Approach to anemia in adults with heart failure

Author:
Wilson S Colucci, MD
Section Editors:
Stephen S Gottlieb, MD
Stanley L Schrier, MD
Deputy Editors:
Susan B Yeon, MD, JD, FACC
Jennifer S Tirnauer, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2018. | This topic last updated: Mar 07, 2018.

INTRODUCTION — Anemia is a frequent finding in adults with heart failure (HF), with
prevalence varying depending upon the population studied [1]. As an example, 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, prognosis, and treatment of anemia in patients with HF will be reviewed here
[5]. Diagnosis and general approaches to anemia in adults and older adults are presented
separately. (See "Approach to the adult with anemia" and "Anemia in the older adult".)

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 "Approach to the adult with anemia", section on
'Signs and symptoms of anemia'.)

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 [6]. 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 [7]. The net effect is that
oxygen delivery can be maintained at rest at a hemoglobin concentration below
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 — Anemia is one of the major signs of disease, and its
cause should always be sought. Evaluation of anemia in patients with HF should include
consideration of etiologies related to HF as well as other causes. (See "Approach to the
adult with anemia", section on 'Causes of anemia'.)

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)
●Renal 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

A serum ferritin <41 ng/mL or a transferrin saturation (TSAT) <20 percent is strongly
suggestive of iron deficiency in patients with comorbidities such as 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'.)

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. (See "Approach to the adult with anemia" and "Anemia
in the older adult".)

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 [8-14]. Such changes are
consistent with those found in patients with the anemia of chronic inflammation, as well as
in those with unexplained anemia in the older adult. (See "Anemia of chronic
disease/inflammation", section on 'The role of cytokines' and "Anemia in the older adult",
section on 'Inflammation'.)

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 [14-16]. (See "Anemia of chronic
disease/inflammation", section on 'Hepcidin'.)

Dilutional anemia — 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) [11]. 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' below.)

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 "Erythrocytosis following
renal transplantation".)

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.

Renal dysfunction and other contributing factors — When measured, mean serum
creatinine levels have been elevated in a number of studies of anemic patients with HF,
including those with cardiorenal syndrome [11,21-25]. Other contributing factors may
include poor nutrition due to right-sided HF [1,10].

Given the increased age of many of these patients, the possibility of anemia of chronic
disease (ACD), unexplained anemia in the elderly (UAE), and/or myelodysplasia needs to
be considered as a cause of the anemia. (See "Anemia in the older adult", section on
'Etiology'.)

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.

A number of retrospective studies have evaluated the relationship between anemia and
mortality in patients with HF [1-3,8,20,26-37]. Three studies found a J- or U-shaped
relationship between mortality and hemoglobin, with increased mortality associated with
hemoglobin levels <13 to 14 or >15 to 17 g/dL [36-38]. Some studies have suggested that
anemia independently predicts worse outcomes [1-3,8]. 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 [35].

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 [8]. 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 [34]. 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 [39] 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 [35]. 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 [40-
42]. As an example, in one report of 108 patients with HF and 45 controls, plasma
erythropoietin increased progressively with NYHA class (from 1.4 mU/mL for NYHA class I
to 34 mU/mL for NYHA class IV).

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 [43]. 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 [31]:
 ●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 renal
disease [44,45]. 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 [44]. (See "Myocardial dysfunction in end-stage renal disease".)

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 be reduced to <20 percent in both iron deficiency and the 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 [46]. 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 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. 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 [47]. Further study is needed to determine whether there is a
relationship between myocardial iron deficiency and HF.

TREATMENT — When a specific cause of anemia can be identified (eg, iron, vitamin B12,
or folate deficiency), appropriate treatment should be instituted. Folate deficiency is
increasingly rare in individuals who consume a normal diet, due to routine supplementation
of flours and grains in many countries. Data on use of transfusions in patients with HF are
limited. Erythropoietic agent trials in patients with HF have found no benefit and an
increased risk of thromboembolism. Iron may provide symptomatic benefit in selected
patients with HF and iron deficiency but further study is needed.
Transfusion — Based upon low quality evidence, we suggest using a restrictive red blood
cell transfusion strategy (eg, trigger hemoglobin threshold of 7 to 8 g/dL) in asymptomatic
patients with HF, rather than a more liberal threshold (such as <10 g/dL). In general,
transfusion should be considered when the hemoglobin is 7 to 8 g/dL, although some
patients may require transfusion at higher levels. Symptomatic anemia should be treated
with transfusion in patients with hemoglobin <10 g/dL, provided that the symptoms are
severe enough and are clearly related to the anemia rather than the underlying condition.
(See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult",
section on 'Overview of our approach'.)

No large randomized, controlled trials have been published on the effect of a liberal (ie,
transfusion for hemoglobins of 10 or less) or restrictive (ie, transfusion for hemoglobins of 8
or less) transfusion regimen in patients with either stable or decompensated HF. A meta-
analysis of the available studies in patients with anemia and heart disease has concluded
the following [48]:

●Three randomized trials included a small number of patients with stable HF. However,
data specific to patients with isolated HF and no coronary heart disease were available
in only one trial of patients with HF and hip fracture surgery [49]. This study found no
difference in mortality or myocardial infarction outcomes on the use of a liberal or
restrictive transfusion regimen.
●Two observational studies in patients with decompensated HF found conflicting
results: One showed harm and the other no significant difference [50,51].
●Low-quality evidence from six trials and 26 observational studies suggests that liberal
transfusion protocols in patients with anemia and heart disease (coronary heart
disease and/or HF) do not improve short-term mortality rates compared with less
aggressive transfusion protocols (risk ratio [RR] 0.94, 95% CI 0.61-1.42).

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 "Use of blood products in the critically ill", section
on 'Red blood cells' and "Transfusion-associated circulatory overload (TACO)".)

Iron — As a general rule, iron supplementation is recommended only when clinically

indicated to treat documented iron deficiency or iron deficiency anemia. (See 'Iron
deficiency' above.)

Some studies have evaluated the efficacy and safety of iron supplementation in patients
with HF who have iron deficiency with mild or no anemia (ie, hemoglobin level 9.5 to
13.5 g/dL). One limitation of these studies is that they used serum ferritin criteria for
identification of iron deficiency that were well above limits generally considered diagnostic of
iron deficiency.

Treatment of iron deficiency anemia is discussed in detail separately. (See "Treatment of

iron deficiency anemia in adults".)

Intravenous iron — While the available evidence suggests that intravenous (IV) iron
provides symptomatic benefit in selected patients with HF, such therapy requires further
study since the mechanism of benefit, optimum target population, and the long-term effects
of such treatment are not known. Three randomized trials, one large [12] and two small
[13,52], and a number of observational studies [21,23,24,53] have provided evidence of
symptomatic benefit from treating patients with chronic HF with IV iron with or without an
erythropoiesis-stimulating agent [48,54]. Iron deficiency as diagnosed by ferritin
level and/or transferrin saturation (TSAT) was a criterion in the three randomized trials,
although not all patients were anemic, and serum ferritin cutoff values were higher than
those generally used in other populations to diagnose iron deficiency. As a result, these
studies probably included a mixture of patients, some of whom had anemia that was due, at
least in part, to chronic inflammation rather than iron deficiency [11].
(See 'Evaluation' above and "Causes and diagnosis of iron deficiency and iron deficiency
anemia in adults" and "Anemia of chronic disease/inflammation".)

The FAIR-HF trial enrolled 459 patients with New York Heart Association (NYHA) functional
class II or III HF, left ventricular ejection fraction of ≤40 to 45 percent, iron deficiency, and a
hemoglobin level of 9.5 to 13.5 g/dL [12]. For the purposes of this study, iron deficiency was
defined as a serum ferritin level <100 mcg/L, or a ferritin level of 100 to 299 mcg/L with
TSAT <20 percent. Participants were excluded if they had "inflammation," although this was
not defined within the paper. Patients were randomly assigned to receive IV iron (ferric
carboxymaltose) or placebo at regular intervals during correction and maintenance phases.

Compared with placebo, IV iron improved self-reported Patient Global assessment and
NYHA functional class (28 versus 50 percent) [12]. IV iron was also associated with
improvement on the disease-specific Kansas City Cardiomyopathy Questionnaire, six-
minute walk distance, and health-related quality of life at 24 weeks [12,55]. These benefits
were similar in patients with hemoglobin levels ≤12 or >12 g/dL. The rates of death and
adverse events were similar in the two groups.

These results are intriguing and raise several questions. The first is related to the underlying
iron status of the study patients. The mean ferritin levels were 52.5 and 60.1 mcg/L in
the ferric carboxymaltose and placebo groups, respectively. Thus, many patients had ferritin
levels well above a cutoff usually considered diagnostic of iron deficiency. However,
because of the poor sensitivity of ferritin in this population, many of these individuals may
have been iron deficient. Moreover, the combination of a ferritin level >100 mcg/L and TSAT
<20 percent is highly suggestive of the anemia of inflammation rather than absolute iron
deficiency, despite the exclusion of subjects with "inflammation." (See "Anemia of chronic
disease/inflammation".)

It is also of interest that the clinical benefit of IV iron was not correlated with changes in the
patients' hemoglobin levels, suggesting that alternate mechanisms led to the observed
improvements. Finally, it is important to note the possibility of inadequate blinding of
patients to their treatment group, due to differences in the color of the ferric
carboxymaltose and placebo solutions, particularly in light of the relatively subjective
outcome measures used [56].

Oral iron — The available evidence has demonstrated no benefit from use of oral iron
supplements in patients with HF without anemia. The Iron Repletion effects on Oxygen
Uptake in Heart Failure (IRONOUT HF) trial enrolled 225 patients with HF with reduced
ejection fraction (HFrEF; EF ≤40 percent), ferritin <100 ng/mL or ferritin 100 to
299 ng/mL plus TSAT <20 percent, and hemoglobin levels between 9 and 15 g/dL (for men)
or 9 and 13.5 g/dL (for women) [57]. Similar to the IV iron trials described above, iron
parameter criteria exceeded cutoffs usually considered diagnostic for iron deficiency. The
participants were randomly assigned to receive either oral iron polysaccharide 150 mg twice
daily or placebo for 16 weeks. There were no significant differences between the treatment
groups in peak VO2 at 16 weeks, six-minute walk distance, Kansas City Cardiomyopathy
Questionnaire score assessment of quality of life, or N-terminal pro-brain natriuretic peptide
levels.

Erythropoiesis-stimulating agents — We recommend against the use of erythropoiesis-

stimulating agents in patients with mild to moderate anemia and HF. The available evidence
does not support the use of erythropoiesis-stimulating agents to treat mild to moderate
anemia in patients with HF and suggests an increased risk of venous thromboembolism
[48]. 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 [58]. 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) [59,60]. 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 hemodialysis patients".)

A meta-analysis of 17 trials of erythropoiesis-stimulating agents in patients with heart

disease (HF or coronary heart disease), including the RED-HF trial, found no consistent
clinical benefit from erythropoiesis-stimulating agents and found an increased risk of
thromboembolism with such treatment [48]. Analysis limited to trials in patients with HF
produced similar findings.

Society guidelines — The following recommendations from the 2013 Practice Guidelines
from the American College of Physicians (ACP) [61] are based upon a systematic review of
published literature in the English language on anemic or iron deficient adults with heart
disease [48].

●The ACP 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 (weak recommendation based on
low-quality evidence; equivalent to Grade 2C). We agree with using a more restrictive
threshold in most patients, 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. (See 'Transfusion' above.)
●The ACP recommends against the use of erythropoiesis-stimulating agents in
patients with mild to moderate anemia and HF or coronary heart disease (strong
recommendation based on moderate quality evidence; equivalent to Grade 1B). We
agree with this recommendation. (See 'Erythropoiesis-stimulating agents' above.)

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

●Anemia is frequently present in patients with heart failure (HF). Multiple factors,
including increased levels of circulating cytokines, hemodilution, iron deficiency, use of
angiotensin converting enzyme inhibitors, renal insufficiency, and poor nutrition may be
operative in an individual patient.
●Anemia is a major sign of disease and its cause should be sought in all patients.
(See 'Evaluation' above.)
●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.)
●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" and "Use of blood products in the critically ill", section on 'Red blood cells'.)
●When red blood 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 "Use of blood
products in the critically ill", section on 'Red blood cells' and "Transfusion-associated
circulatory overload (TACO)", section on 'Prevention'.)
●Iron supplementation is recommended when clinically indicated to treat documented
iron deficiency or iron deficiency anemia. While the available evidence suggests that
intravenous (IV) iron provides symptomatic benefit in selected patients with HF with
iron deficiency with mild or no anemia (ie, hemoglobin level 9.5 to 13.5 g/dL), the long-
term effects of such treatment are not known. Further studies are needed to investigate
whether patients with more stringently defined iron deficiency anemia (versus the
anemia of inflammation) are more likely to benefit from IV iron, to investigate potential
underlying mechanisms leading to benefit, and to confirm that there is no increased
risk of adverse events over extended follow-up, before IV iron can be recommended as
the standard of care in patients with HF with iron deficiency and mild or no anemia.
(See 'Iron' above and "Treatment of iron deficiency anemia in adults".)
●We recommend against the use of erythropoiesis-stimulating agents in patients with
mild to moderate anemia and HF. (Grade 1B). (See 'Erythropoiesis-stimulating
agents' above.)

REFERENCES
1. Felker GM, Adams KF Jr, Gattis WA, O'Connor CM. Anemia as a risk factor and
therapeutic target in heart failure. J Am Coll Cardiol 2004; 44:959.
2. Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function and anemia as
risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol
2001; 38:955.
3. 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; 107:223.
4. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and
intravenous iron for the treatment of the anemia of severe, resistant congestive heart
failure improves cardiac and renal function and functional cardiac class, and
markedly reduces hospitalizations. J Am Coll Cardiol 2000; 35:1737.
5. Shah R, Agarwal AK. Anemia associated with chronic heart failure: current concepts.
Clin Interv Aging 2013; 8:111.
6. Brannon ES, Merrill AJ, Warren JV, Stead EA. THE CARDIAC OUTPUT IN
PATIENTS WITH CHRONIC ANEMIA AS MEASURED BY THE TECHNIQUE OF
RIGHT ATRIAL CATHETERIZATION. J Clin Invest 1945; 24:332.
7. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic
response to acute, severe isovolemic anemia. JAMA 1998; 279:217.
8. 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.
9. Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in
patients with depressed left ventricular ejection fraction: a report from the Studies of
Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27:1201.
10. Anand IS. Anemia and chronic heart failure implications and treatment options. J Am
Coll Cardiol 2008; 52:501.
11. Nanas JN, Matsouka C, Karageorgopoulos D, et al. Etiology of anemia in patients
with advanced heart failure. J Am Coll Cardiol 2006; 48:2485.
12. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with
heart failure and iron deficiency. N Engl J Med 2009; 361:2436.
13. Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-
brain natriuretic peptide in anemic patients with chronic heart failure and renal
insufficiency. J Am Coll Cardiol 2007; 50:1657.
14. Jankowska EA, Malyszko J, Ardehali H, et al. Iron status in patients with chronic
heart failure. Eur Heart J 2013; 34:827.
15. Matsumoto M, Tsujino T, Lee-Kawabata M, et al. Iron regulatory hormone hepcidin
decreases in chronic heart failure patients with anemia. Circ J 2010; 74:301.
16. Divakaran V, Mehta S, Yao D, et al. Hepcidin in anemia of chronic heart failure. Am
J Hematol 2011; 86:107.
17. Androne AS, Katz SD, Lund L, et al. Hemodilution is common in patients with
advanced heart failure. Circulation 2003; 107:226.
18. Adlbrecht C, Kommata S, Hülsmann M, et al. Chronic heart failure leads to an
expanded plasma volume and pseudoanaemia, but does not lead to a reduction in
the body's red cell volume. Eur Heart J 2008; 29:2343.
19. Grote Beverborg N, Klip IT, Meijers WC, et al. Definition of Iron Deficiency Based on
the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients. Circ Heart
Fail 2018; 11:e004519.
20. Ishani A, Weinhandl E, Zhao Z, et al. Angiotensin-converting enzyme inhibitor as a
risk factor for the development of anemia, and the impact of incident anemia on
mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2005; 45:391.
21. Comín-Colet J, Ruiz S, Cladellas M, et al. A pilot evaluation of the long-term effect of
combined therapy with intravenous iron sucrose and erythropoietin in elderly patients
with advanced chronic heart failure and cardio-renal anemia syndrome: influence on
neurohormonal activation and clinical outcomes. J Card Fail 2009; 15:727.
22. Silverberg DS, Wexler D, Iaina A, Schwartz D. The correction of anemia in patients
with the combination of chronic kidney disease and congestive heart failure may
prevent progression of both conditions. Clin Exp Nephrol 2009; 13:101.
23. Pagourelias ED, Koumaras C, Kakafika AI, et al. Cardiorenal anemia syndrome: do
erythropoietin and iron therapy have a place in the treatment of heart failure?
Angiology 2009; 60:74.
24. Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without
erythropoietin for the treatment of iron deficiency anemia in patients with moderate to
severe congestive heart failure and chronic kidney insufficiency. J Nephrol 2008;
21:236.
25. Lu KJ, Kearney LG, Hare DL, et al. Cardiorenal anemia syndrome as a
prognosticator for death in heart failure. Am J Cardiol 2013; 111:1187.
26. He SW, Wang LX. The impact of anemia on the prognosis of chronic heart failure: a
meta-analysis and systemic review. Congest Heart Fail 2009; 15:123.
27. Anand I, McMurray JJ, Whitmore J, et al. Anemia and its relationship to clinical
outcome in heart failure. Circulation 2004; 110:149.
28. Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure:
the prospective randomized amlodipine survival evaluation (PRAISE). J Am Coll
Cardiol 2003; 41:1933.
29. Kosiborod M, Smith GL, Radford MJ, et al. The prognostic importance of anemia in
patients with heart failure. Am J Med 2003; 114:112.
30. Felker GM, Gattis WA, Leimberger JD, et al. Usefulness of anemia as a predictor of
death and rehospitalization in patients with decompensated heart failure. Am J
Cardiol 2003; 92:625.
31. Anand IS, Kuskowski MA, Rector TS, et al. Anemia and change in hemoglobin over
time related to mortality and morbidity in patients with chronic heart failure: results
from Val-HeFT. Circulation 2005; 112:1121.
32. Maggioni AP, Opasich C, Anand I, et al. Anemia in patients with heart failure:
prevalence and prognostic role in a controlled trial and in clinical practice. J Card Fail
2005; 11:91.
33. Komajda M, Anker SD, Charlesworth A, et al. The impact of new onset anaemia on
morbidity and mortality in chronic heart failure: results from COMET. Eur Heart J
2006; 27:1440.
34. Tang WH, Tong W, Jain A, et al. Evaluation and long-term prognosis of new-onset,
transient, and persistent anemia in ambulatory patients with chronic heart failure. J
Am Coll Cardiol 2008; 51:569.
35. Kosiborod M, Curtis JP, Wang Y, et al. Anemia and outcomes in patients with heart
failure: a study from the National Heart Care Project. Arch Intern Med 2005;
165:2237.
36. Dunlay SM, Weston SA, Redfield MM, et al. Anemia and heart failure: a community
study. Am J Med 2008; 121:726.
37. Go AS, Yang J, Ackerson LM, et al. Hemoglobin level, chronic kidney disease, and
the risks of death and hospitalization in adults with chronic heart failure: the Anemia
in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.
Circulation 2006; 113:2713.
38. Sharma R, Francis DP, Pitt B, et al. Haemoglobin predicts survival in patients with
chronic heart failure: a substudy of the ELITE II trial. Eur Heart J 2004; 25:1021.
39. Kalra PR, Collier T, Cowie MR, et al. Haemoglobin concentration and prognosis in
new cases of heart failure. Lancet 2003; 362:211.
40. Volpe M, Tritto C, Testa U, et al. Blood levels of erythropoietin in congestive heart
failure and correlation with clinical, hemodynamic, and hormonal profiles. Am J
Cardiol 1994; 74:468.
41. Chatterjee B, Nydegger UE, Mohacsi P. Serum erythropoietin in heart failure
patients treated with ACE-inhibitors or AT(1) antagonists. Eur J Heart Fail 2000;
2:393.
42. Guo L, Wang AH, Sun YL, et al. Serum erythropoietin level predicts the prognosis of
chronic heart failure with or without anemia. Exp Ther Med 2013; 6:1327.
43. van der Meer P, Voors AA, Lipsic E, et al. Prognostic value of plasma erythropoietin
on mortality in patients with chronic heart failure. J Am Coll Cardiol 2004; 44:63.
44. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy,
morbidity, and and mortality in end-stage renal disease. Am J Kidney Dis 1996;
28:53.
45. Silberberg JS, Rahal DP, Patton DR, Sniderman AD. Role of anemia in the
pathogenesis of left ventricular hypertrophy in end-stage renal disease. Am J Cardiol
1989; 64:222.
46. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron
homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia,
exercise capacity, and survival. J Am Coll Cardiol 2011; 58:1241.
47. Maeder MT, Khammy O, dos Remedios C, Kaye DM. Myocardial and systemic iron
depletion in heart failure implications for anemia accompanying heart failure. J Am
Coll Cardiol 2011; 58:474.
48. Kansagara D, Dyer E, Englander H, et al. Treatment of anemia in patients with heart
disease: a systematic review. Ann Intern Med 2013; 159:746.
49. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk
patients after hip surgery. N Engl J Med 2011; 365:2453.
50. Garty M, Cohen E, Zuchenko A, et al. Blood transfusion for acute decompensated
heart failure--friend or foe? Am Heart J 2009; 158:653.
51. Kao DP, Kreso E, Fonarow GC, Krantz MJ. Characteristics and outcomes among
heart failure patients with anemia and renal insufficiency with and without blood
transfusions (public discharge data from California 2000-2006). Am J Cardiol 2011;
107:69.
52. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on
exercise tolerance in anemic and nonanemic patients with symptomatic chronic
heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-
blinded trial. J Am Coll Cardiol 2008; 51:103.
53. Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of
anemia in patients with chronic heart failure. J Am Coll Cardiol 2006; 48:1225.
54. Jankowska EA, von Haehling S, Anker SD, et al. Iron deficiency and heart failure:
diagnostic dilemmas and therapeutic perspectives. Eur Heart J 2013; 34:816.
 55. Comin-Colet J, Lainscak M, Dickstein K, et al. The effect of intravenous ferric
carboxymaltose on health-related quality of life in patients with chronic heart failure
and iron deficiency: a subanalysis of the FAIR-HF study. Eur Heart J 2013; 34:30.
56. Dec GW. Anemia and iron deficiency--new therapeutic targets in heart failure? N
Engl J Med 2009; 361:2475.
57. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of Oral Iron Repletion on
Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and
Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA 2017;
317:1958.
58. Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa
in systolic heart failure. N Engl J Med 2013; 368:1210.
59. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2
diabetes and chronic kidney disease. N Engl J Med 2009; 361:2019.
60. Marsden PA. Treatment of anemia in chronic kidney disease--strategies based on
evidence. N Engl J Med 2009; 361:2089.
61. Qaseem A, Humphrey LL, Fitterman N, et al. Treatment of anemia in patients with
heart disease: a clinical practice guideline from the American College of Physicians.
Ann Intern Med 2013; 159:770.

Topic 3483 Version 31.0