University of Groningen
Anemia, erythropoietin and iron in heart failure
Grote Beverborg, Niels
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2
Anemia in heart failure:
still relevant?
Niels Grote Beverborg, Dirk J. van Veldhuisen, Peter van der Meer
ABstrAct
One third of all patients with heart failure have anemia, and its presence is associated with more symptoms, increased rates of hospitalization and mortality. The etiology of anemia is multifactorial, complex and varies between patients. The most important factors leading to anemia in heart failure are inadequate erythropoietin production re-sulting 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 contrary, use of ESAs led to increased rates of thromboembolic events and ischemic stroke. Therefore, the use of ESAs for the treatment of anemia in heart failure cannot be recommended. In addition, these results question whether anemia is a therapeutic target or merely a marker of disease severity. Other therapies are being studied and include agents targeting the erythropoietin receptor, hepcidin pathway or iron availability. This review focuses on the pathophysiology of anemia in heart failure, explanations why investigated therapies might not have led to the desired results and discusses promising future therapies.
INtroductIoN
In patients with heart failure (HF), organ systems receive, in varying degrees, an inad-equate supply of oxygen and nutrients. Together with inflammation and neurohormonal pathway activation, comorbidities such as iron deficiency (50%) and anemia (37%) are highly prevalent.1 Conventionally, iron deficiency and anemia were considered cause
and consequence. However, with the latest results of large trials targeted at either iron deficiency or anemia, striking differences were observed in treatment effect. Therapies aimed at raising hemoglobin (Hb) itself did not seem to be beneficial to date while treating iron deficiency resulted in substantial clinical benefits, also in HF patients without anemia. This raises several questions: is a low Hb 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 management strategies? Or, in short, is anemia in patients with HF still relevant? In this review, we will summarize the literature on anemia in patients with HF.
dIAGNosIs ANd PrevAleNce
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, derived parameters such as Hb and hematocrit are merely used. Hb and hematocrit are concentration dependent, and in volume overloaded HF patients hemodilution induced “pseudo-anemia” is a recurrent phenomenon.2
Accord-ing to the WHO, anemia is present at a Hb of <13g/dl in men and <12g/dl in women. This definition has not been validated, but in the general population with a normal renal function, serum erythropoietin levels rise exponentially in those with hemoglobin levels below 13 and 12 g/dl respectively.3 In patients with HF, studies have reported a wide
range of anemia prevalence (17–70%), which may be the result of differences in anemia definition, patient demographics, comorbidities, study type (registry vs. trial) and HF severity.4-6
etIoloGy ANd PAthoPhysIoloGy
The etiology of anemia in patients with HF is multifactorial. Patients with concomitant chronic kidney disease (CKD) or diabetes mellitus, higher age and more advanced dis-ease are at the highest risk of anemia.5,6 HF can cause anemia through different
Patients with HF often have hematinic deficiencies, especially iron deficiency, which is present in around 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, on the other hand, are often seen in patients with concomitant CKD as the production of erythropoietin takes place in the kidney.11
Additionally, bone marrow unresponsiveness to erythropoietin due to intrinsic bone marrow defects further increases the susceptibility to anemia.12 This is associated with
excessively elevated erythropoietin levels in HF patients with preserved erythropoietin production, and high erythropoietin levels are associated with unfavorable outcome
figure 1 - Anemia in heart failure: common ground, cause or consequence? Anemia and heart failure share several prevalent risk factors. Additionally, heart failure can lead to anemia via a large number of mechanisms, and anemia on its turn can lead to an increased cardiac workload and pos-sibly further deterioration of cardiac function and prognosis. ASA – AcetylSalicylic Acid, ACEi – Antio-tensin Converting Enzyme inhibitor.
in these patients and the development of HF in the general population.13,14 Also the
activated RAAS system results in salt and fluid retention 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 trial with enalapril.15,16 Additionally,
there is evidence that carvedilol might decrease hemoglobin levels by blocking the β-2 adrenergic receptor.17
clINIcAl coNsequeNces
In healthy individuals, oxygen delivery at hemoglobin 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, and subsequently aggravation of symptoms such as dyspnea and fatigue and further impair exercise tolerance and quality of life.19
In a large meta-analysis with 153,180 HF patients the crude mortality risk of anemia was an odds ratio of 1.96 (95% confidence interval: 1.74–2.21), and the adjusted hazard ratio was 1.46 (95% confidence interval: 1.26–1.69), with no difference between patients with a reduced or preserved LVEF.4 In two observational studies, anemia resolved in 6
months’ time in over 40% of outpatients.5,6 These patients had similar prognosis to those
without anemia, while persistent anemia was associated with the poorest survival.5,6 Iron
supplementation and ESA therapy rate were relatively low (21 and 8%, respectively), and resolution of anemia was hypothesized to be the effect 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 is often present, 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, symptomatic anemia, blood transfusion with packed red blood cells is often considered. However, data in patients with HF are limited. Transfusion therapy has only temporary benefits and additional risks in patients with HF such as volume overload and ischemic events. Two observational studies (n=596,456 and n=4,102)
conclude that HF patients who received blood transfusion have worse clinical features and prognosis, although the smaller study notes that the transfusion itself seemed to be safe and even beneficial when compared to propensity score matched HF patients that did not receive blood transfusion.21,22 Because of the risks of acute hemolytic reactions,
infection, acute lung injury, allergic reactions and the lack of evidence to suggest a lib-eral transfusion strategy in patients with heart disease, a restrictive transfusion strategy (trigger threshold of 7–8 g/dl) is recommended by the American College of Physicians.23
erythropoiesis stimulating agents (esAs)
Exogenous erythropoietin is approved for the treatment of anemia as a result of CKD or chemotherapy induced anemia. In HF, the effect of treatment of anemia with ESAs on outcome was examined in the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF), with 2278 patients the largest trial to date.24 In this trial, patients
with symptomatic chronic HF (LVEF≤40%) and anemia (hemoglobin [Hb] 9.0–12.0 g/ dl) were randomized to darbepoetin alfa (with a target of 13–14.5 g/dl) or placebo. Co-treatment with oral or intravenous iron was allowed in both groups. Median Hb levels of 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.24 To the contrary, rates of ischemic stroke (41 [4.5%] vs. 32 [2.8%], p=0.03)
and embolic/thrombotic events (153 [13.5%] vs. 114 [10.0%], p=0.009) were increased in those treated with darbepoetin alfa.24,25 This led to further safety concerns since also
in patients with CKD and chemotherapy-induced anemia, increased rates of ischemic stroke and thrombotic events with ESAs were observed.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 TSAT<15% were excluded from the RED-HF, but this still leaves patients with iron deficiency with TSAT 15-20% and ferritin 100-300 ng/mL or a ferritin <100 ng/mL included in the trial. Additionally, 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 demonstrated in a small study of 28 anemic patients treated with erythropoietin alfa.29 Since a large part of HF patients already have
a disproportionately high erythropoietin level associated with bone marrow resistance to erythropoietin, giving even more erythropoietin to these patients would be coun-terintuitive.13 This is supported by data from the RED-HF, showing that approximately
one quarter of HF patients do not exhibit any increase in Hb after 4 weeks of ESAs and this unresponsiveness 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 is 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 administered as co-therapy in trials with ESAs, mainly as oral therapy.24 More recently, the awareness of the high prevalence of iron deficiency (~70%
in the anemic and ~50% 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 first 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 gastro-intestinal side effects, and impaired iron uptake. The latter was also observed in the only randomized placebo controlled phase-2 study with oral iron, the IRONOUT. This study included 225 HF patients with a reduced LVEF and iron deficiency. Patients received 150 mg polysaccharide iron complex or placebo, twice daily for 16 weeks.31 Only a
marginal increase of 11 ng/mL ferritin and 3 % TSAT with oral iron was observed, with no significant effect on exercise capacity (measured by VO2 max) or NT-pro BNP.31 In
exploratory analyses, changes in TSAT correlated with changes in VO2 max and NT-pro
BNP. The only patients that responded to oral iron were those with low hepcidin levels.31
Hepcidin is the regulator of iron metabolism and involved in the pathophysiology of the anemia of chronic disease. The hormone is upregulated in inflammation and degrades the iron exporter ferroportin, thus blocking iron uptake from the gut and iron release from macrophages. This provides a possible explanation for the neutral results of the IRONOUT study.
Intravenous iron has been studied in 5 randomized clinical trials, see table 1.32-35 All
studies included patients based on their ferritin and TSAT levels, Toblli and Anker addi-tionally used a relatively low Hb level as inclusion criteria, respectively <12.5 and <13.5 g/dl.32,34 Despite differences in treatment strategies and follow-up, the overall results
of the trials were broadly similar: treatment with intravenous iron led to improvements in NYHA class, exercise capacity and quality of life in a short period of time. In two of the largest trials, FAIR-HF and CONFIRM-HF, significant overall increases in Hb were observed, but the treatment effect was similar in anemic and non-anemic patients.34,35
The third study is the EFFECT-HF, a randomized controlled trial of intravenous ferric car-boxymaltose compared to standard of care in a total of 172 iron deficient HF patients. Primary analysis showed an increase in VO2 max in patients treated with ferric
carboxy-maltose when compared to a not treated control group.36 Additionally, an increase of
the hemoglobin level of 0.74 ± 0.17 g/dl was seen after 24 weeks. However, subgroup analyses of anemic and non-anemic patients are not yet available.
table 1 - randomized controlled trials with intravenous iron in patients with heart failure
study N Population
Iron deficiency
definition therapy study period
effect on hemoglobin results Toblli et al 2007(32) 40 Hb <12.5 g/dl, LVEF ≤35 % eGFR <90 ml/ min Ferritin <100 ng/ mL + TSAT <20 % Iron sucrose 200 mg every 5 weeks 26
weeks From 10.3 ± 0.6 at baseline to 11.8 ± 0.7 g/ dl at 6-months (P<0.01) in the intervention group, no significant difference in control group NT-proBNP ↓ CRP ↓ NYHA ↓ LVEF ↑ eGFR ↑ 6MWT ↑ MLHFQ ↑ Okonko et al FERRIC-HF 2008(33)
35* NYHA Class II-III, LVEF ≤45 %, VO2 max <18 ml/kg/min Hb <14.5 g/dl Ferritin <100 ng/mL or ferritin 100 – 300 ng/mL + TSAT <20 % Iron sucrose 200 mg weekly till ferritin > 500 ng/mL § 16 weeks 0.1 (-0.8 – 0.9) g/dl at 16 weeks (P=0.87) VO2 max ↑ (P=0.08) VO2 max/kg ↑ NYHA ↓ PGA ↑ Anker et al FAIR-HF 2009(34)
459* NYHA Class II-III LVEF ≤40 % Hb 9.5 – 13.5 g/dl Ferritin <100 ng/mL or ferritin 100 – 299 ng/mL + TSAT <20 % FCM 200 mg until normalized iron status† 24 weeks FCM vs. Placebo13.0 ± 1 vs. 12.5 ± 1 g/dl (P<0.001) at 24 weeks NYHA ↓ PGA ↑ 6MWT ↑ EQ-5D ↑ KCCQ ↑
Ponikowski et al. CONFIRM-HF 2014(35)
304 NYHA Class II-III, LVEF ≤45 %, Hb <15 g/dl, NTproBNP >400 pg/ml or BNP >100 pg/ml Ferritin <100 ng/mL or ferritin 100 – 300 ng/mL + TSAT <20 % FCM 500 – 2000 mg at baseline and after 6 weeks, subsequently 500mg every 12 weeks if still iron deficient 52
weeks 0.6 ± 0.2 and 1.0 ± 0.2 g/dl after 24 and 52 weeks (both P<0.001) 6MWT ↑ NYHA ↓ PGA ↑ EQ-5D ↑ HF hospitalizations ↓ (not a predefined endpoint) van V eldhuisen et al EFFECT-HF(36)
172 NYHA Class II-III, LVEF ≤45 %, VO2 max 10 – 20 ml/ kg/min, Hb <15 g/dl, NTproBNP >400 pg/ml or BNP >100 pg/ml Ferritin <100 ng/mL or ferritin 100 – 300 ng/mL + TSAT <20 % FCM 500 – 2000 mg at baseline and after 6 and 12 weeks if still iron deficient
24
weeks 0.74 ± 0.17 g/dl after 24 weeks (P<0.0001)
VO2 max ↑ NYHA ↓ PGA ↑
*Two:one 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 = 6-min walking test; BNP = brain natriuretic pep-tide; CONFIRM-HF = Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination With Chronic Heart Failure; CRP = C-reactive protein; EFFECT-HF = Effect of Ferric Carboxy-maltose on Exercise Capacity in Patients With Iron Deficiency and Chronic Heart Failure; eGFR = estimated glomerular filtration rate; EQ-5D = 5-dimension European Quality of Life; FCM = ferric carboxymaltose; Hb = hemoglobin; HF = heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NYHA = New York Heart Association; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PGA = patient global as-sessment; TSAT = transferrin saturation; VO2 max = maximum oxygen uptake per minute.
Summarizing, although anemia and iron deficiency show large overlap, isolated iron de-ficiency is prevalent and the benefits of treating iron dede-ficiency probably extend beyond hematopoiesis. The effects of intravenous iron on hard clinical endpoints remain to be established. Given these results, it is recommended to screen for iron deficiency in all patients with HF, independent of their hemoglobin level. To diagnose iron deficiency, the combination of TSAT and ferritin levels (ferritin<100ng/l or a ferritin 100-300ng/l with a TSAT<20%) has most often been used in large clinical trials. However, this defini-tion has not been validated and ferritin levels are often unreliable as it is an acute phase reactant. We recently presented data from a study in which we validated the cutoff of TSAT<20% using the gold standard of bone marrow iron staining.37 Ferritin had no
diagnostic value. We supported these findings by showing that a low TSAT, and not a low ferritin, was associated with an increased risk of mortality.37 This is in line with results
from the recently published meta-analysis of Anker et al. who show, using interaction analysis, that patients with a TSAT≥20.1% do not respond to iron therapy with improved outcome, while those in the lower tertiles of TSAT do.38
current guideline recommendations
The most recent guidelines of the ACCF/AHA and the ESC both recognize anemia as an important comorbidity in patients with HF.39,40 Management recommendations focus on
seeking the underlying etiology and subsequent treatment, although often no specific cause is found. Special attention is paid to iron deficiency and its treatment with intra-venous ferric carboxymaltose. The use of the ESA darbepoetin-alfa is not recommended by the ESC.39
AreAs of develoPmeNt
Several different strategies are currently being explored for the treatment of anemia in HF, aimed directly at the process of erythropoiesis by targeting the erythropoietin receptor or hypoxia pathway but also indirectly via the hepcidin pathway, see figure 2.
Iron dependent phase
Production
Neutralizing
Binding
Pluripotent stem cell BFU-E CFU-E Proerythroblasts Erythroblasts Reticulocytes RBCs
GDF11+ cells
Efficacy
Hepcidin
Ferroportin
+
Erythropoietin dependent phase HIF-stabilizers Activin traps BMP inhibitors Anti-cytokines siRNAs rhEPO EPO mimetics mAb Spiegelmers Anticalins Anti-ferroportin antibodies EPO Iron + + +
figure 2 – New therapies for anemia and their targets in erythropoiesis. The process of produc-tion of new red blood cells: erythropoiesis. The fi rst stages are dependent on erythropoietin. During the erythroblasts stage, iron availability is essential as it is incorporated in hemoglobin. Most new therapies target either erythropoietin or iron. HIF-stabilizers aff ect both pathways. Although not fully understood, data suggest activing receptor ligand traps also address both pathways and increase effi cacy of erythropoiesis by reducing the number of GDF11 positive cells. Hepcidin can be antago-nized 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. HIF – hypoxia inducible factor, EPO – erythropoietin, rhEPO – recombinant human erythropoietin, GDF11+ – growth diff erentiation factor 11 positive, BMP – bone morphogenic protein, siRNA – small interfering RNA, mAb – Monoclonal antibodies, BFU-E – erythroid burst-forming units, CFU-E – erythroid colony-forming units, RBCs – red blood cells.
hepcidin
Hepcidin, the master iron regulator, can be antagonized in several ways: 1) decreasing 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 and TSAT in patients with cancer and anemia.41 Another hepcidin binding agent, the Spiegelmer lexaptepid
(NOX-H94), has shown to increase serum iron in healthy persons subjected to infl ammation by injection of lipopolysacharides.42 A small phase-II study showed an Hb increase of ≥1
g/dl after 4 weeks of treatment with lexaptepid in 5 out of 12 patients with functional iron defi ciency anemia.43 Currently, the results of trials investigating the eff ects of these
agents in ESA hyporesponsive anemic dialysis patients are awaited.
erythropietin receptor targeting
Drugs directly targeting erythropoiesis include erythropoietin 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 IgG1 Fc domain linked to the extracellular domain of the activin receptor IIA. These binds a number of TGF-β superfamily ligands including activin A, and activin B and thereby inhibit their signaling. Sotatercept, the most studied activin trap, was initially studied as an osteoporosis agent. By surprise, an increase in Hb level, red blood cell number and hematocrit were observed.44 Together with the prevention of vascular
cal-cification shown in a small trial with 43 patients with end-stage renal disease this drug might prove beneficial for the elderly CKD population.45 Animal models point to GDF11
as the target for these drugs, which is a differentiator inhibitor present on erythroid progenitors.46 However, 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 via induction of erythropoietin production by the kidney.47 Increased angiotensin II levels are clearly not desirable in a
HF population and so far, no studies in HF have been conducted yet.
hIf-stabilizers
The final and most promising drugs are the hypoxia inducible factor (HIF)-stabilizers. HIF is the master regulator of the cellular response to hypoxia.48 It is rapidly degraded in
the presence of oxygen, but in low oxygen conditions it induces transcription of over 60 genes including erythropoietin and vascular endothelial growth factor. HIF-stabilizers can be administered orally and induce physiologic erythropoietin levels. Several phase I and II studies in CKD patients have shown promising results with increasing levels of hemoglobin and decreasing levels of hepcidin after therapy.49 One of the compounds
with the most data available is FG-4592, or roxadustat. Roxadustat recently showed to be effective in increasing Hb levels and superior over epoetin alfa in correcting anemia in patients with CKD in two different phase 2 trials.50 One study consisted of 87 patients
on dialysis who received different doses of roxadustat or placebo and the other study comprised 91 patients who were not yet dialysis-dependent who continued with epo-etin alfa or switched to different doses of roxadustat.50 Although only oral iron
supple-mentation was allowed, iron indices remained stable or increased and reduced hepcidin levels were observed in both studies. However, caution is warranted: as HIF-stabilizers affect many biological pathways (including fatty acid and glucose metabolism, and angiogenesis), such ancillary properties may have unknown side effects and there is fear of serious adverse events like tumor growth promotion. Future studies are needed to address safety and efficacy.
coNclusIoN
Anemia in patients with HF is still relevant even though studied therapies so far have not shown positive clinical results. It is present in around one third of the HF patients and these patients have a worse prognosis and poor quality of life. Anemia may indicate several underlying conditions, such as nutritional deficiencies, renal disease and volume overload, although in the latter case this is called pseudo-anemia. Despite the consen-sus that underlying disorders should be addressed, there is no evidence for the clinical benefit of increasing Hb levels as such. ESA therapy has shown neutral results on rates of death and HF rehospitalization and leads to more ischemic strokes, which outweigh their marginal effect on symptom improvement. Intravenous iron therapy looks promis-ing for iron deficiency anemia, but its benefit is partly independent from Hb levels and data on hard clinical endpoints are not yet available.
AckNowledGemeNts
We would like to acknowledge M.A. Kooij, BSc. for assistance with the illustrations.
disclosures
Dr. Grote Beverborg has nothing to disclose. 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. The University Medical Center of Groningen has received an unrestricted grant from Vifor Pharma.
refereNces
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