INTRODUCTION — Anemia and iron deficiency are frequent findings in adults with heart failure (HF) [1].
The evaluation, prognosis, and treatment of anemia in patients with HF will be reviewed here.
The diagnosis and management of anemia and iron deficiency in adults are presented separately:
●Anemia. (See "Diagnostic approach to anemia in adults".)
●Iron deficiency. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)
EPIDEMIOLOGY — The prevalence of anemia and iron deficiency vary depending upon the population studied [1]. As examples:
●In an analysis from the SOLVD trial, 22 percent of patients had a hematocrit ≤39 percent, and 4 percent had values below 35 percent [2].
●A similar rate of anemia (17 percent) was noted in a population-based cohort of 12,065 patients with newly diagnosed HF [3].
●The incidence of anemia appears to increase with worsening functional class (from 9 percent for New York Heart Association class I to 79 percent for class IV in one report) (table 1) [4].
EVALUATION
Clinical presentation
General considerations — Symptoms related to anemia can result from decreased oxygen delivery to tissues, and, in patients with acute, severe bleeding, the added insult of hypovolemia. Symptoms of anemia such as dyspnea and fatigue may be difficult to distinguish from symptoms of HF. (See "Diagnostic approach to anemia in adults".)
Symptoms from reduced oxygen delivery due to anemia generally occur only with severe anemia, but may occur at less severely reduced hemoglobin levels in patients with HF. Since the extraction of oxygen by tissues can increase from 25 to approximately 60 percent with anemia or hypoperfusion, in individuals with normal hemodynamics, normal oxygen delivery is preserved by extraction alone down to a hemoglobin concentration of approximately 8 g/dL. The hemodynamic effects of chronic anemia were evaluated in a right heart catheterization study [5]. Normal cardiac hemodynamics were maintained in patients with hemoglobin values as low as 7 g/dL; the cardiac output increased at lower hemoglobin concentrations.
In healthy individuals, acute, isovolemic reduction in the hemoglobin concentration induces a variety of compensatory changes including increases in heart rate, stroke volume, and cardiac index along with enhanced tissue oxygen extraction [6]. The net effect is that oxygen delivery can be maintained at rest at a hemoglobin concentration as low as 5 g/dL (equivalent to a hematocrit of 15 percent) if intravascular volume is maintained.
In patients with HF, oxygen delivery may be impaired due to reduced cardiac output, and thus symptoms may arise at higher hemoglobin levels in patients with anemia and HF.
Development of high-output heart failure — Severe anemia is a rare cause of high-output HF. High-output HF in the setting of anemia is more likely to occur in the setting of impaired cardiac reserve associated with an underlying cardiac abnormality such as valvular heart disease or left ventricular dysfunction. Only severe degrees of anemia (ie, hemoglobin <5 g/dL) can produce HF in the absence of underlying heart disease. (See "Causes and pathophysiology of high-output heart failure".)
Evaluation of cause of anemia — Evaluation of anemia in patients with HF should include consideration of etiologies related to HF as well as other causes. (See "Diagnostic approach to anemia in adults".)
Suggested initial testing includes:
●Complete blood count, including red cell indices, reticulocyte count, and evaluation of the peripheral blood smear
●Iron studies (serum iron, transferrin, iron saturation, ferritin)
●Kidney function (eg, serum creatinine, creatinine clearance)
●C-reactive protein and erythrocyte sedimentation rate (may be useful if ferritin is borderline to assess for inflammation as a factor)
●Serum levels of vitamin B12 and folate
If preliminary testing does not reveal a specific diagnosis, it may be appropriate to refer the patient to a hematologist for additional evaluations such as bone marrow examination for possible myelodysplastic syndrome or testing for hemolysis. (See "Diagnostic approach to anemia in adults".)
Potential causes of anemia related to heart failure — Factors that may contribute to the development of anemia in patients with HF are discussed here. Most of these factors are suggested by their association with HF, although causal relationships remain largely unproven.
Increased circulating cytokines and the anemia of inflammation — Inflammation may contribute to the anemia seen in chronic HF. This view is supported by the finding of increased levels of circulating cytokines, such as tumor necrosis factor-alpha and interleukin-6 in patients with HF, and increased levels of the acute phase reactants C-reactive protein, erythrocyte sedimentation rate, and serum ferritin [7-13]. Such changes are consistent with those found in patients with the anemia of chronic disease/anemia of inflammation (ACD/AI) as well as in some older adults with unexplained anemia. (See "Anemia of chronic disease/anemia of inflammation", section on 'Cytokine effects'.)
While the regulatory peptide hepcidin plays a central role in the anemia of inflammation, its role in the anemia seen in patients with HF is uncertain [13-15]. (See "Anemia of chronic disease/anemia of inflammation", section on 'Hepcidin (primary regulator of iron homeostasis)'.)
Dilutional anemia — Individuals with HF may have increased plasma volume that causes a decrease in hemoglobin despite a normal red blood cell mass, referred to as dilutional anemia [16].
In a report of 37 patients with HF and anemia in whom the plasma volume was directly determined using iodine-131 labeled albumin, 17 had anemia on the basis of hemodilution (ie, an expanded plasma volume) [17]. The patients with hemodilution appeared to have a worse prognosis.
In another study in 99 patients with HF, those with anemia had significantly increased plasma volume and no significant reduction in red cell volume, as measured by a chromium-51 assay [18].
Iron deficiency — Iron deficiency may be more common in HF patients than is suggested by iron studies alone since the ferritin level may not correlate with low iron stores. This has been illustrated in series of patients with HF who have been tested simultaneously with bone marrow iron staining and serum iron studies. As examples:
●In a 2018 series of 42 individuals with HF (mean left ventricular ejection fraction [LVEF] 38 percent, mean age 68 years, 76 percent male), 17 (40 percent) had absent bone marrow iron [19]. Among those with iron deficiency, serum ferritin levels ranged from 44 to 162 ng/mL. Serum iron ≤13 plus TSAT <20 had the best diagnostic performance.
●In a 2006 series of 37 patients with advanced HF (mean LVEF 22 percent; mean New York Heart Association class 3.7) and anemia, there was no stainable bone marrow iron (ie, iron deficiency) in 27 (73 percent) [10]. Serum ferritin levels, however, were reduced in only two of the iron deficient patients, indicating that elevated serum ferritin levels do not reliably exclude iron deficiency in this population.
These studies reinforce the importance of evaluating for iron deficiency in individuals with HF and anemia. (See 'Evaluation of cause of anemia' above.)
Whether these results reflect the prevalence of iron deficiency in populations with less severe HF is not known. In addition, the benefit of iron replacement was not assessed in these studies. Additional details of testing and treatment are discussed separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and 'Iron supplementation' below.)
The other major cause of microcytic anemia other than iron deficiency is thalassemia. Individuals with thalassemia can develop HF due to iron overload, even if they have not had transfusions. (See 'Other causes of anemia' below and "Diagnosis of thalassemia (adults and children)".)
Use of angiotensin converting enzyme inhibitors — Angiotensin converting enzyme (ACE) inhibitors, which prolong survival in patients with HF, also appear to induce anemia in selected patients. These drugs also reduce the hematocrit following renal transplantation and have been used to treat erythrocytosis in these patients. (See "Kidney transplantation in adults: Posttransplant erythrocytosis".)
The impact of ACE inhibitors was evaluated in a report from the SOLVD trial in which patients with left ventricular dysfunction were randomly assigned to enalapril or placebo [20]. At one year after randomization, the rate of new anemia (hematocrit ≤39 percent in men and ≤36 percent in women) was significantly higher in the enalapril group (11.3 versus 7.9 percent with placebo, adjusted odds ratio 1.56). The difference in hematocrit between the two groups was evident as early as six weeks.
The effect of ACE inhibitors on hematocrit may be mediated by Ac-SDKP (goralatide), a tetrapeptide that inhibits erythropoiesis. Ac-SDKP is metabolized by ACE and would be expected to accumulate in the presence of an ACE inhibitor, thereby inhibiting erythropoiesis.
Reduced kidney function — When measured, mean serum creatinine levels have been elevated in a number of studies of anemic patients with HF, including those with cardiorenal syndrome [10,21-25]. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology" and "Cardiorenal syndrome: Prognosis and treatment".)
Other causes of anemia — Other factors contributing to anemia may include:
●Undiagnosed thalassemia, which causes microcytic anemia and iron overload. (See "Diagnosis of thalassemia (adults and children)", section on 'Anemia'.)
●Nutritional deficits [1,9]. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
●Other conditions associated with anemia of chronic disease/anemia of inflammation (ACD/AI). (See "Anemia of chronic disease/anemia of inflammation".)
●Myelodysplastic syndrome (MDS) or monoclonal gammopathies such as multiple myeloma. (See "Diagnostic approach to anemia in adults", section on 'Older adults'.)
DIAGNOSIS — The diagnosis of anemia and iron deficiency in patients with HF includes:
●Anemia – In patients with HF, the definitions of anemia are the same as those for the general population. (See "Diagnostic approach to anemia in adults", section on 'Anemia definitions'.)
As in the general population, a finding of anemia should prompt evaluation for a specific diagnosis in most cases. (See 'Evaluation of cause of anemia' above.)
●Iron deficiency – Iron deficiency is diagnosed using iron studies, with the caveat that serum ferritin is an acute phase reactant and may be increased in some individuals with comorbidities such as HF. Examples of findings in HF patients are listed above. (See 'Iron deficiency' above.)
A serum ferritin <41 ng/mL or a transferrin saturation (TSAT) <20 percent is strongly suggestive of iron deficiency in patients with HF. For individuals with values above these thresholds for whom there is a strong suspicion of iron deficiency, additional testing such as soluble transferrin receptor may be appropriate. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)
TREATMENT — When a specific cause of anemia can be identified (eg, iron, vitamin B12, or folate deficiency), appropriate treatment should be instituted to replace the deficient iron or vitamin:
●Folate deficiency is increasingly rare in individuals who consume a balanced diet; flours and grains are routinely supplemented with folic acid in many countries.
●Trials of erythropoiesis-stimulating agents (ESAs; erythropoietin) in patients with HF have found no benefit and an increased risk of thromboembolism.
●Data on use of transfusions in patients with HF are limited.
●Iron deficiency should be corrected and the cause investigated.
Transfusion — In patients with HF who do not have symptoms attributable to anemia, we suggest using a restrictive red blood cell transfusion strategy (reserving transfusion for a lower hemoglobin level rather than transfusing at a higher hemoglobin level). In general, transfusion should be considered when the hemoglobin is ≤7 to 8 g/dL, with the specific threshold matched to the clinical trial population most closely matched by the patient, as summarized in the table (table 2). (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Overview of our approach'.) (Related Pathway(s): Anemia: Indications for red blood cell transfusion in hospitalized adults.)
Some patients may require transfusion at higher levels if they have symptoms related to anemia such as ischemic chest pain or signs of hemodynamic compromise due to anemia. Transfusion is appropriate when symptoms are severe enough and clearly related to the anemia rather than to HF or another underlying condition.
Transfusion thresholds in HF are based on low-quality evidence. No large randomized controlled trials have been published on the relative efficacy of a restrictive versus a liberal transfusion threshold specifically in HF (stable or decompensated). A systematic review from 2013 focused on individuals with heart disease identified six trials evaluating transfusion thresholds in other populations that included patients with HF; patient-level meta-analyses did not show a survival benefit from a more liberal transfusion approach (relative risk [RR] 0.94, 95% CI 0.61-1.42) [26]. Additional details regarding the individual trials are presented separately. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Thresholds for specific patient populations'.)
When red cell transfusion is required in a patient with HF, careful attention to volume status is recommended, including adjustment of transfusion rate and supplemental diuretics as needed to avoid volume overload. (See "Transfusion-associated circulatory overload (TACO)", section on 'Prevention'.)
Our approach is consistent with a systematic review of the literature and practice guideline published by the American College of Physicians (ACP) in 2013 [26,27]. The guideline suggests using a restrictive red blood cell transfusion strategy (trigger hemoglobin threshold of 7 to 8 g/dL), rather than a more liberal threshold, in hospitalized patients with coronary heart disease. We agree with using a restrictive threshold in most patients with heart disease who lack symptomatic anemia, with individualized transfusion decisions based upon clinical judgment, including assessment of whether the patient appears to have symptoms from anemia rather than the underlying cardiac condition. Links to this and other guidelines are listed below. (See 'Society guideline links' below.)
Iron supplementation — Patients with HF who have iron deficiency anemia or iron deficiency without anemia should receive iron and should be evaluated for the cause of the deficiency.
For most patients with HF who have iron deficiency, we suggest intravenous iron, typically ferric carboxymaltose, rather than oral iron supplements or dietary interventions. However, other forms of intravenous iron are likely effective, and a trial of oral iron is also a reasonable option for initial therapy. Dietary interventions are insufficient to treat iron deficiency.
The dosing of IV (table 3) and oral iron (table 4) is described separately. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron' and "Treatment of iron deficiency anemia in adults", section on 'Oral iron'.)
Once iron stores are repleted, iron supplements should be stopped, as excess iron deposition is cardiotoxic. In patients whose iron deficiency does not improve with oral supplementation, intravenous iron is the next step in management. In addition, a comprehensive evaluation for the cause of iron deficiency should be performed, and any causes of anemia should be appropriately treated to prevent recurrent anemia. (See 'Evaluation of cause of anemia' above.)
Professional societies suggest that iron replacement is reasonable for patients with HF who are iron deficient, but they differ on the benefits of iron replacement; the American guidelines suggest that iron replacement may improve quality of life, while the European guidelines suggest that iron therapy may reduce hospital admissions [28,29].
Intravenous and oral iron have not been directly compared in patients with HF. However, trials that showed beneficial effects of iron replacement have used intravenous iron:
●Intravenous iron trials
•In the 2022 IRONMAN trial, which included 1869 patients with HF who had an ejection fraction ≤45 percent and either serum ferritin <100 mcg/L or transferrin saturation (TSAT) <20 percent, patients assigned to receive intravenous ferric derisomaltose or to usual care had similar rates of cardiovascular death (21 versus 24 percent; hazard ratio 0.86, 95% CI 0.67-1.1) and HF hospitalizations (17 versus 21 admissions per 100 patient-years; rate ratio 0.8, 95% CI 0.62-1.03) [30]. The effect of iron replacement on quality of life was unclear; the physical domain of the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score was higher in the iron therapy group, but the overall MLHFQ score was similar between the two groups at 20 months. A subgroup analysis designed to address the effects of the coronavirus 2019 pandemic found similar results.
•In a 2022 meta-analysis that included trials of patients with HF with reduced ejection fraction (HFrEF) with iron deficiency alone or iron deficiency anemia and did not include the results of IRONMAN, intravenous iron reduced the rate of hospitalization for worsening HF (odds ratio [OR] 0.49, 95% CI 0.29-0.83) but did not clearly reduce the risk of mortality (OR 0.68, 95% CI 0.37-1.27) [31].
•The 2020 AFFIRM-AHF trial found a benefit of intravenous iron in reducing HF hospitalizations in individuals with iron deficiency [32]. The trial randomly assigned 1132 individuals who were hospitalized with acute HF and concomitant iron deficiency (ferritin <100 ng/mL or TSAT <20 percent) to receive intravenous ferric carboxymaltose (FCM) or placebo. Hospitalizations over the course of the 52-week trial were lower in the FCM group (RR 0.74, 95% CI 0.58-0.94); cardiovascular mortality was similar between groups. Those assigned to FCM had a median increase in hemoglobin of 0.8 g/dL, compared with 0.3 g/dL in the placebo group. Therapy was well tolerated, with serious adverse events, mostly cardiac, occurring in 45 percent of those assigned to FCM and 51 percent of those assigned to placebo.
●Oral iron trials – In contrast to intravenous iron, trials of oral iron replacement have shown no improvement in health outcomes and minimal improvement in iron stores:
•In a meta-analysis that included 10 trials, eight trials used an intravenous iron formulation, and the two trials that evaluated oral iron failed to show a statistically significant benefit [33].
•A randomized trial comparing oral iron versus placebo involved 225 individuals with HFrEF (LVEF ≤40 percent) and iron deficiency (ferritin <100 ng/mL or ferritin 100 to 299 ng/mL plus TSAT <20 percent) [34]. The mean baseline hemoglobin was 12.6 g/dl. At 16 weeks of observation, there was a slightly greater increase in ferritin level in patients receiving oral iron (18 versus 1 ng/mL). The change in hemoglobin levels was not reported. There was a trend towards an increase in the six-minute walk test that did not reach statistical significance (-13 meters; 95% CI -32 to 6 meters). Limitations included the relatively high baseline hemoglobin level, the small sample size, the short duration of follow up, and the high dropout rate (22 individuals [10 percent]).
ESAs (not recommended) — We recommend against the use of ESAs in patients with mild to moderate anemia and HF. The available evidence does not support the use of ESAs to treat mild to moderate anemia in patients with HF alone and suggests an increased risk of venous thromboembolism [26].
The best evidence on the lack of efficacy and risk of complications of such treatment in this population comes from the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial, which randomly assigned 2278 patients with HFrEF to treatment with either darbepoetin alfa (to achieve a hemoglobin target of 13 g/dL) or placebo [35]. Darbepoetin alfa- and placebo-treated groups had similar rates (50.7 and 49.6 percent) of the primary outcome of death from any cause or hospitalization for worsening HF at median 28-month follow-up. Rates of stroke were not significantly different in the two groups (3.7 and 2.7 percent), but thromboembolic adverse events were more frequent in the darbepoetin alfa-treated group (13.5 versus 10 percent).
The finding of a significantly higher thromboembolic event rate along with a nonsignificantly higher stroke rate in the darbepoetin alfa group in the RED-HF trial is similar to the results of the TREAT trial, which compared darbepoetin alfa with placebo therapy in 4038 patients with diabetes, chronic kidney disease, and anemia (one-third with HF) [36,37]. In the TREAT trial, the darbepoetin alfa-treated group had a significantly higher thromboembolic rate as well as a significantly higher stroke rate compared with the placebo group. Possible mechanisms for an adverse effect of erythropoietin therapy include worsening hypertension, increased risk of thrombotic events, and increased release of endothelin [1]. (See "Treatment of anemia in patients on dialysis".)
A meta-analysis of 17 trials of ESAs in patients with heart disease (HF or coronary heart disease), including the RED-HF trial, found that ESAs provided no consistent clinical benefit but were associated with an increased risk of thromboembolism [26]. Analysis limited to trials in patients with HF produced similar findings.
Our approach is consistent with the 2013 ACP guideline, which also recommends against the use of ESAs in patients with mild to moderate anemia and HF or coronary heart disease (strong recommendation based on moderate quality evidence; equivalent to Grade 1B) [27].
PROGNOSIS — In patients with HF, anemia is associated with increased mortality, although it remains uncertain whether anemia is an independent predictor of outcomes or reflects more advanced disease and more extensive comorbidities. In a meta-analysis from 2021 that included over 50,000 individuals with HF, the odds ratio for mortality in individuals with concomitant anemia was 1.43 (95% CI 1.29-1.84) [38].
A number of retrospective studies have evaluated the relationship between anemia and mortality in patients with HF [1-3,7,20,39-50]. Three studies found a J-shaped or U-shaped relationship between mortality and hemoglobin, with increased mortality associated with hemoglobin levels <13 to 14 or >15 to 17 g/dL [49-51]. Some studies have suggested that anemia independently predicts worse outcomes [1-3,7]. However, the largest observational study that controlled for the greatest number of possible confounding variables found that anemia was not an independent predictor of outcome [48].
The independent prognostic significance of anemia in HF patients was suggested in a review of 1061 patients with New York Heart Association (NYHA) class III or IV HF (table 1) and a left ventricular ejection fraction <40 percent [7]. The following findings were noted:
●Lower hemoglobin concentrations were associated with worse hemodynamics, higher blood urea nitrogen and serum creatinine concentrations, and a lower serum albumin concentration.
●Patients with lower hemoglobin concentrations (<13.6 g/dL) had a significantly greater frequency of NYHA class IV HF and lower peak oxygen consumption.
●On multivariate analysis, a low hemoglobin concentration was an independent predictor of mortality (relative risk 1.13 for each 1 g/dL fall in hemoglobin concentration).
Similarly, in an analysis from the SOLVD trial, a low hemoglobin concentration was an independent predictor of mortality [2]. At a mean follow-up of 33 months, each percentage point reduction in hematocrit was associated with a 3 percent increase in mortality. These effects were seen in patients treated with enalapril or placebo. As noted above, the incidence of anemia was higher in the enalapril-treated group [20]. (See 'Evaluation' above.)
The time course of anemia appears to affect its prognostic significance. In a review of 6159 patients with chronic HF, anemia was present at baseline in 17.2 percent [47]. At six-month follow-up, persistent anemia was associated with higher mortality risk than no anemia (58 versus 31 percent), while transient anemia, which was present in almost one-half of anemic patients, conferred no excess mortality risk.
These analyses, however, do not establish a causal role for anemia in worse outcomes in HF. Among the possible confounding variables is the possibility that advanced HF exacerbates anemia. If this were the case, anemia would be a marker for advanced disease. Two studies evaluated patients with new onset HF, in whom the anemia would be less likely to be due to the HF. Results from these observational studies were conflicting as to whether anemia is [3] or is not [52] an independent predictor of outcome. (See 'Evaluation' above.)
In a larger study, anemia was not an independent predictor of outcomes in over 50,000 HF patients ≥65 years of age who were admitted to the hospital with a principal diagnosis of HF, either new or recurrent [48]. Although anemia was a significant predictor of one-year mortality, it was also associated with a wide range of possible confounding factors, including cardiac and noncardiac comorbidities, indices of HF severity, age, gender, and nursing-home residence. In a multivariate analysis incorporating these variables, there was no difference in one-year mortality between patients with a normal hematocrit (40 to 44 percent) and those with severe anemia (hematocrit ≤24 percent). The authors suggested that prior studies were limited by exclusion criteria, small sample size, and, most importantly, failure to incorporate the broad range of possible confounders.
Endogenous erythropoietin — The low hemoglobin concentrations seen in patients with HF are associated with elevated plasma erythropoietin concentrations in some studies [53-55].
Elevated plasma erythropoietin has been correlated with a lower rate of survival. This was illustrated in a study of 74 patients with HF; approximately one-third each were NYHA class II, III, and IV [56]. Two-year mortality was significantly higher for patients with elevated (≥22.6 mU/mL) plasma erythropoietin (32 versus 16 percent). Both the hemoglobin concentration and plasma erythropoietin were independently predictive of survival.
Changes in hemoglobin — The impact of changes in hemoglobin over time was evaluated in a retrospective analysis from the Val-HeFT trial. Independent of the presence or absence of anemia at baseline, changes in hemoglobin over a one-year period were inversely related to morbidity and mortality, as follows [44]:
●Patients in the quartile with the largest average decrease in hemoglobin (14.2 to 12.6 g/dL) had, when compared with the quartile with little change in hemoglobin (13.7 to 13.8 g/dL), a significantly increased risk of morbid events and death (hazard ratio [HR] 1.4 and 1.6, respectively).
●On the other hand, increasing hemoglobin was associated with a significantly lower mortality rate in patients with and without anemia at baseline (HR 0.78 and 0.79, respectively).
Chronic anemia may indicate risk of development of HF in patients with end-stage kidney disease [57,58]. In one study of 432 such patients, each 1 g/dL decrease in hemoglobin was independently associated with left ventricular dilatation, the development of HF, and mortality [57]. (See "Overview of screening and diagnosis of heart disease in patients on dialysis".)
These observations cannot distinguish between a direct effect of the hemoglobin concentration and the effect of systemic factors that affect both outcomes and the hemoglobin concentration in parallel.
Low transferrin saturation — Transferrin saturation (TSAT), which is normally in the range of 20 to 50 percent, can decrease to <20 percent in both iron deficiency and the anemia of chronic disease/anemia of inflammation. In one study of 157 patients with HF, TSAT was <20 percent in 16, 72, and 100 percent of those with NYHA functional class I or II, III, and IV, respectively [59]. A TSAT <20 percent was associated with lower peak oxygen consumption and increased risk of mortality at median two-year follow-up (HR 3.4, 95% CI 1.5-7.7) and predicted mortality independent of hemoglobin.
Thus, disordered iron homeostasis (ie, iron deficiency, anemia of chronic disease/inflammation, or both) in patients with HF is associated with both impaired exercise capacity and survival.
Some have postulated that iron deficiency may directly affect myocardial function. Iron is a necessary component of mitochondrial proteins critical to myocardial energy production. A preliminary study found lower iron content and lower type 1 transferrin receptor mRNA levels in myocardial tissue from six explanted failing hearts compared with tissue from five unused donor hearts [60]. Further study is needed to determine whether there is a relationship between myocardial iron deficiency and HF.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults" and "Society guideline links: Heart failure in adults".)
SUMMARY AND RECOMMENDATIONS
●Causes of anemia in HF – Anemia is common in patients with heart failure (HF). Multiple factors, including increased levels of circulating cytokines, hemodilution, iron deficiency, use of angiotensin converting enzyme (ACE) inhibitors, reduced kidney function, and poor nutrition may be present in an individual patient. (See 'Potential causes of anemia related to heart failure' above.)
●Evaluation of anemia and iron deficiency – Evaluation of anemia in patients with HF should include consideration of etiologies related to HF as well as other causes. (See 'Evaluation of cause of anemia' above and "Diagnostic approach to anemia in adults" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)
Suggested initial testing includes:
•Complete blood count, including red cell indices, reticulocyte count, and evaluation of the peripheral blood smear
•Iron studies (serum iron, transferrin saturation [TSAT], ferritin)
•Kidney function (serum creatinine, creatinine clearance)
•C-reactive protein and erythrocyte sedimentation rate (may be useful if ferritin is borderline to assess for inflammation as a factor)
•Serum levels of vitamin B12 and folate
If preliminary testing does not reveal a specific diagnosis, it may be appropriate to refer the patient to a hematologist for additional evaluations such as bone marrow examination for possible myelodysplastic syndrome or testing for hemolysis.
●Diagnosis
•Anemia – In patients with HF, the definitions of anemia are the same as those for the general population. (See "Diagnostic approach to anemia in adults", section on 'Anemia definitions'.)
•Iron deficiency – A serum ferritin <41 ng/mL or a TSAT <20 percent is strongly suggestive of iron deficiency in patients with HF. For individuals with values above these thresholds for whom there is a strong suspicion of iron deficiency, additional testing such as soluble transferrin receptor may be appropriate. (See 'Diagnosis' above and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)
●Treatment
•Transfusion – We suggest using a restrictive red blood cell transfusion strategy (eg, trigger hemoglobin threshold of 7 to 8 g/dL), rather than a more liberal threshold (such as <10 g/dL) in patients with HF (Grade 2C). Given the low-quality evidence available, we suggest basing individualized transfusion decisions upon clinical judgment, including whether the patient appears to have symptoms from anemia. (See 'Transfusion' above and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".) (Related Pathway(s): Anemia: Indications for red blood cell transfusion in hospitalized adults.)
When red blood cell transfusion is used in a patient with HF, careful attention should be paid to volume status, including adjustment of transfusion rate and supplemental diuretics as needed to avoid volume overload. (See "Transfusion-associated circulatory overload (TACO)", section on 'Prevention'.)
•Iron supplementation – Patients with HF who have iron deficiency anemia or iron deficiency without anemia should receive iron and should be evaluated for the cause of the deficiency.
For most patients with HF who have iron deficiency, we suggest intravenous iron, typically ferric carboxymaltose, rather than oral iron supplements or dietary interventions (Grade 2C). However, other forms of intravenous iron are likely effective (table 3), and a trial of oral iron (table 4) is also a reasonable option for initial therapy. (See 'Iron supplementation' above.)
•Erythropoiesis-stimulating agents – We recommend against the use of erythropoiesis-stimulating agents (ESAs) in patients with mild to moderate anemia and HF (Grade 1B). (See 'ESAs (not recommended)' above.)
●Prognosis – Among patients with HF, it is uncertain whether anemia is an independent predictor of increased mortality or reflects more advanced disease and more extensive comorbidities. (See 'Prognosis' above.)
ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
