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29967232: Anemia and Iron Deficiency in Heart Failure Current Concepts and Emerging Therapies PDF
29967232: Anemia and Iron Deficiency in Heart Failure Current Concepts and Emerging Therapies PDF
IN DEPTH
Anemia and Iron Deficiency in Heart
Failure
Current Concepts and Emerging Therapies
ABSTRACT: Anemia and iron deficiency are important and common Inder S. Anand, MD, DPhil
comorbidities that often coexist in patients with heart failure. Both (Oxon)
conditions, together or independently, are associated with poor clinical Pankaj Gupta, MD
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status and worse outcomes. Whether anemia and iron deficiency are
just markers of heart failure severity or whether they mediate heart
failure progression and outcomes and therefore should be treated is not
entirely clear. Treatment of anemia in patients with heart failure with
erythropoiesis-stimulating agents has been evaluated intensively during
the past several years. Unfortunately, these agents did not improve
outcomes but were associated with a higher risk of adverse events. Iron
deficiency in patients with heart failure can be absolute, when total
body iron is decreased, or functional, when total body iron is normal
or increased but is inadequate to meet the needs of target tissues
because of sequestration in the storage pool. Whereas iron replacement
is appropriate in patients with anemia resulting from absolute iron
deficiency, it has been unclear whether and how absolute or functional
iron deficiency should be treated in nonanemic patients with heart failure.
Recently, small studies found that administration of intravenous iron in
patients with heart failure and absolute or functional iron deficiency with
or without anemia improves symptoms and exercise capacity, but long-
term outcomes and safety data are not yet available. In this review, we
discuss the causes and pathogenesis of and treatment options for anemia
and iron deficiency in patients with heart failure.
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R
emarkable advances in our understanding of the mation/CKD, or unexplained anemia of the elderly (a
pathogenesis of heart failure (HF) have led to ra- hypoproliferative anemia with blunted erythropoietin
data from recent trials suggest that treating ID itself may ease, which could reduce erythropoietin production,
be of benefit, significant knowledge gaps exist in our un- is infrequent. However, an imbalance between oxygen
derstanding of when, how, and for how long anemia or supply and demand related to increased proximal tubu-
ID should be treated in HF and the mechanisms underly- lar sodium reabsorption caused by low renal blood flow
ing the observed effects of treatment. In this review, we and glomerular filtration rate17,18 reduces renal Po2, ac-
describe the magnitude of the problem of anemia and tivates hypoxia-inducible factor-1α and induces eryth-
ID in patients with HF, discuss their impact on long-term ropoietin gene transcription. Therefore, erythropoietin
outcomes, and examine whether and how they should levels are increased in proportion to HF severity but are
be managed in light of recent clinical trial data. lower than expected for the degree of anemia, suggest-
ing blunted erythropoietin production.12,19 However,
the relationship between renal blood flow and eryth-
PREVALENCE OF ANEMIA IN HF ropoietin secretion during HF is complex and not fully
understood.20
The prevalence of anemia in patients with HF (defined
Inflammation is an important component of HF. Tu-
as hemoglobin <13 g/dL in men and <12 g/dL in wom-
mor necrosis factor-α, interleukin-6 and several other
en)6 is ≈30% in stable and ≈50% in hospitalized pa-
proinflammatory cytokines,12,21 and C-reactive protein
tients, regardless of whether patients have HFrEF or HF
are increased in HF11 and inversely related to hemoglo-
with preserved ejection fraction, compared with <10%
bin level.13 Interleukin-6 and tumor necrosis factor-α
in the general population (although prevalence in-
also inhibit renal erythropoietin production by activat-
creases with age, exceeding 20% in subjects ≥85 years ing transcription factors GATA binding protein 2 (which
old).3,7–10 Compared with nonanemic patients with HF, binds nucleotide consensus sequence GATA in target
anemic patients are older and more likely to be female gene promoters) and nuclear factor κ light-chain en-
and to have diabetes, chronic kidney disease (CKD), se- hancer of activated B cells and may explain the blunted
vere HF with worse functional status, lower exercise ca- erythropoietin response. These cytokines also inhibit
pacity, worse health-related quality of life (QoL), greater bone marrow erythroid progenitor cell proliferation.
edema, lower blood pressure, greater requirement of However, in some patients with HF, erythropoietin levels
diuretics, and higher neurohormonal and proinflamma- are excessively elevated, and high erythropoietin levels
tory cytokine activation.3,9,11–13 However, anemic sub- are associated with worse outcomes.19
jects have a better left ventricular (LV) ejection fraction The renin-angiotensin system plays an important
(LVEF): Hemoglobin is inversely related to LVEF,8,11,14 and role in erythropoietin pathophysiology through multiple
an increase in hemoglobin over time is associated with pathways. First, angiotensin II decreases Po2 by reduc-
a decrease, not an increase, in LVEF.11,15 ing renal blood flow and increasing oxygen demand
and thereby stimulates erythropoietin production. An-
giotensin II also directly stimulates bone marrow ery-
CAUSES OF ANEMIA IN HF throid progenitor cell production. Therefore, angio-
In the general elderly population, anemia is caused by tensin-converting inhibitors and angiotensin receptor
nutritional deficiencies (primarily iron), chronic inflam- blockers cause a modest reduction in hemoglobin11 by
Figure 1. Potential mechanisms involved in the pathogenesis of anemia in heart failure (HF).
Multiple, interrelated mechanisms contribute in various degrees to the development of anemia in HF. Of these, functional or absolute iron deficiency, erythropoi-
etin synthesis and response, and the effects of various medications may represent the most important factors. ACE-I indicates angiotensin-converting enzyme
inhibitor; AcSDKP, N-acetyl-seryl-aspartyl-lysyl-proline; ARB, angiotensin receptor blocker; GFR, glomerular filtration rate; HIF-1α, hypoxia-inducible factor-1α; IFN-γ,
interferon-γ; IL, interleukin; and TNF-α, tumor necrosis factor-α.
decreasing production of erythropoietin22 and erythroid matopoiesis results in an increase in inflammatory cyto-
progenitors and by preventing breakdown of the hema- kines, including interleukin-1β and -6, and is associated
topoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline.23 with an increased incidence of coronary heart disease
Finally, anemia might be related to hemodilution,20 al- in humans and with worsening of cardiac remodeling
though clinically euvolemic patients have normal plas- in mice.26,27 Future studies may further elucidate such
ma volume,24 and measurement of hemoglobin reflects mechanistic interactions between the hematopoietic
“true anemia” as assessed by RBC volume in the vast and cardiovascular systems.
majority of anemic patients with HF.14
Opasich and colleagues12 identified a specific cause
of anemia in only 43% of 148 patients with stable HF. PATHOPHYSIOLOGICAL
ID was seen in only 5% of patients. In the remaining
57% of patients, proinflammatory cytokine activation,
CONSEQUENCES OF ANEMIA
inadequate erythropoietin production, or defective iron In patients with very severe anemia (hemoglobin, 4–6
utilization was found despite adequate iron stores, in- g/dL)28,29 and normal LV function, usually seen with
dicative of anemia of chronic disease (functional ID). helminthic infections in developing countries, reduced
Therefore, an activated proinflammatory state and ane- oxygen-carrying capacity evokes nonhemodynamic and
mia of chronic disease25 could be the most frequent hemodynamic compensatory mechanisms (reviewed
underlying cause of anemia in HF. Recent reports show previously3). There is an increase in RBC 2,3-diphospho-
that mutation (eg, clonal hematopoiesis of indetermi- glycerate that displaces the hemoglobin-oxygen dis-
nate potential) or deficiency of genes that regulate he- sociation curve to the right, increasing tissue oxygen
delivery. A low number of circulating RBCs reduces sys- with HF, anemia doubled the relative risk of death.37 A
temic vascular resistance28 by decreasing whole-blood similar relationship was observed in patients with new-
echocardiographic studies have not been reported in outcomes in these patients. Reduced oxygen delivery
patients with HFrEF before and after treating anemia. to metabolizing tissues in anemic subjects triggers a
However, when hemoglobin was increased from 8.5 to host of hemodynamic, neurohormonal, and renal al-
10 to 14 g/dL with erythropoietin in patients with CKD terations,28 leading to increased myocardial workload,
and moderate anemia, cardiac output (7.0 to 6.6 to which could cause adverse LV remodeling and LV hy-
5.2 L/min) and LV fractional shortening (36% to 33% pertrophy.40,41 Moreover, patients with HF and anemia
to 29%) decreased progressively, proportional to the have several comorbidities, including CKD, cardiac ca-
increase in hemoglobin.15 Therefore, all this evidence chexia-associated poor nutritional status, and low albu-
implies that increasing hemoglobin in patients with min,8,11,39 all of which could worsen outcomes. Finally,
HFrEF would increase systemic vascular resistance, raise the neurohormonal and proinflammatory cytokine acti-
the LV afterload, and cause the LVEF to decrease. This vation seen in patients with HF may have diverse delete-
sequence of events could explain the observed inverse rious consequences.13,21,28
relationship of hemoglobin with LVEF8,9,12 and the find-
ings that an increase in hemoglobin over time is associ-
ated with a decrease in LVEF.9,13 These findings might
TREATMENT OPTIONS
also explain why correction of anemia in patients with Should Anemia in Patients With HF Be
HFrEF has not improved outcomes. Treated?
Most of the aforementioned observational studies sug-
ASSOCIATION OF ANEMIA WITH gest that anemia is common in patients with HF and
is associated with poor clinical status and worse prog-
OUTCOMES nosis. It is therefore reasonable to consider whether
Anemia is independently associated with increased treatment of anemia might improve outcomes. Unfor-
mortality and hospitalizations in patients with both tunately, few options are available to increase hemo-
HFrEF and HF with preserved ejection fraction.3,7,8,31 The globin.
association of hemoglobin level with mortality is not Whereas packed RBC transfusion can be used as a
linear, and most of the increased risk occurs at low he- short-term therapy, transfusions are associated with
moglobin.3,32,33 Some studies have reported a J-shaped many risks and provide only temporary benefit. Kao
relationship between hemoglobin and mortality in the and colleagues42 examined the large public discharge
normal population34 and patients with coronary artery database on 596 456 patients admitted for HF. Anemia
disease,35 acute coronary syndromes,36 and HF.31,33 The was present in 27% of patients with HF. Whereas un-
lowest mortality risk was observed in the hemoglobin treated anemia was associated with ≈10% increased
range of 13 to 16 g/dL, and the risk increased with he- adjusted risk of mortality, the adjusted risk of mortal-
moglobin concentrations below or above this range. ity was ≈70% higher in anemic patients with HF who
Thus, the concern is that excessive increases in hemo- received transfusions. Although these data might raise
globin may be associated with increased mortality. In a serious concerns about the potentially harmful effects
meta-analysis of 33 studies involving >150 000 patients of transfusing patients with HF, there are important
limitations in the analysis of this database. For example, 2.29 mL·kg−1·min−1; P=0.007), New York Heart As-
the severity of anemia and clinical reasons for which a sociation (NYHA) class (−0.73; P<0.001), LVEF (5.8%;
STATE OF THE ART
transfusion was required were not available and ad- P<0.001), BNP (brain natriuretic peptide; −227 pg/mL;
justed for. These and other residual measured and un- P<0.001), and QoL indicators with a mean increase in
measured confounders could have affected the results hemoglobin of 2 g/dL. HF-related hospitalizations were
of the multivariable analysis. Prospective randomized reduced by 44% (P=0.005) with ESA therapy, but the
controlled trials (RCTs) are required to clarify the role reduction in all-cause mortality (42%) was of border-
of packed RBC transfusions in patients with anemia line significance (P=0.047; Figure II in the online-only
and HF. Nevertheless, the TRICS III trial (Transfusion Re- Data Supplement). Adverse effects of ESAs were rare,
quirements in Cardiac Surgery) in moderate- to high- with no significant increase in the development of hy-
risk patients undergoing cardiac surgery recently found pertension (odds ratio, 1.37; 95% confidence interval
that the composite primary outcome of death result- [CI] 0.65–2.87; P=0.41), stroke (odds ratio, 1.70; 95%
ing from any cause, myocardial infarction (MI), stroke, CI, 0.52–5.62; P=0.38), MI (odds ratio, 0.67; 95% CI,
and new-onset renal failure with dialysis occurred in 0.28–1.61; P=0.37), and thromboembolic events (odds
11.4% of those randomized to receive intraoperative ratio, 0.60; 95% CI, 0.17–2.11; P=0.43). In contrast,
or postoperative transfusions for hemoglobin <7.5 g/ use of darbepoetin in patients with moderate to severe
dL compared with 12.5% in the more liberal strategy HFrEF was not associated with any increase in exercise
of transfusions for hemoglobin <9.5 g/dL, indicating capacity in STAMINA-HeFT (Study of Anemia in Heart
that, in such patients, a restrictive transfusion strat- Failure Trial), the largest (n=319) of these small stud-
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or on its individual components. The lack of any effect lar safety of higher hemoglobin with the use of ESAs in
of darbepoetin was consistent across all prespecified patients with CKD. In CREATE, 603 patients (hemoglo-
clinically meaningful improvement in these scores were With that background, TREAT (Trial to Reduce Car-
of questionable importance. It is important to empha- diovascular Events With Aranesp Therapy),49 the largest
size that all patients were iron repleted at baseline. The RCT, was designed to compare darbepoetin with pla-
darbepoetin group received more iron during the study cebo (achieved hemoglobin, 12.5 versus 10.6 g/dL) in
because of greater iron requirement for erythropoiesis. 4038 patients with diabetes mellitus and CKD. Unlike
Neither group became ID during the study. previous trials that compared using ESA to achieve a
In summary, this large pivotal trial failed to confirm high or a low hemoglobin, TREAT tested the more ap-
the results of previous smaller studies that treating mild propriate strategy of comparing an ESA with placebo.
to moderate anemia in patients with HFrEF with ESAs Darbepoetin had a neutral effect on the 2 primary com-
improved clinical outcomes. Although an increase in he- posite outcomes (death or a cardiovascular event; death
moglobin was associated with a modest improvement in or a renal event) but was associated with a doubling of
QoL, this was of questionable importance, particularly the risk of stroke. In a post hoc analysis of the TREAT
because the use of darbepoetin was associated with a trial of 1347 patients (33.4%) with HF at baseline, dar-
significant increase in thromboembolic events. Similar bepoetin also had a neutral effect on all-cause mortality
findings in CKD and cancer populations for cardiovascu- (HR, 1.10; 95% CI, 0.93–1.29) or nonfatal HF events
lar safety have raised concerns about the use of ESAs to (HR, 1.02; 95% CI, 0.87–1.20), similar to the entire co-
increase hemoglobin to relatively higher levels.45 There- hort.50 Therefore, increasing hemoglobin to relatively
fore, a brief examination of the CKD data may be helpful. higher levels in patients with CKD is associated with
either neutral or deleterious effects on cardiovascular
Are There Real Risks of Increasing morbidity and mortality with increases in thrombotic
and stroke risk. Consequently, the current (2017) US
Hemoglobin With ESA Therapy? Food and Drug Administration–approved label for ESAs
In the 1990s, several trials were conducted to assess carries Black Box statements for patients with CKD:
whether complete normalization of hemoglobin with
(a) In controlled trials, patients experienced
ESAs would produce additional benefits in patients with
greater risks for death, serious adverse cardio-
CKD. NHCT (Normal Hematocrit Cardiac Trial) random-
vascular reactions, and stroke when admin-
ized 1223 patients with CKD on hemodialysis to epoe-
istered ESAs to target a hemoglobin level of
tin-alfa to achieve a hematocrit of 45% versus 30%.46
greater than 11 g/dL, (b) No trial has identified
The study was terminated early because of a trend to
a hemoglobin target level, ESA dose, or dosing
increased risk of the composite of death or nonfatal
strategy that does not increase these risks, and
MI and a higher incidence of vascular access thrombo-
(c) Use the lowest ESA dose sufficient to reduce
sis in the normal hematocrit group (39% versus 29%;
the need for RBC transfusions.50a
P=0.001). Two trials published more recently (CREATE
[Cardiovascular Risk Reduction by Early Anemia Treat- Consistent with the aforementioned guidance, Kid-
ment With Epoetin Beta]47 and CHOIR [Correction of ney Disease Outcomes Quality Initiative guidelines rec-
Hemoglobin and Outcomes in Renal Insufficiency]48) ommend interrupting or holding ESAs at a hemoglobin
further raised serious concerns about the cardiovascu- of 11.0 g/dL in patients with CKD.51 The US Food and
Drug Administration and the Kidney Disease: Improving dependent on iron for their function and structural in-
Global Outcomes guidelines6 recommend initiating ESA tegrity.55,56 Iron distribution and metabolism in healthy
STATE OF THE ART
therapy at a hemoglobin cutoff of <10 g/dL in patients individuals are illustrated in Figure 2.
with CKD on dialysis and individualizing ESA initiation
at this level in patients with CKD not on dialysis, al-
though the rationale for initiating ESAs at hemoglobin
Iron Deficiency in HF
<10 g/dL rather than an even lower hemoglobin is not ID is a very common comorbidity in HF regardless of
entirely clear if the only indication is to avoid transfu- sex, race, anemia, and LVEF.57,58 Overall, nearly 50% of
sions. However, in a subgroup analysis of 816 TREAT- patients with HF with or without anemia have low lev-
like patients with CKD and diabetes mellitus in RED-HF els of available iron.59,60 ID can be absolute, when total
with baseline hemoglobin 11.0±0.8 g/dL, the use of body iron is decreased, or functional, when total body
darbepoetin to raise hemoglobin had an overall neutral iron is normal or increased but inadequate to meet the
effect on mortality (HR, 0.89; 95% CI, 0.73–1.09) but needs of target tissues because of sequestration in the
was associated with a 2-fold increase in stroke risk (HR, storage pool (iron maldistribution; Figure 3).
2.07; 95% CI, 0.98–4.38), supporting the US Food and
Drug Administration and Kidney Disease: Improving
Diagnosis of ID
Global Outcomes guidelines on interrupting/holding
ESAs at an upper level of hemoglobin ≥11 g/dL. In the absence of inflammation or chronic disease, se-
The overall consequences of correcting anemia in HF rum ferritin correlates strongly with body iron stores: 1
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with ESAs are a tradeoff between the favorable effects μg/L serum ferritin corresponds to ≈10 mg tissue iron.
of improving oxygen delivery and the putative cardio- Serum ferritin of 100 μg/L thus reflects ≈1 g tissue iron
protective effects of ESAs52 and the unfavorable effects stores. In healthy individuals, ferritin below ≈30 μg/L
of higher hemoglobin on increasing viscosity, vascular and TSAT below ≈16% define ID.64 In inflammatory
resistance, and blood pressure and of ESAs on hyper- states (including HF), however, ferritin is nonspecifically
coagulability.11,28,29 Moreover, the starting, achieved, elevated as an acute-phase reactant, making identifica-
change-in, and rates of rise in hemoglobin and the dose tion of absolute or functional ID complex and uncer-
of ESA may influence the net effect of treatment.53 tain.16,65 Consequently, in patients with HF, ferritin <100
Taken together, data from small, short-term trials μg/L or <300 μg/L if TSAT is <20% has been used to
and meta-analyses of ESA in HF and the pivotal RED-HF include patients with both absolute and functional ID in
trial suggest that correcting anemia with ESAs does not iron replacement trials.
improve outcomes but does increase the risk of throm- Table 1 summarizes tests available to diagnose
boembolic events. The findings do not support the use ID.65,71,72 The soluble transferrin receptor (sTfR) level is
of these agents to increase hemoglobin in patients with increased in ID and is not affected by inflammation.
HFrEF and mild to moderate anemia to higher levels. Among the blood parameters, sTfR or TSAT may have
Therefore, although HF guidelines recommend a diag- the strongest correlation with bone marrow iron deple-
nostic workup to seek and treat correctable causes of tion.69,70 Although not commonly available in clinical
anemia, they provide a Class III (no benefit), Level of practice, sTfR, sTfR:log(ferritin) ratio, or hepcidin levels
Evidence BR recommendation: “In patients with HF and may provide better discrimination of absolute and func-
anemia, ESAs should not be used to improve morbidity tional ID.73 Improving the diagnostic accuracy of tests to
and mortality.”1 identify ID remains an area of active investigation.
variability in measured levels of ferritin and TSAT75 may spectively; P<0.05). TSAT was calculated with the use of
partly explain discrepancies between blood parameters transferrin rather than total iron-binding capacity in the
and bone marrow iron. Recently, Grote Beverborg and denominator (thus, TSAT=iron/transferrin). It is notable
colleagues69 examined bone marrow iron in a relatively that patients with low ferritin (<100 ng/mL) but nor-
small cohort of 42 patients with HFrEF undergoing cor- mal TSAT (>20%) did not have bone marrow ID. In 387
onary artery bypass surgery and found bone marrow patients with HF, TSAT or serum iron (but not ferritin)
ID in 17 patients (40%). The commonly used definition below these cutoffs was independently associated with
of ID (ferritin <100 µg/L or 100–300 µg/L with TSAT higher all-cause mortality (P=0.015 and P=0.022, re-
<20%) had a sensitivity of 82% and a specificity of spectively), underscoring their prognostic significance.
72% for true ID. As single parameters, TSAT ≤19.8% An individual patient data meta-analysis of 4 clinical tri-
and serum iron ≤13 µmol/L (≤72.6 µg/dL) were highly als (n=839) of the effects of intravenous ferric carboxy-
correlated with absolute or functional bone marrow ID maltose (FCM) in patients with HFrEF found that TSAT
(sensitivity, 94% for both; specificity, 84% and 88%, re- ≤19.8% (but not serum iron [interaction P=0.077] or
Figure 3 Continued. hepcidin-induced downregulation of iron transporters such as ferroportin. Other causes include gastrointestinal blood losses related to use of
aspirin, antiplatelet agents, or anticoagulants or important coexisting conditions such as malignancies of the gastrointestinal or genitourinary tract.61–63 Functional
ferritin) identified patients who experienced reduction more relevant for monitoring iron overload rather than
in cardiovascular hospitalizations and mortality (risk re- diagnosis of ID in patients with HF.
duction 0.45 [95% CI, 0.29–0.71] versus 1.55 [95%
CI, 0.69–3.47] for patients with TSAT >19.8%; interac-
tion P=0.009).69 Thus, although the conventional defi-
Pathophysiological Consequences of ID
nition of ID (ferritin <100 µg/L or 100–300 µg/L with Although ID is associated with several clinical conse-
TSAT <20%) performs reasonably well in diagnosing ID quences related to erythropoiesis, chronic ID by itself,
in patients with HF, a single parameter (TSAT ≤19.8% independently of anemia, impairs oxidative metabo-
alone) performed at least as well in detecting true ID lism, cellular energetics, and immune mechanisms that
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and identified subjects who responded to intravenous can cause structural and functional change in the myo-
FCM on retrospective analysis. Ferritin levels may be cardium, decreasing oxygen storage in myoglobin and
Table 1. Laboratory Tests Available for the Diagnosis of ID and Their Sensitivity and Specificity
Hepcidin, ng/mL‖ 67
M: 29–254; N ↓ ↑ 50–92.5 85–90
F: 17–286
CHr indicates reticulocyte hemoglobin content; F, female; ID, iron deficiency; M, male; MCV, mean red cell volume; N, normal; NA, not available; RBC, red blood cells;
RES, reticuloendothelial cell; sTfR, soluble transferrin receptor; TIBC, total iron binding capacity; TSAT, transferrin saturation; and ZPP, red cell zinc protoporphyrin.
*The normal ranges for various parameters may vary in individual laboratories.
†Data from von Haehling and colleagues65 or as otherwise referenced.
‡Grote Beverborg and colleagues69 reported that the sensitivity and specificity (as single parameters) of TSAT were 94% and 84%, respectively, and for serum iron
were 94% and 88%, respectively, for absolute or functional ID, confirmed by bone marrow examination in patients with heart failure undergoing coronary artery
bypass grafting.
§Jankowska and colleagues70 reported that the sensitivity and specificity of sTfR were 67% and 97%, respectively, for ID confirmed by bone marrow examination
in patients with coronary artery disease.
‖These tests may not be routinely available in clinical laboratories.
reducing tissue oxidative capacity, leading to mitochon- dent predictor of mortality in multivariable models that
drial and LV dysfunction.76,77 Myocardial iron stores may included NYHA class and NT-proBNP (HR, 1.42; 95% CI,
STATE OF THE ART
be depleted in HF but correlate poorly with circulating 1.14–1.77; P=0.002),60 underscoring the importance of
markers of iron stores.78 Melenovsky and colleagues55 ID over anemia in predicting outcomes in HF. Similar
found that myocardial iron content in 91 patients with findings were reported in an Asian cohort.57 Adverse
HF was lower than in 38 normal control organ donors effects of ID on exercise capacity in patients with HF
(156±41 versus 200±38 µg/g dry weight, respectively; may therefore be a consequence of the nonhemato-
P<0.001). Reduced myocardial iron correlated with poietic (rather than erythroid) effects of iron on energy
lower activity of citric acid cycle enzymes (aconitase metabolism and myocardial structure and function.76–79
and citrate synthase); diminished reactive oxygen spe- This possibility needs to be examined prospectively.
cies (ROS) protecting enzymes, including catalase, glu-
tathione peroxidase, and superoxide dismutase; and re-
duced mitochondrial oxygen consumption. Myocardial INTRAVENOUS IRON REPLACEMENT
ID in patients with HF might therefore further promote THERAPY IN HF
glucose rather than fatty acid utilization and, coupled
with impaired protection against ROS, contribute to Although the role of ID in HF pathogenesis is only just
myocardial dysfunction and adverse remodeling. That being clarified, investigators have been testing the safe-
severe myocardial ID can cause mitochondrial dysfunc- ty and efficacy of intravenous iron in patients with HFrEF
tion is supported by the observation that isolated car- and ID for >10 years. As of 2017, 8 studies (2 small un-
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diac ID (induced by myocardial transferrin receptor 1 controlled studies and 6 RCTs [3 small and 3 medium-
inactivation) induces mitochondrial respiratory dysfunc- sized trials]) reported the effects of intravenous iron in
tion and fatal cardiomyopathy in mice.79 Iron supple- patients with HFrEF (Table II in the online-only Data Sup-
mentation partly prevented these adverse effects, sug- plement). The primary objective of these studies was
gesting a possible mechanism for the clinical benefit of to investigate the safety and efficacy of intravenous
intravenous iron in patients with HF (discussed below). iron on exercise capacity, NYHA class, and QoL. Clini-
cal events were recorded as safety and secondary out-
comes. Five studies (n=103 patients) used intravenous
Impact of ID on Exercise Capacity, QoL, iron sucrose; 3 studies (n=504) used FCM. Therefore,
and Outcomes the highest level of evidence for the safety and efficacy
Several studies showed that ID in patients with HF is of intravenous iron therapy in patients with HFrEF and
associated with reduced exercise capacity, impaired ID is with FCM. Four meta-analyses of published data
QoL, and poor prognosis independently of anemia and reported the effects of intravenous iron on the second-
LVEF.58,60,80,81 In a prospective study on 443 patients with ary outcomes of HF hospitalizations and mortality.83–86
stable HF and a mean LVEF of 26%, ID (serum ferritin In addition, a robust meta-analysis of intravenous FCM
<100 μg/L or 100–300 μg/L with TSAT <20%) was pres- on mortality and hospitalizations using individual pa-
ent in 35%. Peak Vo2 was significantly lower in those tient data extracted from 4 RCTs, including data from
with ID compared with those without ID (peak Vo2, 2 small previously unreported studies (FER-CARS-01
13.3±4.0 versus 15.3±4.5 mL·min−1·kg−1). In multivari- and EFFICACY-HF [Effect of Ferric Carboxymaltose on
able models, ID was associated with reduced peak Vo2 Exercise Capacity and Cardiac Function in Patients With
independently of demographics and clinical variables, Iron Deficiency and Chronic Heart Failure]), has recently
including anemia.80 been published.87
Several observational studies have shown that the Bolger and colleagues88 first reported an uncon-
presence of ID in patients with HF with and without trolled open-label study of 16 anemic (hemoglobin ≤12
anemia is significantly associated with mortality inde- g/dL) patients with HF given intravenous iron sucrose
pendently of other prognostic factors.57,60,82 In 546 Pol- for 12 to 17 days and followed up for 92±6 days. Iron
ish patients with HF, absolute or functional ID (ferritin treatment increased serum iron, ferritin, TSAT, and he-
<100 µg/L or 100–300 µg/L with TSAT <20%) was pres- moglobin (11.2±0.7–12.6±1.2 g/dL; P=0.0007) and im-
ent in 37% of patients; 57% were anemic and 32% proved NYHA class, Minnesota Living With Heart Failure
were not anemic.82 On multivariable analysis, ID but not Questionnaire score, and 6MWD. In another open-label
anemia was associated with a higher risk of death or study, intravenous iron sucrose treatment in 32 patients
heart transplantation (HR, 1.58; 95% CI, 1.14–2.17; with anemia and ID was associated with favorable ef-
P<0.01). In a pooled international cohort comprising fects on LV remodeling and NYHA functional class.89
1506 patients with HF, anemia, higher NYHA class, The first randomized study was a double-blind,
higher NT-proBNP (N-terminal pro-BNP) levels, lower placebo-controlled trial in 40 anemic patients with
RBC mean corpuscular volume, and female sex predict- HF.90 Twenty control subjects received intravenous sa-
ed ID. ID but not anemia remained a strong indepen- line and 20 received 200 mg intravenous iron sucrose
weekly for 5 weeks. After 6 months, hemoglobin in- compared with placebo, a benefit sustained at 1 year.
creased by a mean of 1.4 g/dL (P<0.01), and there This was associated with significant improvements in
to no treatment for the next 3 months. The iron re- LVEF <45%, BNP >100 pg/mL or NT-proBNP >400 pg/
quirement was higher in patients with anemia than mL, hemoglobin <15 g/dL, and peak Vo2 of 10 to 20
in those without anemia (1051 versus 781 mg). Iron mL·kg−1·min−1 to FCM (n=86) or standard care (n=86,
therapy increased serum ferritin and improved NYHA who could receive oral iron as needed). At 24 weeks,
class, but unlike the previous 2 studies, hemoglobin the primary end point of change in peak Vo2 from
did not increase. Peak Vo2 increased significantly in baseline was no different between the FCM and con-
anemic but not in nonanemic patients. trol groups (∆peak Vo2, −0.16±0.373 mL·min−1·kg−1 in
FAIR-HF (Ferinject Assessment in Patients With Iron those receiving FCM and −0.63±0.375 mL·min−1·kg−1 in
Deficiency and Chronic Heart Failure) is the largest ran- controls; P=0.23) in an analysis in which missing data
domized study reported so far.92 Patients (n=459) with were not imputed. Patients’ global assessment and
HF and ID (ferritin <100 μg/L or 100–300 μg/L with functional (NYHA) class improved on FCM versus stan-
TSAT <20%), with anemia (hemoglobin 9.5–12.0 g/dL) dard of care. Outcomes were not assessed.
or without anemia (hemoglobin 12.0–13.5 g/dL), were The meta-analysis by Anker and colleagues87 explored
randomly assigned 2:1 to intravenous FCM (n=304) or the effects of intravenous iron on objective cardiovas-
saline (n=155). FCM increased ferritin levels in all pa- cular outcomes and was reported before the results of
tients with a modest increase in hemoglobin only in EFFECT-HF were available. The authors examined indi-
anemic patients (0.9 g/dL; P<0.001 versus controls) but vidual patient data extracted from 4 RCTs comparing
not in those without anemia (0.2 g/dL; P=0.21). FCM FCM with placebo in 839 patients with HFrEF and ID,
improved patients’ global assessment and NYHA class 504 randomized to pooled FCM and 335 to pooled pla-
(both P<0.001), the coprimary end point. The benefi- cebo groups. Approximately 90% of the patients were
cial effect of iron was similar in patients with and with- contributed by FAIR-HF and CONFIRM-HF. Patients in
out baseline anemia. QoL and 6MWD also improved. the 4 RTCs had very similar baseline characteristics; the
However, there were no significant effects on all-cause same criteria were used to diagnose ID; and the same
mortality (3.4% versus 5.5%, FCM versus control) or intravenous iron therapy (FCM) was tested. Therefore,
first hospitalization (17.7% versus 24.8%). FCM was this meta-analysis provides a more accurate and robust
generally well tolerated. Adverse events were similar in assessment of the relative effects of FCM on hard clini-
both groups. cal outcomes compared with other recently performed
The design of CONFIRM-HF (A Study to Compare meta-analyses that used different criteria for diagnos-
the Use of Ferric Carboxymaltose With Placebo in Pa- ing ID, used different intravenous preparations, and in-
tients With Chronic Heart Failure and Iron Deficiency)95 cluded patients prescribed ESAs.83–86 The main finding
was very similar to that of FAIR-HF except for higher of the Anker et al87 meta-analysis is that FCM treatment
doses of FCM given for a longer duration (52 weeks). is associated with lower rates of recurrent cardiovas-
Patients (n=304) with LVEF ≤45%, elevated natriuretic cular hospitalizations and cardiovascular mortality (rate
peptides, and ID (ferritin <100 µg/L or 100–300 µg/L if ratio, 0.59; 95% CI, 0.40–0.88; P=0.009), recurrent HF
TSAT <20%) were randomized 1:1 to intravenous FCM hospitalizations and cardiovascular mortality (rate ratio,
(n=152) or placebo (saline; n=152). FCM significantly 0.53; 95% CI, 0.33–0.86; P=0.011), and recurrent car-
improved the primary end point of 6MWD at week 24 diovascular hospitalizations and all-cause mortality (rate
Table 2. Intravenous Iron Preparations Available for Clinical Use in the United States and Europe
STATE OF THE ART
Evaluated
Iron Maximal Single Dose in in Heart
Preparation Adults* Administration in Adults* Indications* Most Common Adverse Effects Failure†
Ferric 750 mg. Slow intravenous push at 100 Treatment of ID anemia in Nausea, hypertension, Yes
carboxymaltose Can be repeated at least 7 d mg/min or diluted in normal adult patients who have flushing, hypophosphatemia, and
later for a maximal total dose saline and infused over at intolerance to oral iron or dizziness.
of 1500 mg per course. least 15 min. have had unsatisfactory
Warnings: hypersensitivity
Courses can be repeated if response to oral iron reactions, hypertension.
ID recurs. or those who have
non–dialysis-dependent
chronic kidney disease.
Iron sucrose 100–400 mg, depending Slow intravenous injection of Treatment of ID anemia Diarrhea, nausea, vomiting, Yes
on clinical setting. Limited 100–200 mg over 2–5 min. in patients with chronic headache, dizziness, hypotension,
experience with 500 mg. Infusion schedules vary kidney disease. pruritus, pain in extremity,
Doses can be repeated at depending on dose and arthralgia, back pain, muscle
various intervals, depending setting. cramp, injection site reactions,
on setting. chest pain, and peripheral edema.
Courses can be repeated if Warnings: hypersensitivity
ID recurs. reactions, hypotension, iron
overload.
Sodium ferric 125 mg (adults). Adults: slow intravenous Treatment of ID anemia Nausea, vomiting and/or diarrhea, No
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gluconate 1.5 mg/kg (pediatric injection at 12.5 mg/min or in adult patients and injection site reaction, hypotension,
patients). diluted in normal saline and in pediatric patients ≥6 cramps, hypertension, dizziness,
infused over 1 h per dialysis. y of age with chronic dyspnea, chest pain, leg cramps
Pediatric patients: dose kidney disease receiving and pain. In patients 6–15 y of
diluted in normal saline and hemodialysis who are age: hypotension, headache,
infused over 1 h per dialysis. receiving supplemental hypertension, tachycardia, and
erythropoietin therapy. vomiting.
Warnings: hypersensitivity,
hypotension, iron overload, benzyl
alcohol toxicity.
Ferumoxytol 510 mg. Diluted in normal saline or Treatment of ID anemia Diarrhea, nausea, dizziness, No
Second 510-mg dose 3–8 5% dextrose and infused in adults with chronic hypotension, and constipation.
d later. over at least 15 min. kidney disease. Black Box warning: fatal and
serious hypersensitivity reactions,
including anaphylaxis.
Iron dextran 100 mg daily. Slow intravenous injection Treatment of ID anemia Most common side effects not No
Total dose calculated on the not to exceed 50 mg/min. when oral administration separately listed in the label.
basis of body iron deficit. is unsatisfactory or Black Box warning: fatal and
impossible. serious hypersensitivity reactions,
including anaphylaxis.
Iron 20 mg iron/kg. Intravenous injection not Treatment of ID when Nausea, injection site reactions. No
isomaltoside‡ Cumulative dose based on to exceed 250 mg iron/ oral iron preparations Special warnings and precautions:
Ganzoni formula. min; dose ≤500 mg 3 times are ineffective or cannot
hypersensitivity reactions
a week; diluted in normal be used or when there is
including serious and potentially
saline. a clinical need to deliver
fatal anaphylactic/anaphylactoid
Intravenous infusion: diluted iron rapidly.
reactions.
in normal saline and infused Not recommended for
Administer with caution/avoid in
over 15 min (dose ≤1000 mg) age <18 y.
patients with liver dysfunction or
or 30 min (dose >1000 mg).
acute/chronic infection.
Hypotension if infused too rapidly.
Injection site irritation or
discoloration with leakage.
Figure 4. Subgroup analyses for outcomes by baseline tertiles of hemoglobin, serum ferritin, and transferrin saturation (TSAT).
Subgroup analyses for (A) recurrent cardiovascular hospitalizations and cardiovascular mortality, (B) recurrent heart failure hospitalizations and cardiovascular mor-
tality, and (C) recurrent cardiovascular hospitalizations and all-cause mortality from the individual patient data meta-analysis of 4 studies examining the effects of
FCM in iron-deficient patients with heart failure. CI indicates confidence interval; and FCM, ferric carboxymaltose. Reproduced from Anker et al87 with permission
of the publisher. Copyright © 2018, John Wiley & Sons.
ratio, 0.60; 95% CI, 0.41–0.88; P=0.009). Intravenous Intravenous Iron Preparations
iron was not associated with increased risk of adverse
Parenteral iron preparations (Table 2) have seen enor-
events. However, a troublesome and hypothesis-gener-
mous development over the past 20 years. At present,
ating finding comes from a prespecified subgroup anal-
5 intravenous iron preparations are available in the
ysis demonstrating a significant interaction between
United States and Europe, of which 2 preparation (iron
baseline tertiles of TSAT and treatment effect on all 3
sucrose and FCM) have been tested prospectively in pa-
composite outcomes. A TSAT-dependent effect of iron
therapy was seen on all 3 composite outcomes, with tients with HF. In addition, iron isomaltoside is available
greatest benefit in the lowest TSAT tertile (<12.7%) but in Europe but not yet in the United States. Both iron
no benefit in subgroups with TSAT of 12.7% to 20.1% isomaltoside and FCM enable higher doses of iron to
and ≥20.1% (Figure 4). be administered to replenish iron stores more rapidly.
Indeed, a trend to adverse effects of intravenous iron
was seen in the highest TSAT tertile. Separately, Grote
Oral Iron Replacement Therapy in HF
Beverborg and colleagues69 reported in their meta-
analysis of this same group of patients that FCM treat- Although oral iron supplementation is convenient, read-
ment was associated with an improvement in cardio- ily available, and inexpensive, oral iron is not absorbed
vascular hospitalizations and cardiovascular mortality in well, particularly in patients with HF because of effects
those with TSAT ≤19.8% but not in those with TSAT of HF on the gastrointestinal tract and elevated hepci-
>19.8%. If confirmed in prospective studies, these find- din, which inhibits iron absorption by reducing trans-
ings would suggest that there may be no clear benefit membrane ferroportin on enterocytes, thereby reduc-
of intravenous iron in patients with only a modest de- ing iron transfer from enterocytes to blood.97 Moreover,
gree of ID. These findings would be of great interest oral iron is associated with adverse effects, particularly
because, as discussed below, there are concerns about gastrointestinal intolerance, that limit compliance. Few
the deleterious effects of overcorrecting ID, particularly studies have investigated the effects of oral iron in pa-
over prolonged periods. tients with ID and HF.98 The results of IRONOUT HF (Iron
Repletion Effects on Oxygen Uptake in Heart Failure), <20%), intravenous iron replacement might be reason-
the largest randomized study to examine the effects of able to improve functional status and QoL.”1
STATE OF THE ART
high-dose oral iron in patients with HF, was published Despite these recommendations, long-term clinical
recently.99 In this phase 2 double-blind RCT, 225 patients studies are still required to confirm the beneficial effects
with NYHA class II to IV HF (median LVEF, 25%), hemo- of intravenous iron on outcomes; to provide additional
globin of 9 to 15 g/dL (men) or 9 to 13.5 g/dL (women), safety data, particularly on the potential adverse effects
and ID (ferritin 15–100 µg/L or 100–299 µg/L with TSAT of iron overload during long-term administration in pa-
<20%) received either oral iron polysaccharide 150 mg tients with HF; and to determine which parameters best
twice daily or placebo. At 16 weeks, there was no sig- reflect iron stores to guide iron supplementation. Sev-
nificant difference between the groups in the primary eral large long-term studies examining cardiovascular
end point of change in peak Vo2 from baseline or in outcomes are ongoing (Table III in the online-only Data
any secondary end point (6MWD, NT-proBNP levels, Supplement). Some ongoing studies directly examining
or Kansas City Cardiomyopathy Questionnaire score), changes in myocardial iron content, gene expression,
although oral iron increased TSAT, ferritin, and hepci- and skeletal muscle metabolism are also likely to pro-
din and reduced sTfR-1 levels. These findings contrast vide critical insights into the pathophysiological role of
with the results from trials of intravenous iron therapy ID in nonerythroid tissues and the clinical effects of its
in similar patient populations.87 Reasons for a lack of repletion in patients with HF. Data from these studies
response to oral iron are not entirely clear. Robust re- are likely to provide valuable information to guide clini-
pletion of iron stores may be required to achieve clini- cal decision making.
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hemosiderosis, leading to multiple joint disorders, walk- studies are likely to provide valuable information to ad-
ing disability, and asthenia in 1 patient and hypophos- dress these concerns and to help guide future clinical
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Circulation. 2018;138:80-98
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Inder Anand, MD, FRCP, D Phil (Oxon.) and Pankaj Gupta, MD, FACP
SUPPLEMENTAL MATERIAL
Supplemental Table 1: Summary of Studies that Tested the Effects of ESAs in Patients
with Anemia and Heart Failure.
Supplemental Table 2: Summary of Studies that Tested the Effects of Intravenous Iron
in Patients with Anemia and Heart Failure.
Supplemental Figure 1: Effect of ESA Therapy on Hb, LVEF, Exercise Capacity and
NYHA Class from the Meta-analysis of Phase II Randomized
Controlled Studies.
Supplemental Figure 2: Effect of ESA Therapy on Hospitalizations for Heart Failure and
All-Cause Mortality from the Meta-analysis of Phase II
Randomized Controlled Studies.
1
Supplemental Table 1: Summary of Studies that Tested the Effects of ESAs in Patients with Anemia and Heart Failure.
Author Study Design Inclusion Patients (n) Follow- Baseline Target Achieved Agents and dose used Outcomes
Criteria up Hb (g/dL) Hb (g/dL) Hb (g/dL)
Duration
Silverberg1 Single center, LVEF <35%, 26 7.2 ± 5.5 10.2 12.0 12.1 S/C epoetin alfa (mean 5,277 ¯NYHA class (3.7±0.5 to 2.7±0.7,
2000 Uncontrolled Hb <12 g/dL Erythropoietin months IU/week) + IV iron sucrose P <0.05),
Open label (mean 185 mg/month) LVEF (28±5% to 35±8%, P
<0.001),
Decrease in diuretic dose
Decrease in hospitalizations
Silverberg2 Single center NYHA III/IV, 16 Usual care 8.2 ± 2.6 10.3 12.5 12.9 S/C epoetin alfa (4,000 IU 1-3 ¯NYHA class, LVEF +5.5%
2001 Randomized LVEF <40% 16 months x week) Decrease in diuretic dose
No placebo Hb 10-11.5 Erythropoietin IV iron sucrose (200 mg/2 x Decrease in hospitalizations
Open-label g/dL weeks)
Mancini4 Single center NYHA II/IV, 9 Control 3.0 11.0 ± 0.6 Hct >45% 14.3 ± 1.2 S/C epoetin alfa 15,000 to Peak VO2 11 ± 0.8 to 12.7 ± 2.8
2003 Single-blind Hct <35%, 17 months 30,000 IU/ week + oral iron mL/kg/min (P <0.05),
Randomized Erythropoietin 325 mg and folate 1 mg daily 6MWD,
Placebo- Improvement in MLWHFQ
control
Palazzuoli5 Randomized, NYHA II/IV 20 Control 3.0 10.4 ± 0.6 NA 12.4 ± 0.8 Erythropoietin beta and oral ¯NYHA class,
2006 double-blind, Hb 11g/dL 20 months iron exercise capacity,
placebo- Erythropoietin Peak VO2,
controlled ¯ BNP
Palazzuoli6 Single center NYHA III/IV, 25 Control 12 10.4 ± 0.6 NA 12.4 ± 0.8 Erythropoietin beta 6,000 IU LVEF,
2007 Randomized LVEF <40% 26 months S/C 2 x week + oral iron 300 ¯LV volumes, mass,
Double-blind Hb 9.0-12.0 Erythropoietin mg for 1 year ¯PAP and BNP,
Placebo- g/dL beta No change in serum Cr.
control Serum Cr 1.5-
3.0 mg/dL
Ponikowski7 Multi-center Hb 9.0-12.0 22 Placebo, 27 weeks 11.8 ± 0.2 13.0-15.0 13.9±0.4 Darbepoetin 0.75 µg/kg Q2W Mean change in Peak VO2 (45
2007 Randomized g/dL, 19 + 200-300 mg oral iron if ml/min, P=0.27), or (0.5
Double-blind Peak VO2 <16 Darbepoetin serum ferritin <800 µg/mL ml/kg/min, P = 0.40)
Placebo- ml/kg/min Ex duration 108 sec (P=0.08),
controlled PGA (79% vs. 41%, P = 0.01)
No change in KCCQ/ MLHFQ
No change in BNP or Cr
2
Supplemental Table 1 (continued)
Author Study Inclusion Patient (n) Follow- Baseline Hb Target Achieved Agents and dose used Outcomes
Design Criteria up (g/dL) Hb Hb (g/dL)
Duration (g/dL)
van Multi-center Hb >9.0 and 55 Placebo, 27 weeks 11.5 14 ± 1.0 13.3 Darbepoetin weight adjusted Rate of rise Hb 1.87 vs 1.64 g/dL
Veldhuisen8 Randomized <12.5 g/dL, 56 0.75 µg/kg vs fixed dose 50 µg in weight-based vs fixed dose
2007 Double-blind NYHA class Darbepoetin vs placebo Q2W + oral iron (P=0.07), Improvement in KCCQ
Placebo- II/III; CHF, (Wt. based), (200 mg daily if serum ferritin (P<0.03), no significant
controlled LVEF <40% and 54 <800 µg/L improvement in 6MWD (P=
Darbepoetin 0.074), PGA (P = 0.057), NYHA
(Fixed dose) class, LVEF or MLWHFQ score
Parissis9 Randomized Hb <12.5 g/dL 11 Placebo, 12 weeks Placebo NA Placebo Darbepoetin weight adjusted ¯NYHA class, (P = 0.001) vs
2008 single-blind NYHA class 21 11.4, 11.8, 1.5 µg/kg every 20 days + oral placebo
Placebo- II/III Darbepoetin Darbepoetin Darbepoetin iron vs placebo + oral iron 6 MWD (P <0.001) vs placebo
controlled LVEF <40% 11.0 12.8 LVEF (P <0.001) vs placebo
Cr <2.5 mg/dL
Kourea10 Randomized Hb <12.5 g/dL 20 Placebo, 12 weeks Placebo NA Placebo Darbepoetin weight adjusted 6 MWD (P <0.001) vs placebo
2008 single-blind NYHA class 21 11.4, 11.7, 1.5 µg/kg every 20 days + oral LVEF (P <0.003) vs placebo
Placebo- II/III Darbepoetin Darbepoetin Darbepoetin iron vs placebo + oral iron KCCQ (P <0.04) vs placebo
controlled LVEF <40% 10.9 12.8
Cr <2.5 mg/dL
Ghali 200811 Multi-center Hb >9.0 and 157 Placebo, 27 weeks 11.4 14 ± 1.0 13.4 at 27 Darbepoetin dose 0.75 µg/kg No significant difference in
STAMINA- Randomized <12.5 g/dL, 162 for weeks, 13.4 Q2W vs placebo + oral iron exercise duration, NYHA class or
HeFT Double-blind NYHA class Darbepoetin efficacy, at 53 weeks (200 mg daily if serum ferritin QoL scores at 27 weeks but trend
Placebo- II/IV; CHF, 55 weeks <800 µg/L to a decrease in the combined
controlled LVEF <40%, for safety endpoint of death and
hospitalization for HF
Abraham12 Combined Hb >9.0 and 209 Placebo, 55 weeks 11.4 ± 0.8 14 ± 1.0 13.4 Darbepoetin dose 0.75 µg/kg Trend to a decrease in the
2010* safety <12.5 g/dL, 266 or 50 µg vs placebo Q2W + combined endpoint of death and
analysis of NYHA class Darbepoetin oral iron (200 mg daily if hospitalization for HF for
van II/III; CHF, serum ferritin <800 µg/L darbepoetin vs placebo (HR, 0.67;
Veldhuisen8 LVEF <40% 95% CI, 0.44, 1.03; P = 0.06)
and Ghali
200811
3
Supplemental Table 1 (continued)
Author Study Inclusion Patient (n) Follow- Baseline Hb Target Achieved Hb Agents and dose used Outcomes
Design Criteria up (g/dL) Hb (g/dL)
Duration (g/dL)
Cosyns13 Randomized Hb <12 g/dL, 14 Placebo, 2 months NA NA Control 10.1, Erythropoietin vs control, ¯NYHA class, (P <0.01) vs
2010 Controlled CHF LVEF 14 erythropoietin dose NA control, ¯ LV end-systolic and
<45%, CrCl Erythropoietin 13.1 end-diastolic volumes, mitral
<45 mL/min regurgitation.
LVEF and LV dP/dt (P <0.001)
vs control
Swedberg Multi-center Hb >9.0 and 1142 Placebo, 28 11.2 13.0 Not 13.0 (12.4- Darbepoetin dose 0.75 No effect on primary outcome of
201314 RED- Randomized <12.0 g/dL, 1136 months (10.6-11.6) exceedin 13.4) µg/kg vs placebo Q2W until all-cause deaths or hospitalization
HF Double-blind NYHA class Darbepoetin g 14.5 Hb 13g/dL and then to for HF (HR 1.01; 95% CI, 0.90 to
Placebo- II/III; CHF, maintain Hb at 13 g/dL but 1.13; P = 0.87). No effect on fatal
controlled LVEF <40% exceeding 14.5 g/dL + oral or non-fatal MI, fatal or non-fatal
iron (200 mg daily if serum strokes but 35% excess thrombotic
ferritin <800 µg/L events (P = 0.01)
* Combined safety results on studies described by Veldhuisen (2007)8 and Ghali 200811
6MWD, 6-minute walk distance; BNP, brain natriuretic peptide; Cr, creatinine; EPO, erythropoietin; Hb, hemoglobin; Hct, hematocrit; HF, heart failure; HR,
Hazard ratio
IU, international units; IV, intravenous; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; LVEF, left ventricular ejection fraction;
MLHFQ, Minnesota Living with Heart Failure Questionnaire; NYHA, New York Heart Association; PAP, systolic pulmonary artery pressure; PGA, Patient’s
Global Assessment; Q2W, every 2 weeks
QoL, Quality of life; S/C, subcutaneous; VO2, peak oxygen consumption; Wt., weight.
4
Supplemental Table 2: Summary of Studies that Tested the Effects of Intravenous Iron in Patients with Anemia and Heart Failure.
Author Study Inclusion Criteria Patient (n) Follow-up Baseline Hb Achieved Hb Agents and dose Outcomes
Design Duration (g/dL) (g/dL) used
Bolger15 Prospective NYHA class II – III 17 92 ± 6 11.2 ± 0.7 12.6 ± 1.2 1 g iron sucrose ¯ MLHHQ scores (33±19 to 19±14 (P=
2006 uncontrolled Mean LVEF 26% days IV bolus x 12 0.02)
Hb <12 g/dL days 6MWD (242 ± 78 m, P = 0.02)
Usmanov16 Prospective NYHA class III and IV 32 26 weeks NYHA IV NYHA IV 100 mg iron ¯ in NYHA class III
2008 uncontrolled Hb <11g/dL 9.4 ± 0.6 12 ± 0.8 sucrose IV three No change in NYHA class IV
CKD times/week for 26 in Hb
NYHA III NYHA III weeks Improvement in LV remodeling
10.7 ± 0.4 13.7 ± 0.4
Toblli17 Randomized Hb <12.5 g/dL, 20 Saline 6 months Placebo Placebo 9.8 ± 0.7 200 mg iron in Hb 1.4 g/dL
2007 Double-blind TSAT <20%, 10.2 ± 0.5 sucrose weekly LVEF 36 ± 4.7 vs. 29 ± 2.4 (P <0.01)
Placebo- Ferritin <100 µg/L, 20 IV iron IV iron sucrose for 5 weeks ¯ NT-proBNP 118±87 vs. 451±249
controlled CrCl <90 ml/min, sucrose IV iron sucrose 11.8 ± 0.7 pg/mL, P <0.01)
LVEF <35% 10.3 ± 0.6 ¯ CRP (2.3±0.8 vs. 6.5±3.7 mg/L, P
<0.01)
6MWD (P <0.01)
¯ MLHFQ scores (P <0.01)
Okonko Randomized NYHA class II-III, 11 Control 18 weeks Placebo Placebo 200 mg weekly in Peak VO2 (P = 0.009)
200818 Observer- anemic (Hb <12.5 g/dL) 12.2 ± 1.0 12.6 ± 1.2 until ferritin >500 ¯ in NYHA class (P <0.007)
FERRIC- blinded or non-anemic (Hb >12.5 g/dL) 24 IV iron µg/L, 200 mg
HF Placebo- Ferritin <100 µg/L or ferritin sucrose IV iron sucrose IV iron sucrose monthly
controlled 100-300 µg/L with TSAT 12.6 ± 1.2 13.2 ± 1.1 thereafter
<20%
Peak VO2 <18 ml/kg/min
Anker Randomized NYHA class II, LVEF <40% 155 Placebo 24 weeks Placebo Placebo 200 mg weekly PGA improved (P <0.001)
200919 Double-blind NYHA class III, LVEF <45% 11.9 ± 1.4 12.5 ± 1.0 until ferritin >500 KCCQ QoL (P <0.001)
FAIR-HF Placebo- Hb 9.5-13.5 g/dL 304 FCM µg/L, 200 mg EQ-5D Score
controlled Ferritin <100 µg/L or ferritin FCM 11.9 ± 1.3 FCM 13.0 ± 1.0 monthly NYHA class improved
100-300 µg/L with TSAT<20% thereafter 6MWD
Beck-da- Randomized NYHA class II, LVEF <40% 6 Placebo 5 weeks to Placebo ∆ Hb 1.04 in IV Iron sucrose 200 Peak VO2 by 3.5 ml/kg/min in IV
Silva 2013 Double-blind Anemia (Hb 9.0-12.0 g/dL) 3 months 10.9 ± 0.7 iron group; mg/week x 5; group
20
Placebo- Ferritin <500 µg/L and TSAT 10 IV iron ∆ Hb 1.69 in oral Oral ferrous ¯ Peak VO2 by 0.86 in oral iron
IRON-HF controlled <20% sucrose Iron 11.2 ± 10.6 iron group; sulfate 200 mg tid Peak VO2 by 1.86 in placebo
∆ Hb 1.1 in for 8 weeks
7 Oral iron placebo group versus placebo
5
Supplemental Table 2 (continued)
Author Study Inclusion Criteria Patient (n) Follow-up Baseline Hb Achieved Hb Agents and dose Outcomes
Design Duration (g/dL) (g/dL) used
Ponikowski Randomized NYHA class II, LVEF <45% 152 Saline 52 weeks Placebo ∆ Hb at 52 wks. FCM 500-2000 PGA improved (P <0.001)
201521 Double-blind BNP >100 pg/mL, NT-proBNP 12.4 ± 1.3 1.0 (FCM vs mg at baseline KCCQ QoL (P <0.001)
CONFIRM- Placebo- >400 pg/mL, Hb <15 g/dL 152 FCM placebo; P and week 6 then EQ-5D Score
HF controlled Ferritin <100 µg/L or 100-300 FCM 12.37 ± 1.4 <0.001) 500 mg at weeks NYHA class improved
µg/L if TSAT <20% 12, 24, & 36 if ID 6MWD
still present
van Randomized NYHA class II-III, 86 Control 24 weeks Control 13 ± 1.5 Control 13.2 ± 1.4 FCM 500-1000 ∆ in Peak VO2 by -0.16 ml/kg/min in
Veldhuisen controlled LVEF<45% mg at baseline FCM and -0.63 ml/kg/min in control (P
201722 BNP >100 pg/mL, 86 FCM FCM 12.9 ± 1.3 FCM 13.9 ± 1.3 and week 6 based = 0.23) not imputed
EFFECT- NT-proBNP >400 pg/mL, on weight and Hb PGA improved (P <0.05)
HF Hb <15 g/dL then at week 12 if NYHA class improved (P <0.05)
Ferritin <100 µg/L or 100-300 ID still present
µg/L if TSAT <20%,
Peak VO2 10 to 20 ml/kg/min
6MWD, 6-minute walk distance; CrCl, creatinine clearance; CRP, C-reactive protein; Hb, hemoglobin; IV, intravenous; KCCQ, Kansas City Cardiomyopathy
Questionnaire; LVEF, left ventricular ejection fraction; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NT-proBNP, N-terminal brain natriuretic peptide;
NYHA, New York Heart Association;
PGA, Patient’s Global Assessment; TSAT, Transferrin saturation; VO2, peak oxygen consumption.
6
Supplemental Table 3: Recently Completed and Ongoing Trials of Intravenous Iron Supplementation in Patients with
Heart Failure (Registered with ClinicalTrials.gov)
Trial name, Status Study Design Inclusion Criteria Number of Study Intravenous iron Primary Endpoint
ClinicalTrials.gov ID subjects duration preparation used
Pilot RAndomized Controlled Completed Randomized, Acutely decompensated HF 50 12 weeks FCM (1,000 mg) vs Change in 6MWD
Trial of FerrIC placebo- (regardless of LVEF), TSAT placebo from baseline to 4th
CarboxymaltosE in ASIAns controlled, <20%, ferritin <300 µg/L and Hb and 12th week.
With Heart Failure. phase 4 ≤14 g/dL
PRACTICE-ASIA-HF,
NCT01922479
Short-Term Effects & Safety of Completed Single arm, Admitted with HF, NYHA II-IV, 13 4 weeks Sodium ferric gluconate Change in Hb
an Accelerated Intravenous Iron phase 4 LVEF <40%, Hb <12.0 g/dL, 250 mg every 12 hours compared to baseline
Regimen in Patients With Heart ferritin <100 µg/L or 100-299 until iron repletion and at follow-up
Failure, µg/L with TSAT <20%. completed (as determined within 1-4 weeks
NCT01925703 by Ganzoni formula) or after last iron infusion
patient discharge,
whichever comes first.
Iron in Congestive Heart Terminated Randomized, LVEF ≤45%, NYHA II-III, iron 18 subjects 12 weeks FCM vs placebo Change in LVEF by
Failure (iCHF) double-blind, deficiency enrolled cardiac MRI from
Randomized, Double-blind, placebo- baseline to 12 weeks
Placebo-controlled Trial of controlled
Ferric Carboxymaltose Versus
Placebo in Patients With
Congestive Heart Failure.
NCT01837082
Intravenous Iron in Patients Withdrawn Randomized, LVEF <40%, NYHA III, stable 200 (no subjects 12 Treatment: Ferric sucrose Percentage of patients
With Severe Chronic Heart open label, stage 3 chronic kidney disease enrolled) months 200 mg weekly x 4, then with increased LVEF
Failure and Chronic Kidney phase 3 (eGFR 30-59 mL/min/1.73 m2), every other week until Hb at 12 months
Disease, Hb <12 g/dL, ferritin <100 µg/L = 12 g/dL, then 100 mg
NCT00384657 or ferritin 100-299 µg/L and every 2-4 weeks to
TSAT <20% maintain Hb and ferritin ≤
500 µg/L. Iron held for
ferritin > 500 µg/L.
Control: Conventional HF
treatment.
7
Supplemental Table 3 (continued)
Trial name, ClinicalTrials.gov Status Study Design Inclusion Criteria Number of Study Intravenous iron Primary Endpoint
ID subjects duration preparation used
A Randomized, Double-Blind Recruiting Randomized, Acute HF randomized before 1,100 12 FCM (first dose prior to HF hospitalizations
Placebo Controlled Trial double-blind, discharge from hospital, ferritin months discharge, subsequent and CV death
Comparing the Effect of placebo <100 µg/L or ferritin 100- 299 doses as outpatient, based (composite endpoint)
Intravenous Ferric controlled, µg/L with TSAT <20%, prior on weight and Hb) vs
Carboxymaltose on phase 4 LVEF <50% placebo
Hospitalizations and Mortality
in Iron Deficient Patients
Admitted for Acute Heart
Failure.
AFFIRM-AHF,
NCT02937454
Intravenous Iron in Patients Recruiting Randomized, HF, confirmed iron deficiency, 1,200 12 FCM (1,000 mg, then 500- HF hospitalizations
With Systolic Heart Failure and double-blind, Hb 9.5-14.0 g/dL months 1,000 mg within 4 weeks and CV death
Iron Deficiency to Improve placebo [max 2,000 mg total], then (composite endpoint)
Morbidity & Mortality. controlled, 500 mg every 4 months
FAIR-HF2, phase 4 except with Hb >16 g/dL
NCT03036462 or ferritin >800 µg/L) vs
placebo
A Randomized, Double-Blind, Recruiting Randomized, NYHA II-IV, LVEF ≤35% or 3,014 12 FCM (2 doses of 15 mg/kg Rates of death and
Placebo-Controlled Study to double-blind, LVEF ≤25% in prior 2 years, Hb months to a maximum individual hospitalization for
Investigate the Efficacy and placebo >9.0 g/dL and <13.5 g/dL (F) or dose of 750 mg 7 days worsening heart
Safety of Injectafer® (Ferric controlled, <15.0 g/dL (M), ferritin <100 apart and a maximum failure at 1 year, and
Carboxymaltose) as Treatment phase 3 µg/L or 100 - 299 µg/L with combined dose of 1,500 change in 6MWD at 6
for Heart Failure With Iron TSAT <20%, either mg, repeated every 6 months
Deficiency. hospitalization for HF within 12 months as indicated by
HEART-FID, months or elevated natriuretic iron indices) vs placebo
NCT03037931 peptides.
Effectiveness of Intravenous Recruiting Randomized, NYHA II-IV, LVEF <45%, Hb 1,299 At least Iron isomaltoside (doses CV mortality or
Iron Treatment vs Standard single blind, ≥9.0 g/dL and ≤13.0 g/dL (F) or 30 based on weight and Hb) hospitalization for
Care in Patients With Heart phase 4 ≤14.0 g/dL (M), ferritin <100 months vs "usual care" worsening HF
Failure and Iron Deficiency: a µg/L and/or TSAT <20% (with
Randomized, Open-label ferritin ≤400 µg/L), either
Multicenter Trial. hospitalization for HF within 6
IRONMAN, months or elevated natriuretic
NCT02642562 peptides.
8
Supplemental Table 3 (continued)
Trial name, ClinicalTrials.gov Status Study Design Inclusion Criteria Number of Study Intravenous iron Primary Endpoint
ID subjects duration preparation used
Treatment With IV Iron in Not yet Randomized, NYHA III-IV, LVEF <40%, Hb 60 1 month FCM (2 doses) vs Improvements in
Hospitalized Patients With recruiting open label, >10 g/dL, serum iron > 50 "standard of care" NYHA class and QoL
Severe Heart Failure But phase 4 µg/dL, TSAT >20% (KCCQ score)
Without Iron Deficiency,
NCT03042130
Effect of IV Iron (Ferric Recruiting Randomized HF with preserved LVEF 200 12 FCM vs placebo Exercise capacity:
Carboxymaltose, Ferinject) on phase 2 (HFpEF) and diastolic months change in 6MWD
Exercise Tolerance, Symptoms dysfunction, LVEF ≥45%, from baseline to 12
and Quality of Life in Patients NYHA II-III, either HF months
With Heart Failure With hospitalization within 1 year or
Preserved Ejection Fraction elevated natriuretic peptides, Hb
(HFpEF) and Iron Deficiency >9.0 g/dL and ≤14.0 g/dL,
With and Without Anemia. ferritin <100 µg/L or ferritin
FAIR-HFpEF, 100-299 with TSAT <20%,
NCT03074591 6MWD <450 m
Changes in myocardial iron Recruiting Randomized, NYHA II-III, LVEF <50%, Hb 50 30 days FCM (1000 mg) vs Change in myocardial
after iron administration. triple-blind, <15.0 g/dL, ferritin <100 µg/L or placebo iron content at 7 and
MYOCARDIAL IRON, placebo 100 - 299 µg/L with TSAT 30 days, assessed by
NCT03398681 controlled, <20%, elevated natriuretic cardiac T2* and T1-
phase 4 peptides. mapping MRI
Differential Gene Expression in Recruiting Randomized, LVEF ≤40% (NYHA II) or 20 12 weeks FCM vs placebo Change in
Patients With HF and Iron triple-blind, LVEF ≤45% (NYHA III), Hb mitochondrial gene
Deficiency - Effects of FCM. placebo 9.5-13.5 g/dL, ferritin <100 µg/L activation pattern at
NCT01978028 controlled, or 100 - 299 µg/L with TSAT 12 weeks
phase 4 <20%,
FCM to Improve Skeletal Recruiting Randomized, NYHA II-III, LVEF <40% or 32 4 weeks FCM (750 mg) vs placebo Change in skeletal
Muscle Metabolism in HF double-blind, LVEF ≥40% with left atrial muscle mitochondrial
Patients With Functional Iron placebo enlargement or LV hypertrophy, oxidative capacity at
Deficiency. controlled, Hb >13 g/dL (M) and >12 g/dL 4 weeks:
NCT03218384 phase 2 (F) post-exercise
phosphocreatine
recovery time
measured non-
invasively with 31P-
magnetic resonance
spectroscopy.
6MWD, 6-minute walk distance; F, females; FCM, ferric carboxymaltose; HF, heart failure; LVEF, left ventricular ejection fraction; M, males; MRI,
magnetic resonance imaging; TSAT, transferrin saturation.
9
Supplemental Figure 1: Effect of ESA Therapy on Hemoglobin, Left Ventricular Ejection
Fraction, Exercise Capacity and NYHA Class from the Meta-analysis of Phase 2
Randomized Controlled Studies.
A meta-analysis of 11 small phase 2 randomized controlled studies comprising 657 patients showed that treatment
of anemia with ESA improved (A) hemoglobin level, (B) left ventricular ejection fraction, (C) exercise capacity
and (D) NYHA class. Weighted mean differences are shown on a logarithmic scale; the size of each square is
proportional to the weight of the individual study, and the diamond represents the pooled difference using a
random effects model. I2 is the percentage of total variation across studies due to heterogeneity.
Figure reproduced from Kotecha D et al. Am Heart J 2011;161:822-831 e8223 with permission from Elsevier.
10
Supplemental Figure 2: Effect of ESA Therapy on Hospitalizations for Heart Failure and
All-Cause Mortality from the Meta-analysis of Phase 2 Randomized Controlled Studies.
Effect of ESA therapy on clinical outcomes including (A) heart failure hospitalizations and (B) all-cause
mortality, from the meta-analysis of 11 small phase 2 randomized controlled studies. Odds ratios are shown on
a logarithmic scale; the size of each square is proportional to the weight of the individual study, and the diamond
represents the pooled difference using a fixed effects model.
Figure reproduced from Kotecha D et al. Am Heart J 2011;161:822-831 e8223 with permission from Elsevier.
11
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