JACC: HEART FAILURE VOL. 6, NO.

3, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

STATE-OF-THE-ART REVIEW

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 increased 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
thromboembolic 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, explains
why investigated therapies might not have led to the desired results, and discusses promising future therapies.
(J Am Coll Cardiol HF 2018;6:201–8) © 2018 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
cause and consequence. However, with the latest re-
sults of large trials targeted at either iron deficiency
or anemia, striking differences were observed in
treatment effect. Therapies aimed at raising hemoglo-
bin (Hb) levels did not seem to be beneficial to date,
whereas treating iron deficiency resulted in substan-
tial clinical benefits, also in HF patients without ane-
mia. This outcome raises several questions: is a low
Hb level a therapeutic target? Is it merely a signal of
disease severity or an underlying comorbidity (e.g.,
renal failure, iron deficiency)? Are we using the right
The strict definition of anemia is an absolute decrease
in red blood cell mass, which can be determined by an
extensive and costly analysis of radiolabeled blood
volume analysis. In clinical practice, however, only
derived parameters such as Hb level and hematocrit
are used. Hb and hematocrit are concentration
dependent, and in volume overloaded HF patients,
hemodilution-induced “pseudo-anemia” is a recur-
rent phenomenon (2). According to the World Health
Organization, anemia occurs at an Hb level <13 g/dl in
men and <12 g/dl in women. This definition has not
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.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2017.08.023

202 Grote Beverborg et al.
Anemia in Heart Failure
ABBREVIATIONS normal renal function, serum erythropoietin
AND ACRONYMS levels rise exponentially in those with Hb
levels <13 and 12 g/dl, respectively (3). In
CKD = chronic kidney disease
patients with HF, studies have reported a
ESA = erythropoiesis-
wide range of anemia prevalence (17% to
stimulating agent
70%), which may be the result of differences
Hb = hemoglobin
in anemia definition, patient demographic
HF = heart failure
characteristics, comorbidities, study type
HIF = hypoxia-inducible factor
(registry vs. trial), and HF severity (4–6).
LVEF = left ventricular ejection
fraction ETIOLOGY AND PATHOPHYSIOLOGY
TSAT = transferrin saturation
VO2 max = maximal oxygen The etiology of anemia in patients with HF is
consumption multifactorial. Patients with concomitant
chronic kidney disease (CKD) or diabetes mellitus,
higher age, and more advanced disease are at the
highest risk of anemia (5,6). HF can cause anemia
through different pathophysiological mechanisms,
and both conditions share several risk factors (Central
Illustration). Patients with HF often have hematinic
deficiencies, especially iron deficiency, which is pre-
sent in approximately one-half of the patients (7–9).
The presence of chronic inflammation in HF is an
important cause of (functional) iron deficiency and of
erythropoietin resistance (10). Inadequate levels of
erythropoietin, conversely, are often seen in patients
with concomitant CKD because the production of
erythropoietin occurs in the kidney (11). In addition,
bone marrow unresponsiveness to erythropoietin due
to intrinsic bone marrow defects further increases the
susceptibility to anemia (12). This action is associated
with excessively elevated erythropoietin levels in
patients with HF and preserved erythropoietin pro-
duction; high erythropoietin levels are associated
with unfavorable outcome in these patients and the
development of HF in the general population (13,14).
In addition, the activated renin-angiotensin-
aldosterone system results in salt and fluid reten-
tion leading to pseudo-anemia (2,11).
Medication prescribed in HF can result in anemia.
Angiotensin-converting enzyme inhibitors inhibit
hematopoietic activity via N-acetyl-seryl-aspartyl-
lysyl-proline, leading to a higher risk of anemia as
observed in the SOLVD (Studies of Left Ventricular
Dysfunction) trial with enalapril (15,16). In addition,
there is evidence that carvedilol might decrease Hb
levels by blocking the b2-adrenergic receptor (17).
CLINICAL CONSEQUENCES
In healthy individuals, oxygen delivery at Hb levels
as low as 5 g/dl are compensated by increases in both
heart rate and stroke volume, mechanisms already
impaired in patients with HF (18). Anemia in HF,
therefore, could lead to decreased oxygen delivery
JACC: HEART FAILURE VOL. 6, NO. 3, 2018
MARCH 2018:201–8
and, subsequently, aggravation of symptoms such as
dyspnea and fatigue, and thus further impair exercise
tolerance and quality of life (19).
In a large meta-analysis with 153,180 patients with
HF, the crude mortality risk of anemia was an odds
ratio of 1.96 (95% confidence interval: 1.74 to 2.21),
and the adjusted hazard ratio was 1.46 (95%
confidence interval: 1.26 to 1.69), with no difference
between patients with a reduced or preserved left
ventricular ejection fraction (LVEF) (4). In 2
observational studies, anemia resolved in 6 months’
time in >40% of outpatients (5,6). These patients
had a prognosis similar to those without anemia,
whereas persistent anemia was associated with the
poorest survival. Iron supplementation and the
erythropoiesis-stimulating agent (ESA) therapy rate
were relatively low (21% and 8%, respectively), and
resolution of anemia was hypothesized to be the ef-
fect of HF treatment for a large part, particularly
better control of fluid status, and thus resolving
pseudo-anemia (5). The combination of anemia, CKD,
and/or iron deficiency in patients with HF often oc-
curs, and is associated with progression of CKD and
HF and unfavorable prognosis (20). However, it is
unclear whether anemia leads to advanced HF and
worse outcome or if anemia is merely a sign of more
advanced disease.
MANAGEMENT OPTIONS
TRANSFUSION THERAPY. In case of severe, symp-
tomatic anemia, blood transfusion with packed red
blood cells is often considered. However, data in pa-
tients with HF are limited. Transfusion therapy has
only temporary benefits and additional risks in pa-
tients with HF such as volume overload and ischemic
events. Two observational studies (n ¼ 596,456 and
n ¼ 4,102) concluded that patients with HF who
received blood transfusions have worse clinical fea-
tures and prognosis, although the smaller study
noted that the transfusion itself seemed to be safe
and even beneficial compared with propensity score–
matched patients with HF who did not receive a blood
transfusion (21,22). Because of the risks of acute he-
molytic reactions, infection, acute lung injury,
allergic reactions, and the lack of evidence to suggest
a liberal transfusion strategy in patients with heart
disease, a restrictive transfusion strategy (trigger
threshold of 7 to 8 g/dl) is recommended by the
American College of Physicians (23).
ERYTHROPOIESIS-STIMULATING AGENTS. Exogenous
erythropoietin is approved for the treatment of ane-
mia as a result of CKD or chemotherapy-induced
anemia. In HF, the effect of anemia treatment with
JACC: HEART FAILURE VOL. 6, NO. 3, 2018 Grote Beverborg et al. 203
MARCH 2018:201–8 Anemia in Heart Failure

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

Grote Beverborg, N. et al. J Am Coll Cardiol HF. 2018;6(3):201–8.

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
(Reduction of Events by Darbepoetin Alfa in Heart
Failure) trial, which, with 2,278 patients, is the largest
study to date (24). In this study, patients with
symptomatic chronic HF (LVEF #40%) and anemia
(Hb level 9.0 to 12.0 g/dl) were randomized to receive
darbepoetin alfa (with a target of 13 to 14.5 g/dl) or
placebo. Co-treatment with oral or intravenous iron
was allowed in both groups. Median Hb levels in the
intervention group increased, but no effect was
observed on the primary composite endpoint of death
or hospitalization for worsening HF or any of the
other endpoints. To the contrary, rates of ischemic
stroke (41 [4.5%] vs. 32 [2.8%]; p ¼ 0.03) and embolic/
thrombotic events (153 [13.5%] vs. 114 [10.0%];
p ¼ 0.009) were increased in those treated with dar-
bepoetin alfa (24,25). This outcome led to further
safety concerns because increased rates of ischemic
stroke and thrombotic events with ESAs were also
observed in patients with CKD and chemotherapy-
induced anemia (26,27). Possible reasons for these
results include the wrong therapy, wrong target
population, or wrong target Hb level.
As noted earlier, the etiology of anemia in HF is
very heterogeneous (7–12,28). Patients with a trans-
ferrin saturation (TSAT) <15% were excluded from
the RED-HF trial, but this method still leaves
patients with iron deficiency with TSAT 15% to 20%
204 Grote Beverborg et al.
Anemia in Heart Failure
and a ferritin level 100 to 300 m g/l or a ferritin
level <100 mg/l included in the trial. In addition, no
other investigations into the cause of anemia were
performed. The presence of pseudo-anemia has been
proposed as a possible reason for the neutral results,
which was also reported in a small study of 28
anemic patients treated with erythropoietin alfa (29).
Because a large portion of patients with HF already
have a disproportionately high erythropoietin level
associated with bone marrow resistance to erythro-
poietin, administering even more erythropoietin to
these patients would be counterintuitive (13). This
approach is supported by data from the RED-HF trial,
which showed that approximately one-quarter of
patients with HF did not exhibit any increase in Hb
level after 4 weeks of ESA treatment, and this unre-
sponsiveness to ESAs is independently associated
with hospitalizations and all-cause mortality (30).
Regarding the Hb target, no data comparing different
targets in patients with HF are available, but data
from trials in CKD indicate that higher Hb targets may
result in worse cardiovascular outcome (27).
IRON THERAPY. Iron therapy was initially adminis-
tered as co-therapy in trials with ESAs, mainly as oral
therapy (24). More recently, the awareness of the high
prevalence of iron deficiency (w70% in the anemic
and w50% of the entire HF population), the clinical
consequences of iron deficiency, and the availability
of new intravenous iron formulations have led to the
design of trials investigating iron therapy without
ESAs. The initial trials were performed in patients
with anemia but later also in patients with iron
deficiency irrespective of the presence of anemia.
Although oral iron has practical advantages over
intravenous iron, its use in HF seems limited because
of therapy compliance issues due to gastrointestinal
side effects and impaired iron uptake. The latter was
also observed in the only randomized placebo-
controlled Phase II study with oral iron, the IRON-
OUT (Oral Iron Repletion Effects On Oxygen Uptake
in Heart Failure) (31). This study included 225 HF
patients with a reduced LVEF and iron deficiency.
Patients received 150 mg of polysaccharide iron
complex or placebo, twice daily for 16 weeks. Only a
marginal increase of 11 mg/l of ferritin and 3% TSAT
with oral iron was observed, with no significant effect
on exercise capacity (measured according to maximal
oxygen consumption [VO 2 max]) or N-terminal pro–B-
type natriuretic peptide level. In exploratory ana-
lyses, changes in TSAT correlated with changes in VO2
max and N-terminal pro–B-type natriuretic peptide
levels. The only patients who responded to oral iron
therapy were those with low hepcidin levels.
JACC: HEART FAILURE VOL. 6, NO. 3, 2018
MARCH 2018:201–8
Hepcidin is the regulator of iron metabolism and is
involved in the pathophysiology of the anemia of
chronic disease. The hormone is upregulated in
inflammation and degrades the iron exporter ferro-
portin, thus blocking iron uptake from the gut and
iron release from macrophages. This process provides
a possible explanation for the neutral results of the
IRONOUT study.
Intravenous iron has been studied in 5 randomized
clinical trials (Table 1) (32–35). All studies included
patients based on their ferritin and TSAT levels; Toblli
et al. (32) and Anker et al. (34) additionally used a
relatively low Hb level as an inclusion criterion (<12.5
and <13.5 g/dl, respectively). Despite differences in
treatment strategies and follow-up, the overall re-
sults of the trials were broadly similar: treatment with
intravenous iron led to improvements in New York
Heart Association functional class, exercise capacity,
and quality of life in a short period of time. In 2 of the
largest trials, FAIR-HF (Ferinject Assessment in
Patients with Iron Deficiency and Chronic Heart
Failure) and CONFIRM-HF (Ferric Carboxymaltose
Evaluation on Performance in Patients With Iron
Deficiency in Combination With Chronic Heart Fail-
ure), significant overall increases in Hb levels were
observed, but the treatment effect was similar
in anemic and nonanemic patients (34,35). The
third study is the EFFECT-HF (Effect of Ferric
Carboxymaltose on Exercise Capacity in Patients
With Iron Deficiency and Chronic Heart Failure), a
randomized controlled trial of intravenous ferric car-
boxymaltose compared with standard of care in 172
iron-deficient patients with HF (36). Primary analysis
showed an increase in VO 2 max in patients treated
with ferric carboxymaltose compared with a control
group that was not treated. In addition, an increase in
the Hb level of 0.74  0.17 g/dl was reported after
24 weeks. However, subgroup analyses of anemic and
nonanemic patients are not yet available.
In summary, although anemia and iron deficiency
exhibit a large overlap, isolated iron deficiency is
prevalent, and the benefits of treating iron deficiency
probably extend beyond hematopoiesis. The effects
of intravenous iron on hard clinical endpoints remain
to be established. Given these results, it is recom-
mended to screen for iron deficiency in all patients
with HF, independent of their Hb level. To diagnose
iron deficiency, the combination of TSAT and ferritin
levels (ferritin <100 m g/l or a ferritin level 100 to
300 mg/l with a TSAT<20%) has most often been used
in large clinical trials. However, this definition has not
been validated, and ferritin levels are often unreliable
because it is an acute-phase reactant. We recently
presented data from a study in which we validated the
JACC: HEART FAILURE VOL. 6, NO. 3, 2018 Grote Beverborg et al. 205
MARCH 2018:201–8 Anemia in Heart Failure

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 VO2 max [
FERRIC-HF, II–III, LVEF #45%, VO2 ferritin 100–300 mg/l weekly till ferritin 16 weeks (p ¼ 0.87) (p ¼ 0.08)
2008 (33) max <18 ml/kg/min, þ TSAT <20% >500 mg/l† VO2 max/kg [
Hb <14.5 g/dl NYHA functional
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, LVEF #40%, ferritin 100–299 mg/l normalized iron 13.0  1 g/dl vs. 12.5  1 class Y
Hb 9.5–13.5 g/dl þ TSAT <20% status‡ g/dl (p < 0.001) at PGA [
24 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 VO2 max [
et al., EFFECT- II–III, LVEF #45%, ferritin 100–300 mg/l baseline and after 6 24 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 g/ iron deficient PGA [
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.

cutoff of TSAT<20% by using the gold standard of bone focus on determining the underlying etiology and
marrow iron staining (37). Ferritin had no diagnostic subsequent treatment, although, often no specific
value. We supported these findings by showing that a cause is found. Special attention is paid to iron defi-
low TSAT, and not a low ferritin level, was associated ciency and its treatment with intravenous ferric car-
with an increased risk of mortality. This finding is in boxymaltose. The use of the ESA darbepoetin-alfa
line with results from the recently published meta- is not recommended by the European Society of
analysis of Anker et al. (38) who found that, using Cardiology (39).
interaction analysis, patients with a TSAT $20.1% do
not respond to iron therapy with improved outcomes, AREAS OF DEVELOPMENT
whereas those in the lower tertiles of TSAT do respond.
Several different strategies are currently being
CURRENT GUIDELINE RECOMMENDATIONS explored for the treatment of anemia in HF. These
strategies are aimed directly at the process of eryth-
The most recent guidelines of the American College of ropoiesis by targeting the erythropoietin receptor or
Cardiology Foundation/American Heart Association hypoxia pathway but also indirectly via the hepcidin
and the European Society of Cardiology both recog- pathway (Figure 1).
nize anemia as an important comorbidity in patients HEPCIDIN. Hepcidin, the master iron regulator, can
with HF (39,40). Management recommendations be antagonized in several ways: 1) decreasing
206 Grote Beverborg et al. JACC: HEART FAILURE VOL. 6, NO. 3, 2018

Anemia in Heart Failure MARCH 2018:201–8

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.

hepcidin production; 2) neutralizing hepcidin; or 3)
preventing hepcidin–ferroportin interaction. Agents
neutralizing hepcidin are the most promising to date.
One phase I study showed that a fully humanized
monoclonal antibody against hepcidin (LY2787106)
was well tolerated and resulted in increases in serum
iron levels and TSAT in patients with cancer and
anemia (41). Another hepcidin-binding agent, the
Spiegelmer lexaptepid (NOX-H94), has been shown to
increase serum iron levels in healthy persons sub-
jected to inflammation by injection of lipopolysac-
charides (42). A small Phase II study found an Hb
increase of $1 g/dl after 4 weeks of treatment with
lexaptepid in 5 of 12 patients with functional iron-
deficiency anemia (30). Currently, the results of
trials investigating the effects of these agents in ESA
hyporesponsive, anemic patients undergoing dialysis
are awaited.
ERYTHROPOIETIN RECEPTOR TARGETING. Drugs
directly targeting erythropoiesis include erythropoi-
etin receptor–targeting drugs (receptor antibodies,
fusion proteins, gene therapy, and mimetic peptides)
and activin receptor ligand traps. Activin traps are
recombinant fusion proteins consisting of the
immunoglobulin G1 Fc domain linked to the extra-
cellular domain of the activin receptor IIA. These bind
a number of transforming growth factor-b superfam-
ily ligands, including activin A and activin B, and
thereby inhibit their signaling. Sotatercept, the most
studied activin trap, was initially studied as an oste-
oporosis agent. Surprisingly, an increase in Hb level,
red blood cell number, and hematocrit were observed
(43). Together with the prevention of vascular calci-
fication shown in a small trial with 43 patients with
end-stage renal disease, this drug might prove bene-
ficial for the elderly CKD population (44). Animal
models point to growth differentiation factor 11 as the
target for these drugs, which is a differentiator in-
hibitor present on erythroid progenitors (45). How-
ever, increased expression of angiotensin II has also
been proposed as one of the possible mechanisms of
increased erythropoiesis by stimulating erythroid
differentiation directly through the AT1 receptor or
JACC: HEART FAILURE VOL. 6, NO. 3, 2018 Grote Beverborg et al. 207
MARCH 2018:201–8 Anemia in Heart Failure

via induction of erythropoietin production by the ancillary properties may have unknown side effects,
kidney (46). Increased angiotensin II levels are clearly and there is fear of serious adverse events such as
not desirable in an HF population and thus far, no promotion of tumor growth. Future studies are needed
studies in HF have been conducted. to address safety and efficacy.

CONCLUSIONS
HYPOXIA-INDUCIBLE FACTOR STABILIZERS. The
final and most promising drugs are the hypoxia-
Anemia in patients with HF is still relevant even
inducible factor (HIF) stabilizers. HIF is the master
though the therapies studied thus far have not shown
regulator of the cellular response to hypoxia (47). It is
positive clinical results. It is present in approximately
rapidly degraded in the presence of oxygen, but in
one-third of patients with HF, and these patients
low oxygen conditions, it induces transcription of
have a worse prognosis and poor quality of life.
>60 genes (including erythropoietin and vascular
Anemia may indicate several underlying conditions,
endothelial growth factor). HIF stabilizers can be
such as nutritional deficiencies, renal disease, and
administered orally and induce physiological eryth-
volume overload, although in the latter case, this
ropoietin levels. Several Phase I and II studies in pa-
condition is called pseudo-anemia. Despite the
tients with CKD have shown promising results with
consensus that underlying disorders should be
increasing levels of Hb and decreasing levels of hep-
addressed, there is no evidence for the clinical benefit
cidin after therapy (48). One of the compounds with
of increasing Hb levels as such. ESA therapy has
the most data available is FG-4592, or roxadustat.
shown neutral results on rates of death and HF
Roxadustat was recently shown to be effective in
rehospitalization and leads to more ischemic strokes,
increasing Hb levels and to be superior compared
which outweigh their marginal effect on symptom
with epoetin alfa in correcting anemia in patients
improvement. Intravenous iron therapy looks prom-
with CKD in 2 different phase II trials (49). One study
ising for iron-deficiency anemia, but its benefit is
comprised 87 patients undergoing dialysis who
partly independent from Hb levels, and data on hard
received different doses of roxadustat or placebo, and
clinical endpoints are not yet available.
the other study included 91 patients who were not yet
dialysis-dependent who continued with epoetin alfa or ACKNOWLEDGMENT The authors acknowledge M.A.
switched to different doses of roxadustat. Although Kooij, BSc, for assistance with the illustrations.
only oral iron supplementation was allowed, iron
indices remained stable or increased, and reduced ADDRESS FOR CORRESPONDENCE: Dr. Peter van
hepcidin levels were observed in both studies. How- der Meer, Department of Cardiology, University
ever, caution is warranted: because HIF stabilizers Medical Center Groningen, Hanzeplein 1, PO Box
affect many biological pathways (including fatty acid 30.001, 9700 RB Groningen, the Netherlands.
and glucose metabolism, as well as angiogenesis), such E-mail: p.van.der.meer@umcg.nl.

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KEY WORDS anemia, erythropoiesis-
stimulating agents, heart failure, iron