JACC: HEART FAILURE VOL. -, NO.

-, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER https://doi.org/10.1016/j.jchf.2017.08.023

STATE-OF-THE-ART PAPER

Anemia in Heart Failure

Still Relevant?

Niels Grote Beverborg, MD, Dirk J. van Veldhuisen, MD, PHD, Peter van der Meer, MD, PHD

ABSTRACT

One-third of all patients with heart failure have anemia, and its presence is associated with more symptoms, increased
rates of hospitalization, and mortality. The etiology of anemia is multifactorial, complex, and varies between patients.
The most important factors leading to anemia in heart failure are inadequate erythropoietin production resulting from
renal failure, intrinsic bone marrow defects, medication use, and nutritional deficiencies such as iron deficiency.
Erythropoiesis-stimulating agents (ESAs) have been proven to successfully correct hemoglobin levels, albeit without
significant improvement in clinical outcome. On the contrary, the use of ESAs has led to increased rates of thrombo-
embolic events and ischemic stroke. This use of ESAs for the treatment of anemia in heart failure, therefore, cannot be
recommended. In addition, these results question whether anemia is a therapeutic target or merely a marker of disease
severity. Other therapies are being studied and include agents targeting the erythropoietin receptor, hepcidin pathway, or
iron availability. This review focuses on the pathophysiology of anemia in heart failure, explanations why investigated
therapies might not have led to the desired results, and discussions of promising future therapies. (J Am Coll Cardiol HF
2017;-:-–-) © 2017 by the American College of Cardiology Foundation.

I n patients with heart failure (HF), organ systems

receive, in varying degrees, an inadequate sup-
ply of oxygen and nutrients. Together with
inflammation and neurohormonal pathway activa-
management strategies? Or, in short, is anemia in pa-
tients with HF still relevant? The present review sum-
marizes the literature on anemia in patients with HF.

tion, comorbidities such as iron deficiency (50%) DIAGNOSIS AND PREVALENCE

and anemia (37%) are highly prevalent (1). Conven-
tionally, iron deficiency and anemia were considered The strict definition of anemia is an absolute decrease
cause and consequence. However, with the latest re- in red blood cell mass, which can be determined by an
sults of large trials targeted at either iron deficiency extensive and costly analysis of radiolabeled blood
or anemia, striking differences were observed in volume analysis. In clinical practice, however, only
treatment effect. Therapies aimed at raising hemoglo- derived parameters such as Hb level and hematocrit
bin (Hb) levels did not seem to be beneficial to date, are used. Hb and hematocrit are concentration
whereas treating iron deficiency resulted in substan- dependent, and in volume overloaded HF patients,
tial clinical benefits, also in HF patients without ane- hemodilution-induced “pseudo-anemia” is a recur-
mia. This outcome raises several questions: is a low rent phenomenon (2). According to the World Health
Hb level a therapeutic target? Is it merely a signal of Organization, anemia occurs at an Hb level <13 g/dl in
disease severity or an underlying comorbidity (e.g., men and <12 g/dl in women. This definition has not
renal failure, iron deficiency)? Are we using the right been validated, but in the general population with

From the Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
The University Medical Center of Groningen has received an unrestricted grant from Vifor Pharma. Dr. van Veldhuisen has
received board membership fees and travel expenses from Vifor Pharma. Dr. van der Meer has received consultancy fees from
Vifor Pharma. Dr. Grote Beverborg has reported that he has no relationships relevant to the contents of this paper to disclose.

Manuscript received May 10, 2017; revised manuscript received August 25, 2017, accepted August 31, 2017.
2 Grote Beverborg et al. JACC: HEART FAILURE VOL. -, NO. -, 2017
Anemia in Heart Failure - 2017:-–-

ABBREVIATIONS normal renal function, serum erythropoietin and, subsequently, aggravation of symptoms such as
AND ACRONYMS levels rise exponentially in those with Hb dyspnea and fatigue, and thus further impair exercise
levels <13 and 12 g/dl, respectively (3). In tolerance and quality of life (19).
CKD = chronic kidney disease
patients with HF, studies have reported a In a large meta-analysis with 153,180 patients with
ESA = erythropoiesis-
wide range of anemia prevalence (17% to HF, the crude mortality risk of anemia was an odds
stimulating agent
70%), which may be the result of differences ratio of 1.96 (95% confidence interval: 1.74 to 2.21),
Hb = hemoglobin
in anemia definition, patient demographic and the adjusted hazard ratio was 1.46 (95%
HF = heart failure
characteristics, comorbidities, study type confidence interval: 1.26 to 1.69), with no difference
HIF = hypoxia-inducible factor
(registry vs. trial), and HF severity (4–6). between patients with a reduced or preserved left
LVEF = left ventricular ejection
ventricular ejection fraction (LVEF) (4). In 2
fraction ETIOLOGY AND PATHOPHYSIOLOGY
observational studies, anemia resolved in 6 months’
TSAT = transferrin saturation
time in >40% of outpatients (5,6). These patients
VO2 max = maximal oxygen The etiology of anemia in patients with HF is
had a prognosis similar to those without anemia,
consumption multifactorial. Patients with concomitant
whereas persistent anemia was associated with the
chronic kidney disease (CKD) or diabetes mellitus,
poorest survival. Iron supplementation and the
higher age, and more advanced disease are at the
erythropoiesis-stimulating agent (ESA) therapy rate
highest risk of anemia (5,6). HF can cause anemia
were relatively low (21% and 8%, respectively), and
through different pathophysiological mechanisms,
resolution of anemia was hypothesized to be the ef-
and both conditions share several risk factors (Central
fect of HF treatment for a large part, particularly
Illustration). Patients with HF often have hematinic
better control of fluid status, and thus resolving
deficiencies, especially iron deficiency, which is pre-
pseudo-anemia (5). The combination of anemia, CKD,
sent in approximately one-half of the patients (7–9).
and/or iron deficiency in patients with HF often oc-
The presence of chronic inflammation in HF is an
curs, and is associated with progression of CKD and
important cause of (functional) iron deficiency and of
HF and unfavorable prognosis (20). However, it is
erythropoietin resistance (10). Inadequate levels of
unclear whether anemia leads to advanced HF and
erythropoietin, conversely, are often seen in patients
worse outcome or if anemia is merely a sign of more
with concomitant CKD because the production of
advanced disease.
erythropoietin occurs in the kidney (11). In addition,
bone marrow unresponsiveness to erythropoietin due MANAGEMENT OPTIONS
to intrinsic bone marrow defects further increases the
susceptibility to anemia (12). This action is associated TRANSFUSION THERAPY. In case of severe, symp-
with excessively elevated erythropoietin levels in tomatic anemia, blood transfusion with packed red
patients with HF and preserved erythropoietin pro- blood cells is often considered. However, data in pa-
duction; high erythropoietin levels are associated tients with HF are limited. Transfusion therapy has
with unfavorable outcome in these patients and the only temporary benefits and additional risks in pa-
development of HF in the general population (13,14). tients with HF such as volume overload and ischemic
In addition, the activated renin-angiotensin- events. Two observational studies (n ¼ 596,456 and
aldosterone system results in salt and fluid reten- n ¼ 4,102) concluded that patients with HF who
tion leading to pseudo-anemia (2,11). received blood transfusions have worse clinical fea-
Medication prescribed in HF can result in anemia. tures and prognosis, although the smaller study
Angiotensin-converting enzyme inhibitors inhibit noted that the transfusion itself seemed to be safe
hematopoietic activity via N-acetyl-seryl-aspartyl- and even beneficial compared with propensity score–
lysyl-proline, leading to a higher risk of anemia as matched patients with HF who did not receive a blood
observed in the SOLVD (Studies of Left Ventricular transfusion (21,22). Because of the risks of acute he-
Dysfunction) trial with enalapril (15,16). In addition, molytic reactions, infection, acute lung injury,
there is evidence that carvedilol might decrease Hb allergic reactions, and the lack of evidence to suggest
levels by blocking the b2-adrenergic receptor (17). a liberal transfusion strategy in patients with heart
CLINICAL CONSEQUENCES disease, a restrictive transfusion strategy (trigger
threshold of 7 to 8 g/dl) is recommended by the
In healthy individuals, oxygen delivery at Hb levels American College of Physicians (23).
as low as 5 g/dl are compensated by increases in both ERYTHROPOIESIS-STIMULATING AGENTS. Exogenous
heart rate and stroke volume, mechanisms already erythropoietin is approved for the treatment of ane-
impaired in patients with HF (18). Anemia in HF, mia as a result of CKD or chemotherapy-induced
therefore, could lead to decreased oxygen delivery anemia. In HF, the effect of anemia treatment with
JACC: HEART FAILURE VOL. -, NO. -, 2017 Grote Beverborg et al. 3
- 2017:-–- Anemia in Heart Failure

C ENTR AL I LL U STRA T I O N Anemia in Heart Failure: Common Ground, Cause, or Consequence?

Consequence
Renal dysfunction
Inflammation
Nutritional deficiencies
Cachexia
Blood loss Therapy Effects Current state
(ASA/antiocoagulant)
Medication(ACEi/β-blocker) Hemoglobin Recommended for improving
Symptoms symptoms in patients with
Iron
Heart failure Common ground Exercise capacity iron deficiency
Prognosis ?
Renal dysfunction
Inflammation
Diabetes Mellitus ESAs Hemoglobin
More symptoms Not recommended for the
Advanced age Prognosis =
Impaired prognosis treatment of anemia in heart failure
Toxins: lead, Thromboembolic events
copper,
chemotherapy
Anemia
Hemoglobin
Symptoms ? Awaiting data from clinical trials
New therapies
Prognosis ? mainly in chronic kidney disease

Cause
Increased cardiac workload

Grote Beverborg, N. et al. J Am Coll Cardiol HF. 2017;-(-):-–-.

Anemia and heart failure share several prevalent risk factors. In addition, heart failure can lead to anemia via a large number of mechanisms, and anemia, in turn, can
lead to an increased cardiac workload and possible further deterioration of cardiac function and prognosis. ACEi ¼ angiotensin-converting enzyme inhibitor;
ASA ¼ acetylsalicylic acid.

ESAs on outcome was examined in the RED-HF performed. The presence of pseudo-anemia has been
(Reduction of Events by Darbepoetin Alfa in Heart proposed as a possible reason for the neutral results,
Failure) trial, which, with 2,278 patients, is the largest which was also reported in a small study of 28
study to date (24). In this study, patients with anemic patients treated with erythropoietin alfa (29).
symptomatic chronic HF (LVEF #40%) and anemia Because a large portion of patients with HF already
(Hb level 9.0 to 12.0 g/dl) were randomized to receive have a disproportionately high erythropoietin level
darbepoetin alfa (with a target of 13 to 14.5 g/dl) or associated with bone marrow resistance to erythro-
placebo. Co-treatment with oral or intravenous iron poietin, administering even more erythropoietin to
was allowed in both groups. Median Hb levels in the these patients would be counterintuitive (13). This
intervention group increased, but no effect was approach is supported by data from the RED-HF trial,
observed on the primary composite endpoint of death which showed that approximately one-quarter of
or hospitalization for worsening HF or any of the patients with HF did not exhibit any increase in Hb
other endpoints. To the contrary, rates of ischemic level after 4 weeks of ESA treatment, and this unre-
stroke (41 [4.5%] vs. 32 [2.8%]; p ¼ 0.03) and embolic/ sponsiveness to ESAs is independently associated
thrombotic events (153 [13.5%] vs. 114 [10.0%]; with hospitalizations and all-cause mortality (30).
p ¼ 0.009) were increased in those treated with dar- Regarding the Hb target, no data comparing different
bepoetin alfa (24,25). This outcome led to further targets in patients with HF are available, but data
safety concerns because increased rates of ischemic from trials in CKD indicate that higher Hb targets may
stroke and thrombotic events with ESAs were also result in worse cardiovascular outcome (27).
observed in patients with CKD and chemotherapy-
induced anemia (26,27). Possible reasons for these IRON THERAPY. Iron therapy was initially adminis-
results include the wrong therapy, wrong target tered as co-therapy in trials with ESAs, mainly as oral
population, or wrong target Hb level. therapy (24). More recently, the awareness of the high
As noted earlier, the etiology of anemia in HF is prevalence of iron deficiency (w70% in the anemic
very heterogeneous (7–12,28). Patients with a trans- and w50% of the entire HF population), the clinical
ferrin saturation (TSAT) <15% were excluded from consequences of iron deficiency, and the availability
the RED-HF trial, but this method still leaves of new intravenous iron formulations have led to the
patients with iron deficiency with TSAT 15% to 20% design of trials investigating iron therapy without
and a ferritin level 100 to 300 m g/l or a ferritin ESAs. The initial trials were performed in patients
level <100 m g/l included in the trial. In addition, no with anemia but later also in patients with iron
other investigations into the cause of anemia were deficiency irrespective of the presence of anemia.
4 Grote Beverborg et al. JACC: HEART FAILURE VOL. -, NO. -, 2017
Anemia in Heart Failure - 2017:-–-

T A B L E 1 Randomized Controlled Trials With Intravenous Iron in Patients With Heart Failure

First Author, Definition of Study

Year (Ref. #) N Population Iron Deficiency Therapy Period Effect on Hb Results

Toblli et al., 40 Hb <12.5 g/dl, Ferritin <100 mg/l Iron sucrose 200 mg 26 weeks From 10.3  0.6 g/dl at NT-proBNP Y
2007 (32) LVEF #35% þ TSAT <20% every 5 weeks baseline to 11.8  0.7 CRP Y
eGFR <90 ml/min g/dl at 6 months NYHA functional
(p < 0.01) in the class Y
intervention group; no LVEF [
significant difference in eGFR [
control group 6MWT [
MLHFQ [
Okonko et al., 35* NYHA functional class Ferritin <100 mg/l or Iron sucrose 200 mg 16 weeks 0.1 (–0.8 to 0.9) g/dl at 16 VO2 max [
FERRIC-HF, II–III, ferritin 100–300 mg/l weekly till ferritin weeks (p ¼ 0.87) (p ¼ 0.08)
2008 (33) LVEF #45% þ TSAT <20% >500 mg/l† VO2 max/kg [
VO2 max <18 ml/kg/min NYHA functional
Hb <14.5 g/dl class Y
PGA [
Anker et al., FAIR- 459* NYHA functional class Ferritin <100 mg/l or FCM 200 mg until 24 weeks FCM vs. placebo NYHA functional
HF, 2009 (34) II–III ferritin 100–299 mg/l normalized iron 13.0  1 g/dl vs. 12.5  1 class Y
LVEF #40% þ TSAT <20% status‡ g/dl (p < 0.001) at 24 PGA [
Hb 9.5–13.5 g/dl weeks 6MWT [
EQ-5D [
KCCQ [
Ponikowski et al., 304 NYHA functional class Ferritin <100 mg/l or FCM 500–2,000 mg at 52 weeks 0.6  0.2 g/dl and 1.0  6MWT [
CONFIRM-HF, II–III, LVEF #45%, ferritin 100–300 mg/l baseline and after 6 0.2 g/dl after 24 NYHA functional
2015 (35) Hb <15 g/dl, þ TSAT <20% weeks; subsequently, and 52 weeks (both class Y
NT-proBNP >400 500 mg every 12 p < 0.001) PGA [
pg/ml, or BNP weeks if still iron EQ-5D [
>100 pg/ml deficient HF hospitalizations Y
(not a
predefined
endpoint)
van Veldhuisen 172 NYHA functional class Ferritin <100 mg/l or FCM 500–2,000 mg at 24 weeks 0.74  0.17 g/dl after 24 VO2 max [
et al., EFFECT- II–III, LVEF #45%, ferritin 100–300 mg/l baseline and after 6 weeks (p < 0.0001) NYHA functional
HF, 2017 (36) VO2 max 10–20 þ TSAT <20% and 12 weeks if still class Y
ml/kg/min, Hb <15 iron deficient PGA [
g/dl, NT-proBNP
>400 pg/ml, or
BNP >100 pg/ml

*2:1 randomization, 24 (FERRIC-HF [Ferric Iron Sucrose in Heart Failure]) and 304 (FAIR-HF [Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure]) patients in the treatment group.
†Ferritin >500 mg/l; subsequently, 200 mg once a month. ‡Calculated by using the Ganzoni formula; after iron normalization, 200 mg once every 4 weeks.
6MWT ¼ 6-min walking test; BNP ¼ brain natriuretic peptide; CONFIRM-HF ¼ Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination With Chronic Heart Failure;
CRP ¼ C-reactive protein; EFFECT-HF ¼ Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Iron Deficiency and Chronic Heart Failure; eGFR ¼ estimated glomerular filtration rate; EQ-5D ¼
5-dimension European Quality of Life; FCM ¼ ferric carboxymaltose; Hb ¼ hemoglobin; HF ¼ heart failure; KCCQ ¼ Kansas City Cardiomyopathy Questionnaire; LVEF ¼ left ventricular ejection fraction;
MLHFQ ¼ Minnesota Living with Heart Failure Questionnaire; NYHA ¼ New York Heart Association; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; PGA ¼ patient global assessment; TSAT ¼
transferrin saturation; VO2 max ¼ maximum oxygen uptake per minute.

Although oral iron has practical advantages over levels. The only patients who responded to oral iron
intravenous iron, its use in HF seems limited because therapy were those with low hepcidin levels. Hepci-
of therapy compliance issues due to gastrointestinal din is the regulator of iron metabolism and is
side effects and impaired iron uptake. The latter was involved in the pathophysiology of the anemia of
also observed in the only randomized placebo- chronic disease. The hormone is upregulated in
controlled Phase II study with oral iron, the IRON- inflammation and degrades the iron exporter ferro-
OUT (Oral Iron Repletion Effects On Oxygen Uptake portin, thus blocking iron uptake from the gut and
in Heart Failure) (31). This study included 225 HF iron release from macrophages. This process provides
patients with a reduced LVEF and iron deficiency. a possible explanation for the neutral results of the
Patients received 150 mg of polysaccharide iron IRONOUT study.
complex or placebo, twice daily for 16 weeks. Only a Intravenous iron has been studied in 5 randomized
marginal increase of 11 mg/l of ferritin and 3% TSAT clinical trials (Table 1) (32–35). All studies included
with oral iron was observed, with no significant effect patients based on their ferritin and TSAT levels; Toblli
on exercise capacity (measured according to maximal et al. (32) and Anker et al. (34) additionally used a
oxygen consumption [VO 2 max]) or N-terminal pro–B- relatively low Hb level as an inclusion criterion (<12.5
type natriuretic peptide level. In exploratory ana- and <13.5 g/dl, respectively). Despite differences in
lyses, changes in TSAT correlated with changes in VO2 treatment strategies and follow-up, the overall re-
max and N-terminal pro–B-type natriuretic peptide sults of the trials were broadly similar: treatment with
JACC: HEART FAILURE VOL. -, NO. -, 2017 Grote Beverborg et al. 5
- 2017:-–- Anemia in Heart Failure

intravenous iron led to improvements in New York and the European Society of Cardiology both recog-
Heart Association functional class, exercise capacity, nize anemia as an important comorbidity in patients
and quality of life in a short period of time. In 2 of the with HF (39,40). Management recommendations
largest trials, FAIR-HF (Ferinject Assessment in focus on determining the underlying etiology and
Patients with Iron Deficiency and Chronic Heart subsequent treatment, although, often, no specific
Failure) and CONFIRM-HF (Ferric Carboxymaltose cause is found. Special attention is paid to iron defi-
Evaluation on Performance in Patients With Iron ciency and its treatment with intravenous ferric car-
Deficiency in Combination With Chronic Heart Fail- boxymaltose. The use of the ESA darbepoetin-alfa
ure), significant overall increases in Hb levels were is not recommended by the European Society of
observed, but the treatment effect was similar in Cardiology (39).
anemic and nonanemic patients (34,35). The third
AREAS OF DEVELOPMENT
study is the EFFECT-HF (Effect of Ferric Carbox-
ymaltose on Exercise Capacity in Patients With Iron
Several different strategies are currently being
Deficiency and Chronic Heart Failure), a randomized
explored for the treatment of anemia in HF. These
controlled trial of intravenous ferric carboxymaltose
strategies are aimed directly at the process of eryth-
compared with standard of care in 172 iron-deficient
ropoiesis by targeting the erythropoietin receptor or
patients with HF (36). Primary analysis showed an
hypoxia pathway but also indirectly via the hepcidin
increase in VO 2 max in patients treated with ferric
pathway (Figure 1).
carboxy-maltose compared with a control group that
was not treated. In addition, an increase in the Hb HEPCIDIN. Hepcidin, the master iron regulator, can

level of 0.74  0.17 g/dl was reported after 24 weeks. be antagonized in several ways: 1) decreasing hepci-
However, subgroup analyses of anemic and non- din production; 2) neutralizing hepcidin; or 3) pre-
anemic patients are not yet available. venting hepcidin–ferroportin interaction. Agents
In summary, although anemia and iron deficiency neutralizing hepcidin are the most promising to date.
exhibit a large overlap, isolated iron deficiency is One phase I study showed that a fully humanized
prevalent, and the benefits of treating iron deficiency monoclonal antibody against hepcidin (LY2787106)
probably extend beyond hematopoiesis. The effects was well tolerated and resulted in increases in serum
of intravenous iron on hard clinical endpoints remain iron levels and TSAT in patients with cancer and
to be established. Given these results, it is recom- anemia (41). Another hepcidin-binding agent, the
mended to screen for iron deficiency in all patients Spiegelmer lexaptepid (NOX-H94), has been shown to
with HF, independent of their Hb level. To diagnose increase serum iron levels in healthy persons sub-
iron deficiency, the combination of TSAT and ferritin jected to inflammation by injection of lipopolysac-
levels (ferritin <100 m g/l or a ferritin level 100 to 300 charides (42). A small Phase II study found an Hb
mg/l with a TSAT<20%) has most often been used in increase of $1 g/dl after 4 weeks of treatment with
large clinical trials. However, this definition has not lexaptepid in 5 of 12 patients with functional iron-
been validated, and ferritin levels are often unreliable deficiency anemia (30). Currently, the results of
because it is an acute-phase reactant. We recently trials investigating the effects of these agents in ESA
presented data from a study in which we validated hyporesponsive, anemic patients undergoing dialysis
the cutoff of TSAT<20% by using the gold standard of are awaited.
bone marrow iron staining (37). Ferritin had no ERYTHROPOIETIN RECEPTOR TARGETING. Drugs
diagnostic value. We supported these findings by directly targeting erythropoiesis include erythropoi-
showing that a low TSAT, and not a low ferritin level, etin receptor–targeting drugs (receptor antibodies,
was associated with an increased risk of mortality. fusion proteins, gene therapy, and mimetic peptides)
This finding is in line with results from the recently and activin receptor ligand traps. Activin traps are
published meta-analysis of Anker et al. (38) who recombinant fusion proteins consisting of the
found that, using interaction analysis, patients with a immunoglobulin G1 Fc domain linked to the extra-
TSAT $20.1% do not respond to iron therapy with cellular domain of the activin receptor IIA. These bind
improved outcomes, whereas those in the lower a number of transforming growth factor- b superfam-
tertiles of TSAT do respond. ily ligands, including activin A and activin B, and
thereby inhibit their signaling. Sotatercept, the most
CURRENT GUIDELINE RECOMMENDATIONS studied activin trap, was initially studied as an oste-
oporosis agent. Surprisingly, an increase in Hb level,
The most recent guidelines of the American College of red blood cell number, and hematocrit were observed
Cardiology Foundation/American Heart Association (43). Together with the prevention of vascular
6 Grote Beverborg et al. JACC: HEART FAILURE VOL. -, NO. -, 2017
Anemia in Heart Failure - 2017:-–-

F I G U R E 1 New Therapies for Anemia and Their Targets in Erythropoiesis

Production
HIF-stabilizers
BMP inhibitors
Anti-cytokines
siRNAs

Neutralizing

mAb
EPO Activin traps Hepcidin Spiegelmers
Anticalins

Ferroportin Binding

EPO mimetics Anti-ferroportin

GDF11+ cells
rhEPO antibodies
Iron

+ + + +
Efficacy

Pluripotent stem cell BFU-E CFU-E Proerythroblasts Erythroblasts Reticulocytes RBCs

ErythropoieƟn dependent phase Iron dependent phase

The process of production of new red blood cells (RBCs): erythropoiesis. The first stages are dependent on erythropoietin (EPO). During the erythroblasts stage, iron
availability is essential as it is incorporated in hemoglobin. Most new therapies target either EPO or iron. Hypoxia-inducible factor (HIF) stabilizers affect both
pathways. Although not fully understood, the data suggest that activin receptor ligand traps also addresses both pathways and increases efficacy of erythropoiesis by
reducing the number of growth differentiation factor (GDF)-11-positive cells. Hepcidin can be antagonized by decreasing hepcidin production, neutralizing hepcidin, or
preventing hepcidin–ferroportin interaction. As a result of hepcidin inhibition, ferroportin expression is increased, and iron absorption and iron availability for
erythropoiesis increase. BFU-E ¼ erythroid burst-forming units; BMP ¼ bone morphogenic protein; CFU-E ¼ erythroid colony-forming units; mAb ¼ monoclonal
antibodies; rhEPO ¼ recombinant human erythropoietin; siRNA ¼ small interfering ribonucleic acid.

calcification shown in a small trial with 43 patients endothelial growth factor). HIF stabilizers can be
with end-stage renal disease, this drug might prove administered orally and induce physiological eryth-
beneficial for the elderly CKD population (44). Animal ropoietin levels. Several Phase I and II studies in pa-
models point to growth differentiation factor 11 as the tients with CKD have shown promising results with
target for these drugs, which is a differentiator in- increasing levels of Hb and decreasing levels of hep-
hibitor present on erythroid progenitors (45). How- cidin after therapy (48). One of the compounds with
ever, increased expression of angiotensin II has also the most data available is FG-4592, or roxadustat.
been proposed as one of the possible mechanisms of Roxadustat was recently shown to be effective in
increased erythropoiesis by stimulating erythroid increasing Hb levels and to be superior compared
differentiation directly through the AT 1 receptor or with epoetin alfa in correcting anemia in patients
via induction of erythropoietin production by the with CKD in 2 different phase II trials (49). One study
kidney (46). Increased angiotensin II levels are clearly comprised 87 patients undergoing dialysis who
not desirable in an HF population and thus far, no received different doses of roxadustat or placebo, and
studies in HF have been conducted. the other study included 91 patients who were not yet
dialysis-dependent who continued with epoetin alfa
HYPOXIA-INDUCIBLE FACTOR STABILIZERS. The or switched to different doses of roxadustat.
final and most promising drugs are the hypoxia- Although only oral iron supplementation was
inducible factor (HIF) stabilizers. HIF is the master allowed, iron indices remained stable or increased,
regulator of the cellular response to hypoxia (47). It is and reduced hepcidin levels were observed in both
rapidly degraded in the presence of oxygen, but in studies. However, caution is warranted: because HIF
low oxygen conditions, it induces transcription of stabilizers affect many biological pathways (including
>60 genes (including erythropoietin and vascular fatty acid and glucose metabolism, as well as
JACC: HEART FAILURE VOL. -, NO. -, 2017 Grote Beverborg et al. 7
- 2017:-–- Anemia in Heart Failure

angiogenesis), such ancillary properties may have addressed, there is no evidence for the clinical benefit
unknown side effects, and there is fear of serious of increasing Hb levels as such. ESA therapy has
adverse events such as promotion of tumor growth. shown neutral results on rates of death and HF
Future studies are needed to address safety and rehospitalization and leads to more ischemic strokes,
efficacy. which outweigh their marginal effect on symptom
improvement. Intravenous iron therapy looks prom-
CONCLUSIONS
ising for iron-deficiency anemia, but its benefit is
partly independent from Hb levels, and data on hard
Anemia in patients with HF is still relevant even
clinical endpoints are not yet available.
though the therapies studied thus far have not shown
positive clinical results. It is present in approximately ACKNOWLEDGMENT The authors acknowledge M.A.
one-third of patients with HF, and these patients Kooij, BSc, for assistance with the illustrations.
have a worse prognosis and poor quality of life.
Anemia may indicate several underlying conditions, ADDRESS FOR CORRESPONDENCE: Dr. Peter van
such as nutritional deficiencies, renal disease, and der Meer, Department of Cardiology, University
volume overload, although in the latter case, this Medical Center Groningen, Hanzeplein 1, PO Box
condition is called pseudo-anemia. Despite the 30.001, 9700 RB Groningen, the Netherlands.
consensus that underlying disorders should be E-mail: p.van.der.meer@umcg.nl.

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