circulates throughout the body. Thirty years later, Jan Swammerdam, a Dutch microscopist, described red blood cell morphology.
The first recorded blood transfusion was carried out in 1665 by Richard Lower, who used a syringe made from a goose quill and bladder to connect the jugular vein of one dog to another. The anemic dog survived. Two years later, Jean-Baptiste Denis transfused a teenage boy with camel blood, and the boy lived. In 1795, Philip Syng Physick performed the first human-to-human blood transfusion, although it was not until 1818 that another blood transfusion between humans was published. In 1907, at Mount Sinai Hospital in New York, the first transfusion using crosstyping of blood was performed. In 1917, the United States Army started to use type O blood preserved with a citrate-glucose solution to store blood for casualties during the Battle of Cambrai. This led to the establishment of blood banks in hospitals in the 1920s. During World War II, the Red Cross widely advertised for blood donations using a series of posters to encourage Americans to give blood for the soldiers (Figure 1). In 1963, Paul Beeson reported jaundice in persons who had received a blood transfusion. Thus, the understanding of the nonbenign nature of transfusions was enhanced with the first report of transfusion-transmitted hepatitis.
Erythropoietin is a 30,400 dalton glycoprotein that is produced by the kidney and stimulates erythropoiesis. Its existence was first hinted at by Camot and Deflande in 1906, when they demonstrated that serum from anemic rabbits increased red cell mass inSnonanemic rabbits. They named this substance “hematopoietine,” and it was renamed erythropoietin in 1948 by Bonddorf and Jelaviste after it was shown to have a specific effect on red blood cells. In 1957, Jacobson and colleagues identified the kidney as the source of erythropoietin. Erythropoietin was purified in 1957, and the gene was cloned in 1985. One year later, it was clearly established to reverse the anemia of chronic renal disease.
Prevalence of Anemia in Older Persons
There is a marked increase in the prevalence of anemia with aging. In a population-based study in Olmsted County, Minnesota, among 618 persons older than 65 years, the corrected annual incidence of anemia was higher in men (90.3 per 1000; 95% CI, 79.2-101.4) than women (69.1 per 1000; 95% CI, 62.3-75.8), and rose with age.7 Using the Established Population data for 3946 adults aged 71 years or older in three communities, hemoglobin concentration level was inversely associated with age. In men and women aged 71-74 years, 9% were anemic. The proportion of anemic persons increased differentially with age, reaching 41% for men and 21% for women, aged 90 years or older, respectively.8
In a study of 732 consecutively admitted hospital patients to an acute geriatric ward, 26% had a hemoglobin concentration below 11.5%.9 Recent studies in long-term care institutions in Israel and Spain have shown a very high prevalence of anemia in these settings. In 481 long-term care patients with an average age of 81.4 years, the prevalence of anemia was 31.4%.10 In the Spanish study, the prevalence of anemia was 40%.11
Anemia associated with chronic renal insufficiency is common. Approximately 13.5 million adults have a creatinine clearance of 50 mL/min or less, and about 800,000 adults have chronic renal insufficiency–associated anemia, defined as a hemoglobin concentration of <11 g/dL, according to a study of NHANES III data. In that study, it was found that a statistically significant decrease in hemoglobin concentration was seen among men starting at a creatinine clearance of 70 mL/min or less and among women starting at 50 mL/min or less. At any given level of creatinine clearance, men had a larger decrease in hemoglobin concentration than women. For example, compared to subjects with a creatinine clearance of greater than 80 mL/min, the decrease in hemoglobin concentration for subjects with a creatinine clearance of 20-30 mL/min was 1.0 g/dL in women and 1.4 g/dL in men.7
A substantial number of subjects with chronic renal insufficiency may not have sufficient iron stores to support erythropoiesis, as judged by the National Kidney Foundation targets for transferrin saturation or serum ferritin. In NHANES III, among those persons with a creatinine clearance of 20-30 mL/min, 46% of women and 19% of men had a transferrin saturation of less than 20%, and 47% of women and 44% of men had a serum ferritin of less than 100 ng/mL.12
Effects of Anemia in Older Persons
Anemia is associated with a number of symptoms and conditions including fatigue, weakness, headache, tachycardia, shortness of breath, cognitive impairment, depression, and delirium (Figure 2).
Anemia is an independent risk factor for increased mortality over 5 years.13 In addition, anemia has been associated with frailty14 and mobility impairment.3 Anemia is strongly associated with an increase in myocardial infarction and poor outcomes following an infarct,15 and prolonged anemia results in left ventricular hypertrophy.14,16 Anemia is a risk factor for falls in older persons,17-19 and has been shown to lead to functional impairment.3,14 Quality of life is impaired in patients with anemia,20 and persons with anemia have a high level of fatigue.21 Figure 3 summarizes the major adverse effects of anemia on older persons.
Causes of Anemia
In one study of the prevalence of anemia in hospitalized older persons, the most common cause of anemia was anemia of chronic disease, accounting for 35-40%. Iron deficiency anemia accounted for between 8% and 15%, blood loss accounted for 7%, myelodysplasia for about 5%, Vitamin B12 deficiency for another 5%, and chronic kidney disease was responsible for 6-8%. As in most studies of older persons, a large number of anemias had no diagnosis.9 The causes and prevalence of anemia vary between patient care settings, depending on the population studied and the author’s classification system.
Renal insufficiency accounts for the greatest percentage of anemic individuals with the diagnosis of anemia of chronic disease (27%). Most of these patients have an erythropoietin deficiency. However, other causes of anemia of chronic disease account forý73% of cases. These conditions include cancer (nonchemotherapy patients), congestive heart failure, hepatitis C, inflammation, diabetes, and rheumatoid arthritis. Of course, patients can have more than one cause of anemia of chronic disease (eg, iron deficiency, chronic kidney disease, and rheumatoid arthritis).
Similar findings on the etiology of anemia in long-term care have been reported. In the previously cited study in Israel, it was found that 65.6% of nursing home residents who were anemic had anemia of chronic disease, 13.2% had anemia attributed to chronic kidney disease, and 4% had nutritional causes for their anemia.
In summary, in the older population, anemia of chronic disease and anemia associated with chronic renal disease are the most common causes of anemia. However, nutritional anemias including deficiency in iron, vitamin B12, or folate, and anemia due to blood loss and drug side effects should be excluded.
Erythropoiesis
ýormal hematopoiesis consists of the transformation of multipotential stem cells to committed progenitors and then into erythrocytes (Figure 4). Once a progenitor is committed to forming erythrocytes, it is stimulated by erythropoietin and testosterone, and inhibited by a variety of cytokines (eg, tumor necrosis factor alpha, interferon gamma, and interleukin-6). Dependent on the balance of the stimulus, the cells either become mature erythrocytes or undergo an apoptotic death.
Differential Diagnosis of Anemia
Anemia can be due to failure of the bone marrow to manufacture adequate blood components, gradual or rapid blood loss from hemorrhage, or rapid breakdown of blood components from hemolysis. Causes of failure of the bone marrow to produce adequate blood components include inadequate nutrients (vitamin B12, folate, pyridoxine, or iron) necessary for blood production, primary impairment of hemoglobin synthesis (hemoglobinopathy), or altered maturation of blood cells (myelodysplastic syndromes). This complex progression of erythrocyte maturation lends itself to several strategies for the differential diagnosis of anemia.
A corrected reticulocyte count is useful to determine bone marrow function. Anemia associated with an increased reticulocyte count occurs when the bone marrow responds to red cell destruction (hemolysis) or hemorrhage. The presence of elevated concentrations of unconjugated bilirubin and lactic dehydrogenase usually accompany hemolysis. If these concentrations are normal, a source of blood loss should be sought, including gastrointestinal bleeding, intracranial bleeds, epistasis, hemoptysis, trauma (consider liver, spleen, or hip), vaginal bleeding, and severe ecchymoses. Since gastrointestinal bleeding is the most common cause of occult blood loss, a stool occult blood test should be obtained.
Absence of elevated lactate dehydrogenase (LDH) and indirect bilirubin only tell us that there is no hemolysis. Many conditions—not just blood loss—may be present. For example, myelodysplastic syndrome, which is on the rise in the elderly in the U.S., is associated with a normal LDH, normal bilirubin, and low reticulocyte count. A low or normal corrected reticulocyte count in the presence of anemia indicates an inadequate bone marrow response (Figure 5). In the presence of a low corrected reticulocyte count, determination of red cell morphology indices is useful. An elevated mean corpuscular volume (macrocytosis) suggests vitamin B12¾or folate deficiency, hepatic disease, myelodysplasia, hypothyroidism, and alcoholism. Drugs may cause either hemolysis or macrocytosis—notably, phenytoin, methotrexate, and azathioprine.
Measurement of vitamin B12 and folate concentrations will determine anemia due to these causes in the majority of cases. Confirmation of nutritional deficiency in those patients who have values in the lower normal range should be obtained. Diagnosis of vitamin B12 deficiency is typically based on measurement of serum vitamin B12 levels; however, about 50% of patients with subclinical disease have normal B12 levels. A more sensitive method of screening for vitamin B12 deficiency is measurement of serum methylmalonic acid and homocysteine levels, which are increased early in vitamin B12 deficiency. A homocysteine level will be elevated in both vitamin B12 and folate deficiencies, but a methylmalonic acid level will be elevated only in vitamin B12 deficiency. Renal failure is the only other confounding cause of an elevated methylmalonic acid concentration. Use of the Schilling test for detection of pernicious anemia has been supplanted for the most part by serologic testing for parietal cell and intrinsic factor antibodies.
Myelodysplastic syndrome is a bone marrow failure state associated with varying degrees of pancytopenia. About half of these patients will also have neutropenia. An elevated mean corpuscular volume with abnormalities in red cell corpuscular shape suggests myelodysplastic (MDS) anemia when nutritional deficiency, drugs, and chemotherapy have been excluded. A peripheral blood smear in patients with MDS may show hyposegmented nuclei in the neutrophils (pseudo Pelger-Huët phenomenon) or abnormal granular content in the white cells. Approximately one-quarter of the patients have thrombocytopenia with megakaryocytes in the peripheral smear. Bone marrow examination confirms the diagnosis with increased cellularity, maturational abnormalities, ringed sideroblasts, and an increase in blasts as well as karyotype abnormalities (eg, loss of the long arm of chromosome S). The bone marrow examination may reveal different abnormalities that are useful in classifying the subtype of MDS. Measurements of erythropoietin should be undertaken because those with concentration below 200 µm/mL often have an excellent response to treatment with erythropoietin and granulocyte-colony stimulating factor. The diagnosis and treatment of myelodysplasia are summarized in Table I.
In persons with a low or normal mean corpuscular volume, the likely diagnoses include anemia of chronic disease, anemia of renal disease, iron deficiency anemia, or thalassemia minor. The differential diagnosis of iron deficiency anemia from anemia of chronic disease is given in Table II. Persons with microcytosis, a low serum iron, and low ferritin concentrations have iron deficiency anemia. If the iron is low and the ferritin is high, this is suggestive of anemia of chronic disease. Unfortunately, these and other causes of anemia commonly coexist in older persons. In these cases, soluble transferrin receptor may be useful in determining the diagnosis.
Circulating soluble transferrin receptors are a relatively new tool in the diagnosis of anemia. They are elevated in iron deficiency anemia even in the presence of chronic disease, but normal or only slightly raised in anemia of chronic disease. Since ferritin concentrations are elevated in inflammation, liver disease, renal disease, cancer, and in some elderly women, soluble transferrin receptors, can be of use in making the diagnosis of iron deficiency. Soluble transferrin receptors divided by the log of ferritin (< 2.55) is the best method of differentiating anemia of chronic disease from anemia of chronic disease associated with iron deficiency anemia.22 However, there does not appear to be much advantage of these newer, more expensive methods over measuring total iron-binding capacity.23
Anemia of chronic kidney disease is diagnosed by recognizing renal disease in association with a low erythropoietin level. If the serum creatinine is greater than 2 mg/dL, it is unnecessary to measure erythropoietin. However, older persons can have a declining glomerular filtration rate in face of a relatively normal serum creatinine. This is because of the loss of lean mass (sarcopenia) associated with aging. This can be even more marked in the nursing home resident with cachexia. For example, an 85-year-old female nursing home resident with a hemoglobin concentration of 10 g/dL who weighs 55 kg and has a serum creatinine of 1.3 mg/dL (normal range) will have a creatinine clearance calculated by the Cockcroft-Gault equation (Figure 6) of 27.5 mL/min.24 For this reason creatinine clearance should be calculated in all nursing home residents with anemia to determine their renal status. The Cockcroft-Gault equation will demonstrate that the majority of older female nursing home residents with a creatinine of 1.2 mg/dL or greater have severe renal impairment.
The Cockcroft-Gault equation is not perfect but has been shown to be strongly correlated with more accurate measures of GFR measured creatinine clearance.25,26 A schematic diagram for evaluation of anemia in long-term care is given in Figure 7.
Management of Anemia in Long-Term Care
Nutritional Anemia
Anemia due to folate or vitamin B12 deficiency is treated by replacement of the vitamin. Vitamin B12 can be replaced either by injections (1000 µg weekly for 1 month, then monthly thereafter), orally (1000 µg daily, which should not be given with food), or intranasally. Folate 1 mg should be used to treat folate deficiency and should be used during the first few weeks of vitamin B12deficiency.
In persons with iron deficiency, the recommended treatment is iron sulfate 325 mg three times a day, providing 195 mg of elemental iron per day.27-29 The sulfate moiety can cause gastrointestinal distress, and if this occurs, iron in the form of gluconate or fumerate may be helpful. Some experts suggest that iron sulfate once a day may have a similar effect to three-times-a-day dosing if absorption is normal. The duration of iron therapy may be longer when once-a-day dosing is used. Whatever the chosen dose, a reticulocyte count should be obtained one week after starting iron. If there is not a robust reticulocyte response, intravenous iron should be considered. An approach to the management of anemia in long-term care residents is given in Table III.
Transfusions are regularly given to older persons who become symptomatic, have their hemoglobin concentration drop below 8 g/dL, or who have an acute bleed. However, it is important to realize that despite adequate careful cross-matching of blood, complications are all too common. Transfusion reactions can lead to hemolysis and fever. Transfusions are often associated with circulatory overload. Since the original description of blood-born hepatitis A, numerous infections including AIDS have been transmitted to patients during blood transfusions. For these reasons, attempting to maintain hemoglobin concentration by other approaches is very important in the long-term care resident. Human recombinant erythropoietin administration can reduce blood transfusion requirements.30
Erythropoietin
Since the introduction of human recombinant erythropoietin (epoetin alfa) in 1989 to treat anemia in chronic kidney disease patients (patients on dialysis and patients not yet on dialysis), the treatment of anemia has been revolutionized. In patients with chronic kidney disease, the workup for anemia should begin in an adult female with a hemoglobin concentration of 11 g/dL or less, and in an adult male with a hemoglobin concentration of 12 g/dL or less. Anemia can develop relatively early in the course of chronic renal failure, and has been associated with a serum creatinine as low as 2.0 mg/dL.31 A linear relationship between glomerular filtration rate and anemia has been demonstrated. Significant anemia was noted when the calculated glomerular filtration rate was less than 20-35 mL/min.32,33 In patients with impaired renal function and a normochromic, normocytic anemia, it is rare for the serum erythropoietin level to be elevated. Therefore, measurement of erythropoietin levels in such patients is not likely to guide clinical decision-making or therapy.
While the majority of persons on dialysis receive erythropoietin, there are many persons who have chronic kidney disease who do not receive erythropoietin. This is particularly true in the long-term care setting.
Erythropoietin has been shown to increase hemoglobin concentration in patients with anemia associated with surgical blood loss, cancer chemotherapy, anemia associated with drug therapy for AIDS or hepatitis C virus, myelodysplastic disease, and the anemia of chronic disease, especially when associated with rheumatoid arthritis (See Table IV for Food & Drug Administration-approved indications for use of erythropoietin). Many conditions involve additional causes for an inadequate response to erythropoietin therapy and should be corrected when possible in order to reverse the anemia (Table V34).
Erythropoietin therapy increases hemoglobin concentration, improves quality of life, and may improve long-term health outcome and even survival.20,21 Erythropoietin causes a decrease in the left ventricular hypertrophy associated with anemia.16 As may be expected with increased blood volume, erythropoietin therapy increases blood pressure, necessitating close monitoring in patients with known cardiovascular disease.
Recently, a novel erythropoietin, or erythropoiesis-stimulating protein, darbepoetin alfa, has become available. Darbepoetin alfa is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and those not yet on dialysis, and for chemotherapy-induced anemia in patients with non-myeloid malignancies. Darbepoetin alfa is compared to epoetin alfa in Table VI.35,36 Because of its longer half-life, darbepoetin alfa appears to have great potential in the long-term care setting.
The approximate threefold longer half-life with darbepoetin alfa compared to epoetin alfa has allowed for less frequent administration. Epoetin alfa is given 1-3 times a week or once weekly. A study has evaluated the efficacy of darbepoetin alfa dosed every 2 weeks in anemic patients with chronic renal insufficiency. Darbepoetin alfa has been demonstrated to maintain hemoglobin concentrations between the study target hemoglobin of 11-13 g/dL while being administered every 2 weeks. When administered every 2 weeks, darbepoetin alfa produces a hemoglobin response at a median time of 5-6 weeks with a range of 1-25 weeks. The median darbepoetin alfa dose at the time of hemoglobin response was 60 mcg every 2 weeks. Ninety-five percent of those completing the study reached the target hemoglobin concentration. Side effects seen with darbepoetin alfa were similar to those seen with epoetin alfa.37 Further studies are evaluating extending the dosing interval to once a month. Initial dosing of epoetin alfa and darbepoetin alfa should follow package insert guidelines. Thereafter, dose adjustments should be made as needed based on an individual’s hemoglobin response.
Recommendations of the Council for Anemia Clinical Strategies in Long-Term Care
The Council for Anemia Clinical Strategies in Long-Term Care developed recommendations for the treatment of anemia in long-term care. The Council recommends that a hemoglobin concentration of less than 12 g/dL should be evaluated and treated when appropriate.
The Council recognized that there were limited data on erythropoietin use in long-term care. Nevertheless, there are positive clinical outcomes for treating anemia of chronic kidney disease such as improved quality of life and decreased hospitalization and mortality. Chronic kidney disease and its associated anemia are often underdiagnosed in the elderly. The Council recommends increasing awareness of chronic kidney disease in the elderly by using conventional formulas to calculate the creatinine clearance. Furthermore, the Council recommends consideration of treating the anemia of chronic kidney disease in the long-term care setting. Pending future clinical studies of treating other types of anemia of chronic disease in the elderly, current clinical research on treating anemia of chronic kidney disease should focus on measuring important outcomes in the long-term care patient, such as improved quality of life (physical and mental) and decreased hospitalization (secondary to decreased falls and fractures), and cardiovascular morbidity.
Erythropoietin should clearly be considered in all anemic residents with chronic kidney disease whose serum creatinine is greater than 2 mg/dL. A calculated creatinine clearance should be done to identify residents with chronic renal failure whose creatinine is less than 2 mg/dL. In patients with impaired renal function and a normochromic, normocytic anemia, measurement of erythropoietin levels is not likely to guide clinical decision-making or therapy.
The Council suggests that the long half-life of darbepoetin alfa may make it very useful in long-term care where a once- or twice-a-month dosing regimen could be utilized. When used, the dosing regimen of erythropoietin should lead to an increase of hemoglobin concentration by no more than 1 g/dL in a 2-week period, and target hemoglobin concentration should not exceed 12 g/dL. Transferrin saturation and ferritin concentration should be monitored and iron replaced, either orally or intravenously, if iron deficiency develops. In addition, the Council strongly supports the development of increased research in this area.
References
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14. Kamenetz Y, Beloosesky Y, Zelter C, et al. Relationship between routine hematological parameters, serum IL-3, IL-6 and erythropoietin and mild anemia and degree of function in the elderly. Aging Clin Exp Res 1998;10:32-38.
15. Wu WC, Rathore SS, Wang Y, et al. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med 2001;345:1230-1236.
16. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention. Am J Kidney Dis 1996;27:347-354.
17. The prevention of falls in later life: A report of the Kellogg International Work Group on the Prevention of Falls by the Elderly. Dan Med Bull 1987;34(suppl 4):1-24.
18. Baker SP, Harvey AH. Fall injuries in the elderly. Clin Geriatr Med 1985;1:501-512.
19. Herndon JG, Helmick CG, Sattin RW, et al. Chronic medical conditions and risk of fall injury events at home in older adults. J Am Geriatr Soc 1997;45(6):739-743.
20. Valderrabano F. Quality of life benefits of early anemia treatment. Nephrology Dialysis Transplantation 2000:15(suppl):23-28.
21. Cella D. Factors influencing quality of life in cancer patients: Anemia and fatigue. Semin Oncol 1998;25(3 suppl 7):43-46.
22. Malope BI, MacPhail AP, Alberts M, Hiss DC. The ratio of serum transferrin receptor and serum ferritin in the diagnosis of iron status. Br J Haematol 2001;115(1):84-89.
23. Wians FH Jr, Urban JE, Keffer JH, Kroft SH. Discriminating between iron deficiency anemia and anemia of chronic disease using traditional indices of iron status vs transferrin receptor concentration. Am J Clin Pathol 2001;115(1):112-118.
24. Cockcroft DW, Gault MN. Prediction of creatinine clearance from serum creatinine. Nephroj 1976;349:163:31-41.
25. Robertshaw M, Lai KN, Swaminathan R. Prediction of creatinine clearance from plasma creatinine: Comparison of five formulae. Br J Clin Pharmacol 1989;28:275-80.
26. Waller DG, Fleming JS, Ramsey B, Gray J. The accuracy of creatinine clearance with and without urine collection as a measure of glomerular filtration rate. Postgrad Med J 1991;67:42-46.
27. Provan D. Mechanisms and management of iron deficiency anaemia. Br J Haematol 1999;105(suppl 1):19-26.
28. Goddard AF, McIntyre AS, Scott BB. Guidelines for the management of iron deficiency anaemia. British Society of Gastroenterology. Gut 2000;46(suppl 3-4):IV1-IV5.
29. Frewin R, Henson A, Provan D. ABC of clinical haematology. Iron deficiency anaemia. BMJ 1997;314(7077):360-363.
30. Corwin HL, Gettinger A, Pearl RG, et al. Efficacy of recombinant human erythropoietin in critically ill patients: A randomized controlled trial. JAMA 2002;288(22);2827-2835.
31. Hakim RM, Lazarus JM. Biochemical parameters in chronic renal failure. Am J Kidney Dis 1988;11:238-247.
32. Jacobs A, Worwood M. Ferritin in serum. Clinical and biochemical implications. N Engl J Med 1975;292:951-956.
33. McGonigle RJS, Boineau FG, Beckman B, et al. Erythropoietin and inhibitors of in vitro erythropoiesis in the development of anemia in children with renal disease. J Lab Clin Med 1985;105:449-458.
34. Steinberg EP, Eknoyan G, Levin NW, et al. Methods used to evaluate the quality of evidence underlying the National Kidney Foundation-Dialysis Outcomes Quality Initiative Clinical Practice Guidelines: Description, findings, and implications. Am J Kidney Dis 2000;36:1-11.
35. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer 2001;84(suppl 1):3-10.
36. Macdougall IC, Gray SJ, Elston O, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol 1999;10(11):2392-2395.
37. Suranyi MG, Lindberg JS, Navarro J, et al. Treatment of anemia with darbepoetin alfa administered de novo once every other week in chronic kidney disease. Am J Nephrol 2003;23:106-111.
CME/CE Test Questionnaire
Using a scale from 1 to 5, with 5=excellent, 4=very good, 3=adequate, 2=fair, 1=poor, please circle the number corresponding to your rating of the following:
Excellent Poor
1. Overall quality of the material 5 4 3 2 1
2. Clinical applicability or relevance of the material to participant’s practice 5 4 3 2 1
3. Extent to which the material met stated objectives 5 4 3 2 1
4. Extent to which participant will modify his/her practice as a result of participation in the program 5 4 3 2 1
5. Fair balance and objectivity of the material 5 4 3 2 1
6. Completion time 5 4 3 2 1
Please answer the following questions:
1. A hemoglobin concentration of less than 13 g/dL in men and less than 12 g/dL in women defines anemia, according to World Health Organization standards.
o True
o False
2. Anemia of chronic disease is the most common cause of anemia in older persons.
o True
o False
3. Chronic kidney disease accounts for the greatest percentage of anemic individuals with the diagnosis of anemia of chronic disease.
o True
o False
4. Anemia can be due to a) failure of the bone marrow to manu- facture adequate blood components b) rapid loss of formed blood from hemorrhage c) rapid breakdown of blood components from hemolysis d) all of the above.
5. Amemia in the elderly is not associated with increased mortality or quality of life.
o True
o False
Please provide the following information (please print) in order to receive your CME/CE certificate:
Name Degree
Institution or Affiliation
Address
City, State, Zip
Telephone Fax
To receive credit, participants must complete the form above and fax or mail it to: Medical Education Resources 1500 West Canal Court Littleton, CO 80120 Fax: 303-798-5731
This special report was sponsored by Medical Education Resources, Inc, and produced by MultiMedia HealthCare/Freedom, LLC, under an unrestricted educational grant from Amgen, Inc. The views expressed in this publication are not necessarily those of Amgen, Inc. or the publishers. This publication may not be reproduced in whole or in part without the express written permission of MultiMedia HealthCare/Freedom, LLC.
Copyright © 2003 MultiMedia HealthCare/Freedom, LLC. All rights reserved. Office Center at Princeton Meadows, Building 400, Plainsboro, NJ 08536. Telephone: (609) 275-3800. Printed in USA.
FAX-BACK SURVEY
Please Fax to 1-888-427-4997 (toll free)
The Council for Anemia is working to sponsor educational programming that meets the unique needs of elder care clinicians. In order to provide you with the most valuable and relevant educational programming, we would like to learn more about your elderly patient population and your practice. Please take a few minutes to answer the following questions:
1. Please indicate your area of specialty:
o Medical Director
o Attending Physician
o Consultant Pharmacist
o Director of Nursing
o Other; please specify___________________
2. Overall, how many patients are you responsible for in each of the following settings? If none, please put “0.”
Skilled nursing facility
Assisted living Home health care
Private practice
We’d now like to focus on your skilled nursing patients only.
3. How many skilled nursing facilities do you serve?
o 1-2 o 3-5 o > 5
4. Is your facility(ies) a member of a chain?
o Yes o No
If yes, please specify name of chain: ____________________________________
5. What is the average number of skilled care beds in your facilities?
o < 100 o 100 – 150
o 151 – 200 o > 200
6. On average, how frequently do you see each of your skilled care patients?
o Daily
o Once a week
o At least once a month
o Once every 2-3 months
7. On average, what percentage of your skilled care patients are anemic
(Hgb <12 g/dL)? __________%
8. What are the top three diseases or conditions associated with anemia in your skilled care patients? Please rank in order 1 to 3, with 1 being the most common of the 3.
____ End-Stage Renal Disease (ESRD)
____ Repeated Blood Draws
____ Chronic Kidney Disease (CKD)
____ Poor Diet/Nutrition
____ Cancer (CIA/AOC)
____ Iron Deficiency
____ Acute Illness ____ Myelodysplasia
____ GI Bleeding ____ Vitamin B12 Deficiency
____ Surgery ____ Blood Loss (from dialysis procedure
and/or vascular access site)
B___ Other; please specify: _____________________________________
9. Which of the following assessments do you use to detect anemia in your skilled care patients?
o Circulating Soluble Transferrin Receptor
o Creatinine Clearance
o Erythropoietin Level
o Folate
o Hematocrit
o Hemoglobin Concentration
o Serum Methylmalonic Acid Level
o Serum Vitamin B12 Level
o Iron (T-Sat Ferritin Level)
o Other; please specify_______________
10. How frequently is an anemia assessment typically performed on your skilled care patients?
o Once every 2 weeks
o Once a month
o Once every 3 to 6 months
o If less frequent, please specify _____________________________________
11. Who typically first becomes aware that your skilled care patients have anemia?
o Attending Physician
o Consultant Pharmacist
o Director of Nursing
o Consultant Dietitian
o Other; please specify_______________
12. At what point are your skilled care patients first treated for anemia?
o At a hemoglobin concentration
of <12 g/dL
o At a hemoglobin concentration of <10 g/dL
o Only when the patient is symptomatic
o Other; please specify________________
13. In your anemic skilled care patients with a hemoglobin of less than 12 g/dL but greater than 10 g/dL, what is your first-line treatment?
o Drug Therapy
o Ferrous Sulfate
o Vitamin B12
o Other; please specify__________________
14. In your anemic skilled care patients with a hemoglobin of less than 10 g/dL, what is your first-line treatment?
o Drug Therapy
o Ferrous Sulfate
o Vitamin B12
o Other; please specify__________________
15. In your anemic patients with a hemoglobin of less than 12 g/dL, what percentage is treated at any point with drug therapy? __________%
16. Of the following drugs, please check those with which you are familiar:
o darbepoetin alfa (Aranesp)
o erythropoietin alfa (Epogen, Procrit)
o Other; please specify_________________
17. In your skilled care anemic patients that are currently being treated with drug therapy, please indicate the percentage that are being treated with the following therapies. Total must equal 100%.
o darbepoetin alfa (Aranesp)______%
o erythropoietin alfa
(Epogen, Procrit) _______%
o Other, please specify _______%
18. Considering the most common disease or condition associated with anemia that you ranked as #1 in Question 8, please indicate your most frequent dosing regimen for each of the following therapies:
o darbepoetin alfa (Aranesp)
______ mcg ______ interval o N/A; don’t prescribe
erythropoietin alfa (Epogen,Procrit) ______ units ______ interval o N/A; don’t prescribe
o Other, please specify________ interval_________________________
19. Please rank in order of importance the impact of the following factors in your drug selection using a scale of 1 to 7, where “1” means most important and “7” means least important:
____ Product efficacy
____ Product cost
____ Ease of use and patient compliance
____ Dosing frequency
____ Prior experience with product
____ Patient/family request
____ Product is on formulary or part of
formal protocol
____ Other; please specify_____________
20. Please rate the degree of influence that each of the following parties has on your supportive care prescribing decisions using a scale of 1 to 5, where “1” means not at all influential and “5” means extremely influential (circle rating).
Not at all Extremely
Influential Influential
Skilled nursing home formulary
1 2 3 4 5
Skilled care director of nursing
1 2 3 4 5
Consultant pharmacist
1 2 3 4 5
Consultant dietitian
1 2 3 4 5
Patient/family
1 2 3 4 5
Other; please specify _________________
1 2 3 4 5
21. What type of educational programs focusing on anemia would you like to see?________________________________ ____________________________________
If you would like to be added to the mail list to receive future Council publications and materials, please complete the following information:
Full Name Degree(s)
Title/Position
Practice Name
Full Address
City State Zip
Phone Fax E-mail Thank you for your responses. They are very important to us. |