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INDUSTRY SYMPOSIA

Treatment of Kidney Disease and Anemia in Elderly, Long-Term Care Residents

Symposium Chairperson: Eric G. Tangalos, MD, FACP, AGSF, CMD. Speakers: Jeffrey G. Hoggard, MD, Anne M. Murray, MD, MSc, and David R. Thomas, MD, FACP, AGSF, CMD Given the surprising prevalence of anemia in the elderly population, particularly those individuals in long-term care settings, the differential diagnosis and treatment of this disorder have assumed a more prominent position in health-care management in recent years, with good reason. Whether caused by acute iron deficiency or chronic disease such as chronic kidney disease, anemia has been associated with significant clinical outcomes, including disability, dementia, congestive heart failure, and even mortality. Yet, as this panel of 4 experts discusses, the development of two erythropoietin stimulating proteins, epoetin alfa and darbepoetin alfa, has radically changed the landscape of anemia treatment for most elderly patients. Like with most treatment regimens, however, the process by which patients undergo therapy is critically important to its success, and a team approach will help optimize potential success. DIFFERENTIAL DIAGNOSIS OF ANEMIA IN OLDER PATIENTS With as many as one in four long-term care residents suffering from anemia, and given the spate of evidence linking the disorder to poor clinical outcomes, the importance of differential diagnosis in these individuals remains vital. Moreover, because similar laboratory parameters could or could not indicate anemia in different patients, depending on their existing comorbidities, it is incumbent on clinicians treating these individuals to familiarize themselves with the disorder and its varying diagnoses. The World Health Organization (WHO) currently defines anemia as a hemoglobin concentration less than 13 g/dL in men and 12 g/dL in women. Although these standards could be reasonable, Dr. Thomas said they might not be optimal. Indeed, a 1999 trial by Dutch researchers Izaks et al. of 755 subjects 85 years determined the association between the WHO definitions of anemia with mortality. It was found that anemic women had a 10-year mortality risk 1.6 times higher than their nonanemic counterparts (95% confidence interval [CI], 1.24 to 2.06; P 0.001). Similarly, 10-year mortality rates were 2.29 times higher in anemic men than in nonanemic men (95% CI, 1.60 to 3.26; P 0.001). In both sexes, mortality risk increased with lower hemoglobin concentrations. CAUSES OF ANEMIA Effectively diagnosing anemia in elderly patients necessitates familiarity with its causes. "Anemia can be caused by failure of the bone marrow to produce adequate red blood cells," said Dr. Thomas. "There can be hemolytic anemia or breaking down of the cells when they are formed intravascularly or intramedullary, and there can also be acute blood loss." In a study by Joosten et al., further characterization of these three primary causes reveals that 35% of anemia is the result of chronic disease, with another 15% resulting from iron deficiency. This particular trial also found no obvious cause for anemia in 17% of 178 anemic patients admitted to an acute geriatric ward. "The causes of anemia that we typically look for such as vitamin B12 and folate deficiency are actually fairly small in proportion," he noted. "On the other hand, anemia of chronic disease, anemia of renal disease, and iron-deficiency anemia are going to account for most of the anemias you'll see in your elderly patients." Iron deficiency anemia (IDA) is most clearly diagnosed when serum ferritin levels are 18 ng/mL. Treatment for this type of anemia comprises 325 mg ferrous sulfate three times a day. Hemoglobin will respond to such treatment in approximately 2 months; a reticulocyte count is the first sign that the marrow is responding. Iron therapy is stopped when serum ferritin levels normalize. In many instances, however, patients can suffer IDA even though they have normal or even high levels of serum ferritin. "This is because a number of things affect serum ferritin other than iron and iron deficiency," explained Dr. Thomas. In those instances in which serum ferritin is normal or high, clinicians need to distinguish between IDA and the anemia of chronic disease. In patients with known inflammatory disease,

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Supported by an educational grant from Amgen, Inc.

Copyright ©2004 American Medical Directors Association DOI: 10.1097/01.JAM.0000133674.20476.DC SUPPLEMENT

serum ferritin levels 50 ng/mL suggest IDA. Levels 70 ng/mL suggest IDA in patients with chronic renal disease. "Levels greater than 100 usually exclude iron deficiency anemia in the presence of chronic inflammatory disease," he added. In those cases in which the diagnosis of anemia is clouded by serum ferritin levels, clinicians can turn to the soluble transferrin receptor test, which examines the receptors on the red blood cells that carry iron and transfer it across the membrane into the forming hemoglobin. Serum transferrin receptor is typically 30% saturated but increases in IDA, even in the presence of chronic disease. In the anemia of chronic disease, however, serum transferrin receptor levels are usually normal or only slightly raised. "The problem is that it's about five times more expensive than ferritin," observed Dr. Thomas. "So it's only for that occasional patient where you may have a mixture of iron deficiency and chronic inflammatory disease, or anemia of chronic disease." ANEMIA OF CHRONIC DISEASE There are two primary theories regarding anemia of chronic disease: depressed response to erythropoietin by bone marrow or reticuloendothelial block. "Reticuloendothelial block indicates that iron is retained in the marrow and can't get out," explained Dr. Thomas. "Sometimes referred to as a sideroblastic anemia or reticuloendothelial anemia, it indicates a problem with the transfer of iron, rather than a deficiency of iron." The endogenous erythropoietin response of chronic disease anemia can be divided into three groups: rheumatoid arthritis, cancer, and kidney. The rheumatoid arthritis type, characterized by the inhibition of late hematopoiesis, is fairly responsive to erythropoietin. "So even when the disease is not necessarily chronic renal disease, but due to some other sort of chronic inflammatory condition, erythropoietin can still be helpful in elevating a response to the anemia," he said. The cancer-type anemia of chronic disease is characterized by inhibition of the early phases of hematopoiesis. "In this early phase, it's much more resistant to the effects of endogenous erythropoietin," noted Dr. Thomas. "But it sometimes can still be overcome by high doses. This is why some of your patients who have cancer or are being treated for cancer with chemotherapy actually take higher doses than normal, renal replacement doses of exogenous erythropoietin." The third type of chronic kidney disease--anemia--is the result of the kidneys' inability to produce erythropoietin. Erythropoietin will only work in the presence of a full and complete complement of the hemoglobin substrate. "You have to have iron, you have to have vitamin B12, and you have to have folate," he said. Anemia in chronic kidney disease is generally characterized by hemoglobin levels 11 g/dL and creatinine clearance 60. "In elderly patients, if the serum creatinine level is two or greater, then the patient is highly likely to have anemia of chronic kidney disease, and it is unnecessary to measure the erythropoietin levels," added Dr. Thomas. Also, clinicians will encounter patients with normal or

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high serum ferritin levels and normal iron-binding capacities but who are anemic nonetheless. He advises looking for problems with hemoglobin in these patients. Hemoglobin A2 and F can be determined through hemoglobin electrophoresis, which will yield either normal levels or beta thalassemia. "If these levels are normal, then the possibility exists that you have an alpha thalassemia or sideroblastic anemia and the only way you're going to get that figured out is a bone marrow scan," added Dr. Thomas. One of the final anemias discussed was megaloblastic anemia, which is caused by a cobalamin deficiency, a folate deficiency, or by the ingestion of certain drugs, including antiinflammatory drugs, anticonvulsants, antibiotics, anticoagulants, poisons, antimalarials, and anti-AIDS medications. Although the response of many clinicians is to test patients for vitamin B12 levels, such levels are not very specific. Indeed, some 2.5% of the population will have levels 200 mcg without any evidence of vitamin B12 deficiency. "If you look at patients who have known deficiencies of vitamin B12, you'll find that the levels are scattered all over the place," he said, noting that some 10% of patients with a known deficiency can have cobalamin levels in excess of 350. This is also the case with folate, which does not have a great sensitivity. "You can have large numbers of patients with known deficiency who have normal levels," he said. This diagnosis can be made with a test of methylmalonic acid. In cobalamin deficiency, both methylmalonic acid and homocysteine levels will be elevated. In folate deficiency, by comparison, methylmalonic acid levels are normal and homocysteine is elevated. "You might be wondering why you should even bother because you have lots of people with hemoglobins of 10 g/dL running around the nursing home who don't seem to be suffering at all," observed Dr. Thomas. Nevertheless, as Dr. Murray went on to discuss, there are significant clinical outcomes associated with anemia--none of them good. CLINICAL OUTCOMES ASSOCIATED WITH ANEMIA Evaluating anemia in older patients, especially long-term care residents, becomes even more important when one considers the multiple, significant clinical outcomes associated with this disorder and its prevalence in this population. As Dr. Murray discussed, early intervention in elderly anemic patients can go a long way toward decreasing morbidity and mortality. A study in 1992, "The Established Populations for the Epidemiological Studies of the Elderly (EPESE)" by Salive et al. determined the prevalence of anemia in 3946 adults at least 71 years of age. The researchers found that hemoglobin levels were inversely associated with age, although this phenomenon was far more pronounced in men than women. The anemia prevalence determined by the trial was 8.6% in both men and women aged 71 to 74 years. For women in the 85- to 89-year-old category, this increased to 16.2%, compared with 26.2% for men of the same age. By age 90 , 20.7% of women and 40.7% of men were found to be anemic.

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Significant Clinical Outcomes Given the pervasiveness of anemia in elderly populations, clinicians must be aware of the many significant clinical outcomes associated with the disorder, including disability, dementia, congestive heart failure, and, occasionally, mortality. "I think disability is really the most exciting area of research looking at the associations between anemia and specific outcomes," said Dr. Murray. A 2002 cross-sectional study of 633 women by Chaves et al. evaluated the relationship between hemoglobin concentration, prevalent mobility difficulty, and the Summary Performance Score. "They found that self-reported mobility improved with increasing hemoglobin between the range of 11 and 14 g/dL, and that the optimal range of performance was between 13 and 14 g/dL," she explained. "They also found that the risk of disability increased by about 35% in going from a hemoglobin of 12 to 11 g/dL, and by going up a gram, from 12 to 13.5 g/dL, the disability risk decreased by about 32%. "They concluded that the WHO definition of anemia may actually be low," added Dr. Murray. "We may need to reconsider how we define anemia in elderly females." A more recent study by Penninx et al. examined the longitudinal association between anemia and disability in 1146 Iowa males and females (aged 71 or older) over a 4-year period. The researchers used an assessment of standing balance, a timed 2.4-meter walk, and a timed test of five chair rises to assess physical performance combined in a 12-point summary scale. After adjusting for baseline performance score, health status, and demographic characteristics, anemia was associated with greater mean decline in physical performance as measured by the summary scale over the study period. Indeed, the adjusted mean decline was 2.3 (95% CI, 1.7 to 2.8) in subjects with anemia, compared with 1.4 (95% CI, 1.2 to 1.5) in those without anemia (P 0.003). "In addition they found that hemoglobins in the range of 12 to 13 g/dL for women and 13 to 14 g/dL for men were also associated with greater functional decline," she said. "So all those patients that have hemoglobins that we perceive as normal may actually be slightly low and at increased risk for disability." DIALYSIS PATIENTS AT RISK AS WELL Although investigations into the relationship between anemia and dementia in nondialysis populations have recently begun, several small studies have examined this relationship in dialysis patients. The results of these trials suggest that cognitive function improves after treatment of anemia with erythropoietin. More recently, Dr. Murray and her colleagues investigated anemia as a risk factor for dementia in a Medicare database "We looked at Medicare patients in the year 2000 who had anemia, defining it as a chronic anemia using two claims for anemia that were at least 90 days apart," she related. "We found that chronic anemia is associated with all dementias, with an adjusted hazard ratio of 1.35. The incidence of deSUPPLEMENT

mentia was about 2.6 per 100 nonanemic patients, but over 6 in anemic patients." A medical-records study of 302 patients in the Mayo Clinic patient registry for the years 1980 to 1984 also found a significant association between the presence of anemia and Alzheimer's disease (relative risk, 1.88) when using a casecontrol design but not when using the entire cohort, possibly because vascular dementia was not counted as dementia. ANEMIA AND CONGESTIVE HEART FAILURE The relationship between anemia and congestive heart failure has also been the subject of several investigations. Among other things, these trials have found that in the general elderly population, anemia is associated with increased risk of hospitalization and mortality in congestive heart failure patients. "These studies have also found that anemia in end-stage renal disease patients is associated with both new-onset and recurrent congestive heart failure," added Dr. Murray. Several studies have also found that anemia in patients with non-endstage renal disease is associated with increased risk of hospitalization and mortality. Dr. Murray and her colleagues also examined anemia as a predictor of incident congestive heart failure in a Medicare population of more than 1 million nondialysis patients aged 65 years and older. Using chronic anemia as a predictor (at least two anemia claims at least 90 days apart), the researchers found that the incidence of heart failure among those with anemia was 12.4% compared with 5.9% in those without anemia. Chronic anemia was associated with an increased risk of incident heart failure (1.24 adjusted hazard ratio) and for death in incident congestive heart failure patients (1.28 adjusted hazard ratio). MORTALITY AND ANEMIA Perhaps not surprisingly given these findings, several studies have also concluded that mortality is associated with anemia in the elderly. A Dutch trial by Izaks et al. studied 755 patients aged 85 and older. The investigators found that compared with people with normal hemoglobin concentration, mortality risk was 1.60 (95% CI, 1.24 to 2.06; P 0.001) in women with anemia and 2.29 (95% CI, 1.60 to 3.26; P 0.001) in men with anemia. In both men and women, the mortality risk increased with lower hemoglobin concentrations. "They also found that mortality risk for malignancies and infections was higher in patients with anemia," noted Dr. Murray. "So anemia is very common and under-diagnosed in the elderly and associated with multiple poor outcomes." Given this association, improved detection and treatment of chronic anemia in the elderly could well result in significantly decreased morbidity and mortality. TREATMENT OF ANEMIA ASSOCIATED WITH CHRONIC KIDNEY DISEASE IN THE ELDERLY Chronic kidney disease, a significant problem in the United States, affects 20 million people annually with another 20 million at risk for developing the disease, many of them elderly. The advent of two types of erythropoietin stimulating

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proteins has helped clinicians improve clinical outcomes for their anemic patients with chronic kidney disease. "I don't want you to get the idea that treating this anemia is just buffing up lab values in the chart to make it look good," began Dr. Hoggard. "Treating anemia truly is associated with positive clinical outcomes." The need for effective anemia treatment in patients with chronic kidney disease is evidenced by the fact that anemia is present in all five stages of chronic kidney disease. Anemia is seen even in mild chronic kidney disease and worsens both in degree and prevalence as the chronic kidney disease worsens. Moreover, data from U.S. Renal Data Systems published by Obrador et al. illustrated that patients beginning dialysis have a significant degree of anemia, indicating that clinicians can be doing more to treat the disorder in its early stages of chronic kidney disease. Treatment Based on Underlying Cause Anemia treatment should be based on the underlying cause. "In the case of anemia of chronic kidney disease, decreased red blood cell production is caused by inadequate erythropoietin," said Dr. Hoggard. Although erythropoietin therapy is the foundation of contemporary anemia treatment in patients with chronic kidney disease, iron is critical to the successful management of the disorder's treatment as well. "Iron availability will make the erythropoietin stimulating proteins much more efficient, and therefore less costly to use," he said. Both ferrous gluconate and iron sucrose are very safe intravenous drugs for the timely correction of iron deficiency. Erythropoietin Stimulating Proteins Change Treatment Landscape The two erythropoietin stimulating proteins that have facilitated the treatment of anemia in chronic kidney disease in recent years are epoetin alfa and darbepoetin alfa. Epoetin alfa can be administered either subcutaneously or intravenously one to three times per week at 50 to 100 units/kg. "There's quite a bit of individual variation," noted Dr. Hoggard. "The dose response is indicated within 2 to 6 weeks, as per the product insert." Before starting therapy with epoetin alfa, clinicians should check their patients' iron levels and supplement with iron (if necessary). Recommended maintenance doses of epoetin alfa range from 12.5 to 525 units/kg. "My experience is that if you're starting out at 50 to 100 units per kilogram you're usually, but not always, going to end up on a maintenance dose that is somewhat less than that," he said. If the initial dose of the protein does not achieve a hemoglobin increase of 1 g/dL over a 4-week period, then the dose needs to be increased according to current National Kidney Foundation guidelines. "Although we aren't told how much to increase it by, my recommendation would be about 25%," suggested Dr. Hoggard. Similarly, if the hemoglobin increase exceeds 1 g/dL in any 2-week period, the dose should be decreased in 25% increments. When dose changes have been made, check hemoglobin and hematocrit levels on a weekly basis to gauge the patient's

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response. Once patients reach their maintenance dose, check their hemoglobin levels once a month. "If you exceed the target hemoglobin range you should instead titrate the dose back down and the hemoglobin will come down much more smoothly," he said. "It's not a good idea to stop the erythropoietin, because you lose the momentum you've gained and you may have to start all over again." In comparison with epoetin alfa, darbepoetin alfa has additional sugar side chains that increase the product's half-life from 8.5 hours to 26.3 hours. Darbepoetin alfa also has greater biologic activity than its counterpart and requires less frequent dosing. "So essentially you get a more user-friendly product," said Dr. Hoggard. "You get a product that can achieve the same hemoglobin target just as safely, but with less injections. The patients and nurses appreciate that." Initiation dosing for darbepoetin alfa in epoetin-naïve patients with anemia associated with chronic kidney disease is 0.45 g/kg, either subcutaneously or intravenously, once weekly. For patients who are currently receiving epoetin alfa, "there is a convenient conversion table in the Physician's Desk Reference or [product insert] so that patients can easily be converted from their fixed weekly unit dose of epoetin alfa to a weekly microgram dose of darbepoetin alfa," he noted. The product insert for darbepoetin alfa also states that for patients treated with epoetin alfa once per week, darbepoetin alfa should be administered once every two weeks. Adjust maintenance doses of darbepoetin alfa to maintain a target hemoglobin level that does not exceed 12 g/dL. Studies have also demonstrated the efficacy and safety of once every other week (Q2W) dosing with darbepoetin alfa in epoetin-naïve anemic chronic kidney disease patients using a starting dose of 0.75 mcg/kg. Dr. Hoggard also noted that "most recently, data from a study demonstrated that for patients who achieve a target hemoglobin with Q2W dosing and in whom the hemoglobin is stable, the dosing interval of darbepoetin alfa can be extended to QM using twice the previous Q2W dose. The QM dose should be titrated as necessary to maintain hemoglobin target." TRIALS DEMONSTRATE EFFICACY Several clinical trials have demonstrated the efficacy of these agents in ameliorating the deleterious effects of anemia in patients with chronic kidney disease. Positive outcomes include better survival, improved quality of life, and decreased hospitalizations. For example, a recently published study by Silverberg et al. examined the efficacy of subcutaneous erythropoietin in anemic patients with chronic kidney disease, type II diabetes, and moderate to severe congestive heart failure. "These patients are all at risk for terrible outcomes," explained Dr. Hoggard. "But Dr. Silverberg adds one intervention to their standard care: He treats their anemia." Over a mean treatment period of 11.8 months, the patients' hemoglobin levels increased from 10.4 to 13.1 g/dL, LVEF increased from 34.8 to 39.8, and a VAS index of fatigue dropped from 8.6 to 2.8. "But what's most impressive to me is that the number of annual hospitalizations went down from 3.3 to almost zero [0.16]," he said. "That treating anemia can decrease hospitalJAMDA ­ July/August 2004

ization rates this much for a chronically ill patient population not only impresses nephrologists and cardiologists, but it also impresses the health-care payers as well." POTENTIAL SIDE EFFECTS Any time a patient undergoes erythropoietin therapy, clinicians must consider the potential side effects these agents could cause, the most significant of which could be hypertension. "This has not been a problem in my practice because all my patients are on antihypertensive medication," said Dr. Hoggard. However, should hypertension occur, he recommended the use of antihypertensives, followed by a 24- to 48-hour wait period for blood pressure to normalize before resuming erythropoietin therapy. Injection site pain is also a frequent side effect, albeit a minor one. The treatment of anemia in patients with chronic kidney disease has improved significantly in recent years, particularly with the development of erythropoietin. "The primary goal for seniors may not be increased survival or decreased cardiovascular mortality," he added. "But certainly decreased hospitalizations and improved quality of life are outcomes we can anticipate and measure as we roll out anemia treatment protocols in our long-term care settings." The optimization of patient well-being could also be enhanced by a team approach to treatment, which, as Dr. Tangalos discussed, stands a better chance of success in both identifying the problem and creating a solution. TEAM APPROACH TO ANEMIA IN LONG-TERM CARE SETTINGS Despite the advent of erythropoietin stimulating proteins, successfully treating elderly patients with anemia also depends on the process by which these individuals are treated. As Dr. Tangalos described, a team approach to anemia therapy optimizes patients' chances of successful recovery. He used a case report of a 78-year-old woman to help illustrate the benefits of such an approach. The female in question, who had been a nursing home resident for 5 years, suffered a stroke and subsequent language and cognitive impairment 1 year ago. Although the patient fed herself, she was incontinent of stool and urine. Shortly after the stroke, nursing staff noticed that the patient was not moving as much as she once did, ate only half her meals and required feeding, behaved irritably and unpredictably, and lost 10 pounds in 2 months. Although nursing staff simply believed the patient was tired and restless, a complete examination was ordered by physicians. Initial Workup The initial patient workup revealed that she was experiencing significant dementia, with a Mini Mental State Examination score of 8. Laboratory values were as follows: hemoglobin 11.1 g/dL, creatinine 1.5, sodium 124, potassium 3.7, and glucose 101. "Her creatinine clearance, according to Cockcroft-Gault was 30," noted Dr. Tangalos. "She was significantly impaired." Further evaluation of the patient revealed: HCT 35, MCV 76, ferritin 14, iron 12, and TIBC 400. The patient also

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underwent a computed tomography scan of her abdomen, which showed a 4-cm annular carcinoma in the descending colon. The patient subsequently underwent surgery, after which her creatinine levels increased from 2.3 to 2.6. Her potassium levels stayed in the 5.5 to 5.6 range, whereas her sodium levels hovered between 132 and 137. "She underwent therapy to alkalinize her urine, and she was on iron 3 times per day," added Dr. Tangalos. Her postoperative hemoglobin level dropped to 9.0 g/dL, and her erythropoietin level was 11 (normal range, 4 to 16). "Four months after surgery, her anemia was persisting, with a hemoglobin of 8.7 and MCV of 104.2." Six months after surgery, the patient was started on epoetin alfa therapy. "Three weeks and 3 treatments later her hemoglobin was up to 10.6 g/dL," he related. Within 3 months, the patient's hemoglobin level had reached 12.5 g/dL, and epoetin therapy was discontinued. Erythropoietin Discontinued "Why was the erythropoietin stopped in the first place?" queried Dr. Tangalos. "The physicians were paying close attention to expense, and they simply made an attempt to stop therapy-- only to find out that the patient really did need it." Indeed, within 3 months of discontinuing epoetin alfa therapy, the patient's hemoglobin level had dropped to 9.9 g/dL. Three months later, it was 9.3 g/dL, at which point she was hospitalized for syncope. "So this older woman has had quite a course after her surgery," he said. "She obviously did well with the colon cancer surgery, except for the progressive renal insufficiency." Three months later, 18 months postoperatively, her hemoglobin levels had fallen to 8.7 g/dL, at which point darbepoetin alfa treatment was initiated at 0.45 g/kg for 6 weeks. "Twenty-four months after surgery, her hemoglobin was 11.3 g/dL and she was being maintained on darbepoetin alfa therapy 60-micrograms administered every four weeks," noted Dr. Tangalos. TEAM PLAYS IMPORTANT ROLE Long-term care staff have numerous opportunities to collaborate during the course of patient treatment. "The team played a surprisingly important role with this individual, by first picking her out from the background noise in the nursing home," explained Dr. Tangalos. "We had the opportunity, over the course of 3 years, to experiment with 2 different therapies--1 of which was not available the first time around. And with our patient being in the nursing home, it was much nicer to be able to give her a product with a longer interval and sequence of time between therapies." SUGGESTED READING

Beard CM, Kokmen E, O'Brien PC, et al. Risk of Alzheimer's disease among elderly patients with anemia: population-based investigations in Olmsted County, Minnesota. Ann Epidemiol 1997;7:219 ­224. Chaves PH, Ashar B, Guralnik JM, et al. Looking at the relationship between hemoglobin concentration and

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prevalent mobility difficulty in older women. Should the criteria currently used to define anemia in older people be reevaluated? J Am Geriatr Soc 2002;50:1257­1264. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation 2003;107:223­225. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis 1996;28:53­ 61. Horwich TB, Fonarow GC, Hamilton MA, et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002;39:1780 ­ 6178. Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA 1999;281:1714 ­1717. Joosten E, Pelemans W, Hiele M, et al. Prevalence and causes of anaemia in a geriatric hospitalized population. Gerontology 1992;38:111­117. Kosiborod M, Smith GL, Radford MJ, et al. The prognostic importance of anemia in patients with heart failure. Am J Med 2003;114:112­119. Mancini DM, Katz SD, Lang CC, et al. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation 2003;107:294 ­299. Marsh JT, Brown WS, Wolcott D, et al. rHuEPO treatment improves brain and cognitive function of anemic dialysis patients. Kidney Int 1991;39:155­163. Murray AM, Li S, Collins AJ. Chronic anemia as a risk factor for incident dementia in the 5% Medicare sample

data. Paper presented at the Gerontological Society of America meeting; November 23, 2002; Boston, MA. Nissenson AR. Epoetin and cognitive function. Am J Kidney Dis 1992;20(suppl 1):21­24. Obrador GT, Ruthazer R, Arora P, et al. Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. J Am Soc Nephrol 1999;10:1793­1800. Penninx BW, Guralnik JM, Onder G, et al. Anemia and decline in physical performance among older persons. Am J Med 2003;115:104 ­110. Pickett JL, Theberge DC, Brown WS, et al. Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis 1999;33:1122­1130. Salive ME, Cornoni-Huntley J, Guralnik JM, et al. Anemia and hemoglobin levels in older persons: relationship with age, gender, and health status. J Am Geriatr Soc 1992;40:489 ­ 496. Sandgren PE, Murray AM, Gilbertson D, et al. Chronic anemia as a risk factor for the incidence of new heart failure in the general Medicare population. Paper presented at the American Geriatrics Society conference; May 15, 2003; Baltimore, MD. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol 2001;37:1775­1780. Silverberg DS, Wexler D, Blum M, et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant 2003;18:141­146.

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