I. Anemia: What every physician needs to know.
The presence of anemia in heart failure (HF) patients is associated with cognitive impairment, a higher New York Heart Association (NYHA) class, lower exercise capacity, worse quality of life, increased number of hospitalizations, and higher mortality.
Although the prevalence and prognostic roles of anemia have been well defined, its pathophysiology continues to be investigated. An intense search has been under way to determine whether anemia in HF is a marker or a mediator of adverse prognosis.
II. Diagnostic Confirmation: Are you sure your patient has Anemia?
Anemia is defined by the World Health Organization (WHO) as hemoglobin concentration <13.0 g/dl in men and <12.0 g/dl in premenopausal woman. This definition, however, has several limitations and was not intended to serve as the gold standard to define anemia.
Other definitions include the National Kidney Foundation criteria of hemoglobin <12.0 g/dl in men and <11.0 g/dl in premenopausal women and the newly derived definitions based on large samples from the third U.S. National Health and Nutrition Examination Survey and the Scripps-Kaiser database of hemoglobin with <13.7 and <12.9 g/dl in white and black men, respectively, and <12.2 and <11.5 g/dl in white and black women, respectively.
It is important to note the following regarding definitions of anemia.
The lower values in women compared with men are remarkably consistent across the various definitions.
The lower values in African Americans are not widely recognized.
Volume status may influence the diagnosis of anemia. Hemoglobin and hematocrit values are reduced in the presence of increased plasma volume and they inversely increase with diuresis.
No HF specific criteria for anemia have been developed. (Similar to the revised WHO/National Cancer Institute criteria for men and women with malignancy <14.5 g/dl and 12 g/dl, respectively)
A. History Part I: Pattern Recognition:
Anemia is more common in women, the elderly, African Americans, and in patients with diabetes, chronic kidney disease, and those with a lower body mass index. It is also more common in HF patients with a higher NYHA classification and higher left ventricular ejection fraction (Table 1).
The symptoms of anemia closely mimic those of HF, including dyspnea, fatigue, weakness, cognitive impairment, and poor exercise capacity, and the superimposition of anemia in patients with HF may exacerbate these symptoms (Table 2).
Therefore, the development of anemia may lead to an earlier recognition of the presence of HF.
In patients with ischemic HF, precipitation or potentiation of ischemia may occur when the anemia is severe.
B. History Part 2: Prevalence:
The prevalence of anemia in HF varies (9% to 70%) according to the definition used, and patient population (inpatient vs outpatient, preserved vs impaired left ventricular systolic function, young vs old, men vs women). The overall prevalence in community patients with heart failure approaches 50%.
The prevalence of anemia in HF appears to be increasing as is evident in a study in Olmsted County in two periods (1979-2002, 40%), and (2003-2006, 53%). The reason for the increasing prevalence of anemia has been attributed to the increasing prevalence of diastolic HF.
C. History Part 3: Competing diagnoses that can mimic Anemia.
Several symptoms are shared by HF and anemia, and therefore establishing the presence or absence of anemia in patients with HF by laboratory testing is mandatory.
It should be noted that if anemia is severe, it may cause high output HF.
D. Physical Examination Findings.
In severe anemia, tachycardia and bounding pulses are present, there is pallor of the skin and mucous membranes, and a pulmonary midsystolic murmur is commonly present.
E. What diagnostic tests should be performed?
Complete blood count (CBC) is obtained routinely and includes hemoglobin, hematocrit, red blood cell indices including red cell distribution width, and reticulocyte count.
A standard procedure in the workup of any anemia is the examination of the peripheral blood smear.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
The potential presence of multiple causes of anemia in HF dictates the assessment of the iron profile, the measurement of vitamin B12 folic acid, and the assessment of thyroid function tests.
1. Iron profile includes transferrin saturation, transferrin (total iron binding capacity), serum iron, and ferritin. Low serum iron (<60 mg/dl), elevated transferrin (>410 mg/dl), and reduced transferrin saturation (<15%) define iron deficiency anemia.
Ferritin values of 30 to 40 ng/ml are used to define iron deficiency in individuals who do not have inflammatory disease. In the presence of inflammation, however, ferritin levels are increased because it is an acute phase reactant.
The ratio of serum transferring receptors (reflect tissue iron availability) to ferritin has been proposed to distinguish between anemia due to iron deficiency versus inflammation (anemia of chronic disease). A ratio of <1 favors the presence of inflammation, and >2 the presence of iron deficiency with or without inflammation.
2. Serum creatinine and estimated glomerular filtration rate
3. Serum levels of vitamin B12 and folic acid
4. Thyroid function tests
Functional iron deficiency is characterized by inability to use available iron stores. A criterion of a ferritin level of 100 to 300 mg/dl in combination with transferrin saturation <20% has been suggested to define this condition.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
To verify the presence of hemodilution, blood volume analysis with the 51-chromium labeling technique or with I131 – tagged albumin could be considered; its use, however, has been restricted to research.
The etiology of anemia needs to be identified for the proper management of anemia. The causes of anemia in HF include the following (Table 3): hemodilution, inflammation (Table 4), renal impairment, iron deficiency, medications (angiotensin-converting enzymes inhibitors [Table 5], angiotensin receptor antagonists and carvedilol [Table 6]), vitamin B12 and folic acid deficiency, and thyroid function abnormalities.
The only consensus in the management of anemia in HF is in correcting hematinic deficiencies that include iron, vitamin B12, and folic acid.
Iron deficiency is relatively common (at least one third) in patients with HF and may be caused by interference with iron absorption by hepcidin, poor dietary intake, an edematous gastrointestinal tract, or blood loss secondary to medications (acetylsalicylic acid and warfarin). Iron deficiency should be identified and is usually treated with oral supplementation (Table 7).
Hemoglobin rises within 2 weeks, the deficit is half corrected at 4 weeks, and fully corrected at 8 weeks. On occasion, when a failure to respond to oral supplementation is noted, iron could be administered intravenously. Several preparations are available, such as ferric gluconate complex, iron sucrose, and ferric carboxymaltose (Table 8).
Despite the symptomatic improvement reported with intravenous iron in patients with HF, its role as a therapeutic intervention may await further classification of its impact on morbidity and mortality and long-term safety.
The available evidence does not support the use of erythropoietin stimulating agents (ESA) in the correction of anemia in patients with anemia and HF, because the risk/benefit ratio is not known at present.
A. Immediate management.
The only indication for blood transfusion is the presence of severe anemia. No HF specific cut-off has been proposed and the general recommendation for initiation transfusion when hemoglobin is <7 gm/dl applies. Red cell preparation and not whole blood should be selected to minimize volume overload, and concomitant diuretics need to be administered in the vast majority of patients with HF to avoid volume overload.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
The use of iron supplementation for the correction of iron deficiency anemia could be monitored by repeating hemoglobin in 4 weeks (half way correction) and 8 weeks (Table 9). Restoring iron stores requires a minimum of 6 months of treatment. In the occasional patient who fails to respond to oral supplementation, an intravenous preparation could be considered.
D. Long-term management.
Erythropoietin is a pleiotropic cytokine of renal origin produced in response to hypoxia to promote survival of red blood cells by inhibiting apoptosis of erythroblasts. Increasing hemoglobin and thereby oxygen delivery could be achieved by the administration of erythropoiesis stimulating agents.
However, their use in non-HF patients has been associated with undesirable affects, including elevated blood pressure, thrombotic events including stroke and increased risk of death. Hemodynamically they cause an increase in peripheral vascular resistance, a reduction in cardiac output, and lowering of left ventricular ejection fraction.
The use of erythropoiesis stimulating agents for the treatment of anemia in HF will be determined by the findings of the Reduction of Events with Darbepoetin Alfa in Heart Failure (RED-HF) trial in which patients with systolic HF and anemia were randomized to darbepoetin alfa or a placebo.
E. Common Pitfalls and Side-Effects of Management
Oral iron supplementation may be associated with gastrointestinal side effects, including constipation or diarrhea, abdominal discomfort, or nausea and vomiting.
The side effects of intravenous iron are related to the specific preparation. In the Fair-HF trial, the adverse events in the group receiving ferric carboxymaltose were similar to the placebo group.
IV. Management with Co-Morbidities
There are no data that guide the management of anemia in patients with HF who have concomitant comorbidities including renal impairment and diabetes mellitus.
It would be useful, however, to review the available experience in the predominantly non-HF population.
Chronic kidney disease with anemia
Two studies have suggested that achievement of a higher hematocrit or hemoglobin target was associated with higher cardiovascular risk. In the United States Normal Hematocrit trial, hemodialysis patients (n = 1,233) with a baseline hematocrit of 27% to 33% were randomly assigned to receive epoetin to a target hematocrit of either 30% or 42%.
The study was terminated prematurely because of a trend toward higher mortality and myocardial infarction in the higher hematocrit group. In the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study, patients (n = 1,432) with chronic renal failure (GFR 27.2 ml/min/1.77 m2) and anemia (hemoglobin 10.1 ± 0.9 g/dl) were randomly assigned to receive epoetin alfa to achieve a target hemoglobin of 13.5 g/dl or 11.3 g/dl.
The higher hemoglobin target group experienced an increased incidence of the composite endpoint (death, myocardial infarction, hospitalization for HF and stroke). Only 23% of the patients in CHOIR had a history of HF.
A third study, the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) in a similar patient population (n = 603), GFR 24.5 ml/min/1.73 m2, and hemoglobin 11.06, correction of hemoglobin to a target level of 13.0 to 15.0 g/dl compared with subnormal range (10.5 to 11.5 g/dl) was not associated with an increased incidence of cardiovascular events, (sudden death, myocardial infarction, acute HF, stroke, transient ischemic attack (TIA), hospitalization for angina or arrhythmia, and complication of peripheral vascular disease). Less than one third (32%) of the patients had a history of HF.
Based on these studies, the U.S. Food and Drug Administration (FDA) revised its recommendations for consideration of initiating ESAs to hemoglobin <10 g/dl and removed the previously recommended target range of 10 to 12 g/dl. Instead, it added a statement indicating an increasing risk of serious cardiovascular events when ESAs were dosed to a target hemoglobin >11 g/dl.
Chronic kidney disease, diabetes mellitus, and anemia
In the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT), in which 4,044 patients with type 2 diabetes mellitus, chronic kidney disease, and anemia (hemoglobin ≤ 11.0 g/dl) were randomized to a placebo or darbepoetin alfa with a target hemoglobin of 13.0 g/dl, an increased risk of stroke was associated with treatment with darbepoetin alfa. No excessive risk, however, was noted in patients (n = 1,345) with a history of HF.
A subsequent analysis from TREAT demonstrated that a poor initial response to darbepoetin alfa requiring escalating doses was associated with increased risk of death or cardiovascular events, which raised concerns about the appropriateness and safety of targeting higher hemoglobin level as well as the need to assess responsiveness to ESAs.
Therefore, the available data derived primarily from non-HF patients do not support targeting a higher level of hemoglobin with the use of ESAs.
V. Patient Safety and Quality Measures
A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Until the role of anemia as a marker or a mediator of adverse events is clarified, a firm recommendation cannot be made. One relatively large randomized study documented improvement in NYHA functional class, self-reported patient global assessment, and health-related quality of life with intravenous iron; however, the impact on morbidity and long-term safety has not been assessed.
B. What's the Evidence for specific management and treatment recommendations?
None of the current HF guidelines provide recommendations. The 2008 European Society of Cardiology guidelines state that correction of anemia has not been established as routine therapy.
Beutler, E, Waalen, J. “The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?”. Blood. vol. 107. 2006. pp. 1747-50. (A must read review of the limitations of WHO definition of anemia and the proposed newer criteria stratified by sex and race/ethnicity and derived from two large databases.)
Weiss, G, Goodnough, LT. “Anemia of chronic disease”. N Engl J Med. vol. 352. 2005. pp. 1011-23. (A comprehensive review of anemia of chronic disease [anemia of inflammation]).
Jelkmann, W. “Erythropoietin after a century of research: younger than ever”. Eur J Haematol. vol. 78. 2007. pp. 183-205. (An excellent summary of erythropoietin biology, including its cardioprotective potential.)
Lindenfeld, J. “Prevalence of anemia and effects on mortality in patients with heart failure”. Am Heart J.. vol. 149. 2005. pp. 391-401. (An extensive review of the prevalence of anemia in HF in the inpatient and outpatient settings, as well as its association with mortality.)
Dunlay, DM, Weston, SA, Redfield, MM. “Anemia and heart failure: a community study”. Am J Med. vol. 121. 2008. pp. 726-32. (A study in two cohorts in the community demonstrating an increase overtime in the prevalence of anemia in HF with higher prevalence in patients with preserved left ventricular ejection fraction.)
Groenveld, HF, Januzzi, JL, Damman, K. “Anemia and mortality in heart failure patients: a systematic review and meta-analysis”. J Am Coll Cardiol. vol. 52. 2008. pp. 818-27. (A systematic review of literature involving 153,180 patients with HF demonstrating an independent association of anemia, with mortality in patients with both preserved and impaired left ventricular ejection fraction.)
Tang, WHW, Tong, W, Jain, A. “Evaluation and long-term prognosis of new onset, transient, and persistent anemia in ambulatory patients with chronic heart failure”. J Am Coll Cardiol. vol. 51. 2008. pp. 569-76. (This study shows the dynamic nature of anemia in HF and the relevance of persistent as well as the development of new anemia in long-term prognosis.)
Handelman, GJ, Levin, NW. “Iron and anemia in human biology: a review of mechanisms”. Heart Fail Rev. vol. 4. 2008. pp. 393-404. (An excellent review of the biology of iron in anemia.)
Auerbach, M, Goodnough, LT, Picard, D, Maniatis, A. “The role of intravenous iron in anemia management and transfusion avoidance”. Transfusion. vol. 48. 2008. pp. 988-1000. (An excellent review of intravenous iron supplementation.)
Desai, A, Lews, E, Solomon, S, McMurry, JJV, Pfeffer, M. “Impact of erythropoiesis-stimulating agents on morbidity in patients with heart failure: an updated, post-TREAT meta-analysis”. Eur J Heart Fail. vol. 12. 2010. pp. 936-42. (A systemic review and meta-analysis of nine placebo controlled studies enrolling 2,039 patients with HF. The use of ESAs was associated with a neutral effect on mortality and HF hospitalization.)
C. DRG Codes and Expected Length of Stay.
Several studies have reported an association of anemia with increased length of stay in patients hospitalized with HF. It is not clear, however, whether anemia is a marker or a mediator.
Erythropoietin (EPO): A peptide hormone, made primarily in the kidney, which promotes the maturation of erythrocyte precursors into mature RBC by blocking apoptosis in the blast cell lineage.
Ferritin: The protein in the RES that serves to store extra body iron.
Transferrin: The major plasma transport protein that carries iron from its storage site in reticuloendothelial system (RES) to the bone marrow.
Transferrin receptor (TFR): A receptor on the surface of erythroblasts in the marrow, which internalizes the iron-transferrin complex to provide iron to the cell.
Ferroportin (Fp): A transmembrane protein on the surface of the RES cell that delivers storage iron to the plasma.
Hepcidin: A peptide in the plasma that internalizes Fp, thereby blocking release of storage iron from the RES and limiting absorption of dietary iron.
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- I. Anemia: What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Anemia?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic Anemia.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- III. Management.
- A. Immediate management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- V. Patient Safety and Quality Measures
- A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
- B. What's the Evidence for specific management and treatment recommendations?
- C. DRG Codes and Expected Length of Stay.