Basics
Description
There is dual causation between anemia and heart failure: Chronic heart failure may cause anemia, and anemia may cause heart failure via multiple pathophysiological mechanisms. �
Epidemiology
Prevalence
- Depending on the definition of anemia and the population studied, the prevalence of anemia among heart failure patients ranges from ~14-70%. (Anemia is typically defined as hemoglobin <12 g/dL in women and <13 g/dL in men; 2 standard deviations below the mean hemoglobin level in healthy, iron-replete populations.)
- Hospital-based prevalence: In the OPTIMIZE-HF Registry, a registry of >48,000 patients hospitalized for heart failure, 51.2% of patients had anemia (hemoglobin level ≤12.0 g/dL), and 25% of patients had moderate-to-severe anemia (hemoglobin ≤10.7 g/dL). Lower hemoglobin was associated with female sex, older age, higher creatinine, and higher LV ejection fraction.
- Community-based prevalence: 1 study of 1,740 heart failure patients in the community (in Olmsted County) found the prevalence of anemia was 40% in a retrospective cohort and 53% in a prospective cohort.
- Anemia is prevalent among both those with heart failure with preserved ejection fraction (HFPEF) and those with heart failure with systolic dysfunction (58% among those with HFPEF vs. 48% among those with systolic dysfunction in Olmsted County community-based study).
Risk Factors
- Poor nutrition
- Renal insufficiency
Pathophysiology
- Anemia results from multiple pathophysiological mechanisms related to heart failure.
- Chronic inflammatory state: Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) levels are increased in heart failure, with inverse relations to hemoglobin levels. IL-6 and TNF-α activate GATA-2 and nuclear factor-B in the kidneys, thereby reducing erythropoietin production.
- Iron deficiency: IL-6 stimulates hepatic production of hepcidin, which blocks duodenal iron absorption. IL-6 reduces ferroportin expression, resulting in reduced release of iron from body stores.
- Renal dysfunction/impaired erythropoietin response: Reduced renal blood flow from heart failure results in reduced partial pressure of oxygen (PO2) in the renal cortex; although this reduction in PO2 stimulates erythropoietin production, the degree of erythropoietin increase is inadequate in heart failure patients for reasons not completely understood.
- Medication-induced: Angiotensin II normally decreases renal blood flow, thereby reducing PO2 and stimulating erythropoietin production. ACE inhibitors and ARBs thereby decrease erythropoietin production.
- Hemodilution: Chronic sodium and water retention result in reduced red blood cell concentration in the blood.
- Severe anemia may lead to high-output heart failure: Reduced hemoglobin concentration causes low blood viscosity and low systemic vascular resistance (SVR).
Etiology
- Among chronic heart failure patients, the etiology of anemia is usually multifactorial.
- A specific cause for anemia in individuals with heart failure is identified in <1/2 of patients.
- The most common causes of anemia in chronic heart failure are:
- Anemia of chronic disease (proinflammatory state; bone marrow dysfunction): Present in most chronic heart failure patients.
- Iron deficiency due to poor absorption or aspirin-induced GI blood loss: One review noted iron deficiency in 5-21% of heart failure patients. Iron deficiency may be even more common than most studies suggest, as bone marrow depletion of iron stores may exist despite normal serum iron, ferritin, and erythropoietin levels.
- Renal dysfunction and impaired erythropoietin production
- Hemodilution (pseudoanemia): Expanded plasma volume in CHF results in reduced hemoglobin concentration
Associated Conditions
The term "cardio-renal anemia syndrome"� has been coined to highlight the frequent and complex interactions among these 3 diseases. Heart failure causes renal failure, which both cause anemia. Anemia exacerbates heart failure, leading to worsening renal function and thus worsening anemia. �
Diagnosis
History
- It may be difficult to distinguish symptoms due to anemia vs. symptoms due to heart failure. Anemia causes worsening of heart failure symptoms and fatigue.
- To help determine the etiology of anemia, inquire about bleeding history, diet, bowel habits, travel, family history, and ethnicity (for inherited disorders such as thalassemias and other hemoglobinopathies).
Physical Exam
- Look for signs of anemia and clues to its etiology: Conjunctival pallor, ecchymosis, petechiae, jaundice, lymphadenopathy, bone tenderness, and hepatosplenomegaly.
- Cardiovascular signs: Anemia may cause tachycardia, postural hypotension, systolic flow murmur, dyspnea, elevated JVP, pulmonary rales, peripheral edema, and a 3rd heart sound.
Tests
Lab
- Standard workup should include complete blood count, reticulocyte count, iron, total iron binding capacity (TIBC), ferritin, thyroid stimulating hormone, vitamin B12, folate, erythropoietin level, peripheral blood smear, fecal occult blood test.
- Serum ferritin concentration: This acute phase reactant may be elevated 3-4-fold above the normal level in heart failure patients due to chronic inflammatory state. Ferritin level may be low in patients with iron deficiency. Given the frequent coexistence of iron deficiency and chronic inflammatory state in heart failure patients, the ferritin level may be falsely normal.
- Serum erythropoietin level: May be decreased in chronic renal insufficiency. It may also be increased, but lower than expected for the degree of anemia.
- Vitamin B12 and folate deficiencies: Rarely found in heart failure patients with anemia.
Surgery
- Bone marrow biopsy: May be helpful in determining etiology of anemia.
- Colonoscopy and esophagogastroduodenoscopy: Should be considered in patients with iron deficiency or positive fecal occult blood test. Colon cancer screening should also be performed as recommended by the United States Preventative Services Task Force.
- Right-heart catheterization may reveal increased cardiac output and low systemic vascular resistance in high-output heart failure.
Treatment
Medication
- Iron replacement therapy improves heart failure symptoms in iron-deficient patients:
- The FAIR-HF trial examined IV iron (ferric carboxymaltose) therapy in a randomized placebo-controlled trial involving 459 patients with NYHA class II-III symptoms, reduced LV systolic function (≤45%), and iron deficiency with or without anemia. The result was significant improvement in self-reported patient global assessment, NYHA functional class, 6-min walk test, and 2 quality of life questionnaires. Significant benefits occurred for both those with and without anemia (defined as hemoglobin level ≤12 g/dL).
- Erythropoiesis stimulating proteins (ESPs)- including epoetin-α, epoetin-β beta, darbepoetin-α-may be considered on a case-by-case basis for patients with anemia and heart failure. Guidelines for ESP therapy in patients with anemia and heart failure do not exist. In populations of patients with anemia and chronic renal insufficiency, there is some evidence of increased mortality and stroke when ESPs are used to achieve higher hemoglobin levels (13.0-13.5 g/dL):
- The STAMINA-HeFT Trial examined darbepoetin α therapy in a randomized placebo-controlled trial for 319 patients with anemia and heart failure with reduced LVEF. The result was lack of benefit in regards to exercise duration, NYHA functional class, and quality of life score. Nonetheless, darbepoetin-α successfully increased hemoglobin levels, was well-tolerated, and was associated with a nonsignificant trend toward improved all-cause mortality and time to 1st heart failure hospitalization.
- TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) examined darbepoetin-α use in >4,000 patients with anemia, renal insufficiency (not on dialysis), and diabetes. The treatment arm received darbepoetin-α with a target hemoglobin of 13 g/dL, and the control arm received placebo with rescue darbepoetin-α for hemoglobin <9 g/dL. There was no difference in either composite endpoint: Death or cardiovascular event; and death or end-stage renal disease. However, the risk of stroke was almost double in the treatment arm: 101 cases in the treatment group, compared with 53 cases in the control group (HR 1.92; 95% CI 1.38-1.68; p <0.001).
- The RED-HF (Reduction of Events with Darbepoetin-α in Heart Failure) Study is an ongoing randomized controlled trial of the effects of darbepoetin-α on mortality and hospitalization in outpatients with anemia (hemoglobin <12 g/dL) and heart failure with systolic dysfunction (LVEF <35%). This study will further elucidate the proper use of darbepoetin-α in management of patients with anemia and heart failure.
Additional Treatment
Issues for Referral
A collaborative effort among the primary care physician, hematology, nephrology, and cardiology specialists may be indicated to ensure that the underlying etiology of anemia is determined, and that the proper medication regimen is administered (including IV iron and EPSs in selected cases). �
Additional Therapies
- Transfusion of packed red blood cells (PRBCs): Specific guidelines for blood transfusion in treatment of heart failure or ischemic heart disease do not exist. Transfusion may be harmful due to prothrombotic and proinflammatory effects, and risk-benefit ratio should be considered on a case-by-case basis:
- One retrospective study of >78,000 elderly patients (≥65) with acute coronary syndrome found that among patients with an admission hematocrit ≤30% (4.2% of patients), those who received blood transfusion had improved 30-day survival. Caution should be used translating these results into clinical practice as this was a retrospective study.
- The CRUSADE Investigators performed a retrospective analysis of >44,000 patients with non-ST segment elevation acute coronary syndrome. Those with nadir hematocrit ≤24% who received blood transfusion had improved mortality compared to those who did not receive blood transfusion. Those who received blood transfusion for nadir hematocrit 24-27% had no difference in mortality; and those with nadir hematocrit >27 had increased mortality associated with transfusion. Caution should be used in translating these findings into clinical practice as this was an observational retrospective analysis.
Ongoing Care
Diet
For iron-deficient patients, absorption of non-heme iron (ie, iron from non-meat sources) can be increased by concomitant intake of vitamin C, and by avoidance of products containing tannin (eg, coffee, tea, and wine). �
Prognosis
- Anemia is associated with increased morbidity and mortality among heart failure patients; and in those without known heart disease, anemia is associated with increased risk of developing heart disease, as noted in the following studies:
- In the OPTIMIZE-HF Study, a registry of >48,000 hospitalized heart failure patients, those in the lowest quartile of hemoglobin levels (≤10.7 g/dL) had significantly higher in-hospital mortality (4.8% vs. 3.0%), longer length of hospital stay (6.5 vs. 5.3 days), and higher readmission rates within 90 days (33.1% vs. 24.2%) (all p <0.0001), compared with those in the highest quartile of hemoglobin (>13.5 g/dL).
- In the RENAISSANCE Study, a study of 912 patients with heart failure and reduced LV ejection fraction, for every 1 g/dL increment in baseline hemoglobin, mortality was 15.8% lower (p = 0.0009), and death or heart failure hospitalization was 14.2% lower (p <0.0001).
- In a community study of heart failure patients in Olmsted County, the hazard ratio for death was 2.39 (95% CI 1.37-4.27) for those with hemoglobin levels <10 mg/dL, compared with those with hemoglobin levels 14-16 mg/dL. There was a J-shaped relation between mortality and hemoglobin levels in this study, with hemoglobin levels >16 mg/dL also associated with increased mortality.
- Correction of anemia in heart failure patients is associated with reduced heart failure hospitalization, and improved NYHA functional class and quality-of-life scores.
Additional Reading
1
Anand �I, McMurray �JJ, Whitmore �J. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004;110(2):149-154. �[View Abstract] 2
Anand �IS.
Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol. 2008;52(7):501-511. �[View Abstract] 3
Dunlay �SM, Weston �SA, Redfield �MM. Anemia and heart failure: A community study. Am J Med. 2008;121(8):726-732. �[View Abstract] 4
Ghali �JK, Anand �IS, Abraham �WT. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008;117(4):526-535. �[View Abstract] 5
Pfeffer �MA, Burdmann �EA, Chen �CY. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. �[View Abstract] 6
Singh �AK, Szczech �L, Tang �KL. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098. �[View Abstract]
Codes
ICD9
- 285.9 Anemia, unspecified
- 285.29 Anemia of other chronic disease
- 428.9 Heart failure, unspecified
SNOMED
- 234347009 anemia of chronic disorder (disorder)
- 48447003 chronic heart failure (disorder)
- 271737000 anemia (disorder)
Clinical Pearls
- Anemia and heart failure frequently coexist, and there is a complex causal relation among anemia, heart failure, and renal dysfunction.
- The etiology of anemia in chronic heart failure is usually multifactorial, most commonly due to chronic inflammatory state, renal dysfunction with insufficient erythropoietin production, and iron deficiency.
- The prevalence of anemia in chronic heart failure varies depending on the definition of anemia and the population studied, but is ~50% among hospitalized patients and 40-50% among heart failure patients in the community.
- Anemia is associated with increased morbidity and mortality in heart failure.
- Treatments including IV iron replacement therapy and EPSs may improve heart failure symptoms and reduce heart failure-related hospitalizations. These therapies should be considered on a case-by-case basis, preferably with collaborative input from hematology, nephrology, and cardiology specialists. Ongoing studies should help clarify the appropriate role of these therapies.