University of Groningen
Anemia, erythropoietin and iron in heart failure Grote Beverborg, Niels
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iron in heart failure
Niels Grote Beverborg
Gedrukte versie: 978-94-632-3449-8 Digitale versie: 978-94-034-1333-4
© 2018 Niels Grote Beverborg
Copyright of each chapter is with the publisher of the journal in which the work has appeared. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior permission from the author, or when appropriate, of the publisher of the represented published articles.
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This research was financially supported by:
Graduate School of Medical Sciences Vifor Pharma
Financial support by the Dutch Heart Foundation for the publication of this thesis is
gratefully acknowledged.
Anemia, erythropoietin and iron in heart failure
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op maandag 7 januari 2019 om 16.15 uur door
Niels Grote Beverborg
geboren op 24 september 1992 te Oldenzaal
Anemia, erythropoietin and iron in heart failure
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op maandag 7 januari 2019 om 16.15 uur
door
Niels Grote Beverborg geboren op 24 september 1992
te Oldenzaal
Promotores
Prof. dr. P. van der Meer Prof. dr. D.J. van Veldhuisen
Beoordelingscommissie
Prof. dr. D. de Zeeuw Prof. dr. C.A.J.M. Gaillard Prof. dr. M.P. van den Berg
Paranimfen
Martijn F.G.A. Hoes
Job Grote Beverborg
chapter 1 Introduction 7
PArt I – ANemIA ANd erythroPoIetIN
chapter 2 Anemia in heart failure: still relevant? 19 JACC Heart Failure 2018
chapter 3 Erythropoietin in the general population: reference ranges and clinical, biochemical and genetic correlates
37
PLoS One 2015
chapter 4 High serum erythropoietin levels are related to heart failure development in subjects from the general population with albuminuria: data from PREVEND
71
European Journal of Heart Failure 2016
chapter 5 Hyporesponsiveness to darbepoetin alfa in patients with heart failure and anemia in the RED-HF study (Reduction of Events by Darbepoetin Alfa in Heart Failure): clinical and prognostic associations
93
Circulation Heart Failure 2018
PArt II – IroN
chapter 6 Definition of iron deficiency based on the gold standard of bone marrow iron staining in heart failure patients
113
Circulation Heart Failure 2018
chapter 7 Low iron storage versus defective iron utilisation in heart failure:
differences in clinical profile and outcome
137
Under revision
chapter 8 Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function
165
European Journal of Heart Failure 2018
chapter 9 Genetically determined low ferritin and iron levels are causally linked to coronary artery disease
195 Submitted
chapter 10 Discussion and future perspectives 203
Appendices Dutch summary 221
Publications list 226
Dankwoord 229
1 Introduction
heArt fAIlure
Heart failure (HF) is a state in which cardiac functioning fails to meet the oxygen and nutrient demands required by the body to maintain its normal function. It is a clinical syndrome characterized by symptoms like shortness of breath, leg swelling and exercise intolerance. For a person aged 55 years, the lifetime risk of developing HF is about 30%. 1 In the adult population, 1-2% has HF, but it mainly affects the elderly; 6-10% of people aged 65 or older have HF. 2 Due to the aging population in (Western) countries, the prevalence is expected to double within the next 40 years.
Despite modern treatments, the condition usually worsens over time. Unfortunately, 30 to 40% of patients diagnosed with HF die within one year after receiving the diagnosis and 60-70% die within 5 years. 3 This makes HF more lethal than some common forms of cancer. 4 HF patients die from worsening HF or sudden cardiac death due to ventricular arrhythmia’s.
Heart failure currently has no cure; treatment focuses on improving symptoms and pre- venting acute decompensation or disease progression. This is achieved by addressing reversible causes such as valvular anomalies, providing lifestyle education and treat- ments using pharmacological agents or devices. 5 It is recommended that all HF patients with a reduced ejection fraction receive first-line therapy consisting of angiotensin converting enzyme inhibitors (ACE inhibitors), or when not tolerated angiotensin II re- ceptor blockers (ARBs), and β-blockers. In still symptomatic patients, mineralocorticoid receptor antagonists are added to this regime. Diuretics are used to treat symptoms and congestion. 5 There are far less options for patients with HF with a preserved ejec- tion fraction. No treatment has yet been shown, convincingly, to reduce morbidity or mortality in this population. Currently, treatment consist of diuretics to alleviate signs and symptoms, and the screening and treatment of comorbidities.
comorbidities
An essential part of the management of HF, either with a reduced or preserved ejec-
tion fraction, concerns the diagnosis and treatment of comorbidities. Of all HF patients
older than 65 years, 98% have at least one comorbidity. 6-8 Two prevalent comorbidities
contribute directly to the already impaired peripheral oxygen delivery: iron deficiency
and anemia. First considered cause and consequence, recent results, including ours,
have shown that both have to be considered as separate entities.
ANemIA
Anemia is defined by the WHO as a hemoglobin level of <12g/dL (~7.5mmol/L) in women and <13g/dL (~8.1mmol/L) in men. 9 Worldwide, the prevalence of anemia is 32.9%, with especially high prevalence’s in sub-Saharan Africa and south-east Asia. 10 In chapter 2, we discuss anemia in the context of the HF patient; we describe the pathophysiology and focus on the results of clinical trials aimed at correcting anemia and promising future therapies. The majority of therapies developed for anemia in HF comprise drugs targeting erythropoiesis, mainly through its hormonal stimulation, for instance by the administration of recombinant erythropoietin (EPO).
endogenous ePo
Erythropoietin is the primary regulator of erythropoiesis; in the bone marrow, EPO promotes the proliferation of erythroid progenitor cells and increases the production of red blood cells. 11,12 While normally erythropoiesis takes place at a low basal rate, EPO is capable of enhancing production as much as eightfold compared to the baseline rate.
Eighty percent of EPO is produced in the kidney in reaction to impaired oxygen delivery, the remaining mostly being produced in the liver. 13 To allow for interpretation of EPO levels, we were interested in the normal values, physiological function and regulation of human EPO. In chapter 3, we study endogenous EPO levels in a large sample of the general population of Groningen.
High levels of endogenous EPO are frequently observed in patients with HF. 14-16 The etiology of the elevated EPO levels in HF is multifactorial, but includes direct stimulation of EPO synthesis by renal hypoxia, bone marrow resistance to EPO and increased angio- tensin II concentrations. 17-19 Previous studies showed that the endogenous EPO level is a prognostic marker in patients with chronic HF. 14,20 It is currently unknown if EPO levels are also associated with the incidence of new onset HF. We study the association of endogenous EPO levels with the development of new onset HF and other cardiovascular events in chapter 4.
exogenous ePo
Anemia can successfully be corrected in the majority of HF patients using a recombinant
form of EPO. 21,22 One of these drugs, darbepoetin-alfa was studied in the randomized,
blinded clinical trial the reduction of events with darbepoetin alfa in heart failure trial
(RED-HF). 21 In this trial, 2,278 patients with symptomatic chronic HF (LVEF ≤ 40%) and
anemia (HB level 9.0 to 12.0 g/dL) were treated with darbepoetin-alfa with a target
hemoglobin level of 13.0 to 14.5 g/dL or placebo. Disappointingly, this approach did not
result in a better prognosis. In contrast, rates of stroke and thromboembolic events were
increased in patients treated with darbepoetin-alfa, halting the clinical use of recom- binant EPO in HF patients. Despite these consequences, patients with chronic kidney disease still often use recombinant EPO to prevent the need for blood transfusion. It is known that approximately 25% of chronic kidney disease patients are poor responders, that is a low hemoglobin increase in response to darbepoetin-alfa. 23 This low response is associated with increased mortality. 23 Since the syndromes of HF and chronic kidney disease show large overlap, we study the hematological response to darbepoetin-alfa in the large randomized controlled RED-HF trial in chapter 5.
IroN defIcIeNcy
Next to erythropoietin, iron is an essential factor in the successful production of a red blood cell. A deficiency in iron often leads to anemia, and many of the consequences seen in patients with iron deficiency were thus attributed to anemia. However, data showed that iron deficiency is, independent from the presence of anemia, associated with more signs and symptoms and an increased morbidity and mortality in patients with HF. 24,25 New, safer, iron preparations boosted research in this area and clinical trials showed that treatment with intravenous iron improved signs and symptoms of HF in iron deficient subjects. 26-31 Iron deficiency is present in 30 – 72% of the HF population, depending on its definition and HF severity. 24,32,33 The gold standard of the diagnosis of iron deficiency is a Prussian blue staining of a bone marrow aspirate. This procedure is invasive, painful and time-consuming. In clinical care, but also in research, a definition based on serum biomarkers is therefore used but never validated. Based on data from healthy subjects and other chronic diseases a combination between ferritin and trans- ferrin saturation (TSAT) is often used. However, ferritin is an acute phase reactant and therefore increased in varying degrees in subjects with HF, depending on the severity of the low grade inflammation. In chapter 6, we study bone marrow aspirates in relation with circulating biomarkers in patients with HF to provide an optimal definition of iron deficiency. We subsequently study this definition in two different clinical settings to assess effects on morbidity, mortality and treatment effect. The additional benefit of a bone marrow iron staining is the possibility to assess the pathophysiology of the iron deficit. We can quantify the amount of iron stored in the bone marrow and the actual amount of iron incorporated in the erythroblasts, the precursors of the red blood cells.
Using this method, we assess if iron deficient patients have low iron stores or if they
have defective iron utilization. We study these different pathophysiological mechanisms
in chapter 7.
Iron has more functions besides hematopoiesis. Iron can switch between its ferrous (Fe 2+ ) and ferric (Fe 3+ ) form, which gives it the ability to mediate electron transfer, and play a vital role in many redox reactions. Mitochondria rely in their function of ATP pro- duction on these redox reactions. The mitochondrial electron transport chain complexes I-V contain iron-sulfur clusters, heme and cytochromes. Complexes I, III and IV facilitate the redox reactions required to pump H+ outside the inner membrane. The result is an electrochemical gradient which is used to drive complex V: an ATP synthase which generates ATP from ADP by oxidative phosphorylation. Cells that require a high energy demand, such as the cardiomyocytes and skeletal myocytes, are rich in mitochondria.
Therefore, potential detrimental effects of iron deficiency are expected in these cell types. We study the effects of iron deficiency on mitochondrial function, cell metabolism and contractile function in the human cardiomyocyte in chapter 8.
Aims of this thesis
The aim of this thesis is to evaluate the role of the major factors in oxygen transport and utilization in patients with heart failure. These factors include erythropoietin, hemoglo- bin and iron.
In part I, we study erythropoietin and anemia. In chapter 2, we discuss the patho- physiology of anemia in heart failure, review treatments that have been studied and why some have failed and mention potential new treatments. We study erythropoietin in the general population in chapter 3. We provide reference values and report on clinical and biochemical correlates. Additionally, we provide a novel genetic variant associated with erythropoietin levels. chapter 4 elaborates on this work by assessing associa- tions between endogenous erythropoietin levels and new onset HF and cardiovascular events. In chapter 5, we study the treatment of anemia with recombinant erythropoi- etin. We assess the increase in hemoglobin concentration in reaction to treatment with recombinant erythropoietin, define a group of hypo-responsive subjects and study its consequences.
In part II of this thesis, we focus on the role of iron, and specifically iron deficiency in
HF. In chapter 6 we start defining iron deficiency in HF by using the gold standard for
ID: bone marrow aspirations. We assess the value of different circulating biomarkers
of iron status in HF patients and compare them to the gold standard. Using the same
bone marrow aspiration data, we asses in chapter 7 two distinct pathophysiological
mechanisms of iron deficiency: low iron stores and defective iron utilization. In chapter
8, we study the direct effects of iron deficiency on the human cardiomyocyte. In chapter
9, we assess potential causality between iron levels coronary artery disease, the most
prevalent cause of HF.
refereNces
1. Bleumink GS, Knetsch AM, Sturkenboom MCJM, et al. Quantifying the heart failure epidemic: Prevalence, incidence rate, lifetime risk and prognosis of heart failure - The Rotterdam Study. Eur. Heart J. 2004;25:1614–1619.
2. McMurray JJ V, Pfeffer MA. Heart failure.
Lancet 2005;365:1877–1889.
3. Chun S, Tu J V, Wijeysundera HC, et al. Lifetime analysis of hospitalizations and survival of patients newly admit- ted with heart failure. Circ. Heart Fail.
2012;5:414–21.
4. Mamas MA, Sperrin M, Watson MC, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur. J. Heart Fail.
2017;19:1095–1104.
5. Ponikowski P, Voors AA, Anker SD, et al.
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2016;37:2129–
2200m.
6. Conrad N, Judge A, Tran J, et al. Tempo- ral trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet (London, England) 2018;391:572–580.
7. Lawson CA, Solis-Trapala I, Dahlstrom U, et al. Comorbidity health pathways in heart failure patients: A sequences- of-regressions analysis using cross- sectional data from 10,575 patients in the Swedish Heart Failure Registry. PLoS Med. 2018;15:e1002540.
8. van Deursen VM, Urso R, Laroche C, et al. Co-morbidities in patients with heart failure: an analysis of the European Heart Failure Pilot Survey. Eur. J. Heart Fail. 2014;16:103–11.
9. WHO scientific group. Nutritional anaemias. Report of a WHO group of experts. World Heal. Organ. - Tech. Rep.
Ser. 1972;503:1–29.
10. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010.
Blood 2014;123:615–624.
11. Bunn HF. Erythropoietin. Cold Spring Harb. Perspect. Med. 2013;3:a011619.
12. Mastromarino V, Volpe M, Musumeci MB, Autore C, Conti E. Erythropoietin and the heart: facts and perspectives.
Clin. Sci. (Lond). 2011;120:51–63.
13. Lönnberg M, Garle M, Lönnberg L, Birgegård G. Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glyco- form analysis. J. Pharm. Biomed. Anal.
2013;81–82:187–192.
14. van der Meer P, Voors AA, Lipsic E, Smilde TDJ, van Gilst WH, van Veld- huisen DJ. Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure. J. Am. Coll.
Cardiol. 2004;44:63–7.
15. Belonje AMS, Westenbrink BD, Voors AA, et al. Erythropoietin levels in heart failure after an acute myocardial infarc- tion: Determinants, prognostic value, and the effects of captopril versus losar- tan. Am. Heart J. 2009;157:91–96.
16. George J, Patal S, Wexler D, et al. Cir- culating erythropoietin levels and prog- nosis in patients with congestive heart failure: comparison with neurohormonal and inflammatory markers. Arch. Intern.
Med. 2005;165:1304–9.
17. Okonko DO, Anker SD. Anemia in
chronic heart failure: Pathogenetic
mechanisms. J. Card. Fail. 2004;10:S5-9.
18. Freudenthaler SM, Schreeb K, Körner T, Gleiter CH. Angiotensin II increases erythropoietin production in healthy human volunteers. Eur. J. Clin. Invest.
1999;29:816–23.
19. Weiss G, Goodnough LT. Anemia of Chronic Disease. Inflammation 2012;352:1011–1023.
20. Belonje AMS, Voors AA, van der Meer P, van Gilst WH, Jaarsma T, van Veldhuisen DJ. Endogenous erythropoietin and outcome in heart failure. Circulation 2010;121:245–51.
21. Swedberg K, Young JB, Anand IS, et al.
Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure. N. Engl. J.
Med. 2013;368:1210–1219.
22. van der Meer P, Grote Beverborg N, Pfeffer MA, et al. Hyporesponsiveness to Darbepoetin Alfa in Patients With Heart Failure and Anemia in the RED-HF Study (Reduction of Events by Darbepo- etin Alfa in Heart Failure): Clinical and Prognostic Associations. Circ. Heart Fail.
2018;11:e004431.
23. Solomon SD, Uno H, Lewis EF, et al.
Erythropoietic response and outcomes in kidney disease and type 2 diabetes.
N. Engl. J. Med. 2010;363:1146–1155.
24. Klip IT, Comin-Colet J, Voors AA, et al.
Iron deficiency in chronic heart failure:
an international pooled analysis. Am.
Heart J. 2013;165:575–582.e3.
25. Okonko DO, Mandal AKJ, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure:
Prevalence, predictors, and relation to anemia, exercise capacity, and survival.
J. Am. Coll. Cardiol. 2011;58:1241–1251.
26. Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous Iron Reduces NT-Pro-Brain Natriuretic Peptide in Anemic Patients With Chronic Heart
Failure and Renal Insufficiency. J. Am.
Coll. Cardiol. 2007;50:1657–1665.
27. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J. Am. Coll. Car- diol. 2008;51:103–12.
28. Anker SD, Comin Colet J, Filippatos G, et al. Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency.
N. Engl. J. Med. 2009;361:2436–2448.
29. Ponikowski P, Van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron de- ficiency. Eur. Heart J. 2015;36:657–668.
30. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA 2017;317:1958–1966.
31. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of Ferric Carboxymaltose on Exercise Capac- ity in Patients With Chronic Heart Failure and Iron Deficiency. Circulation 2017;136:1374–1383.
32. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency: An ominous sign in patients with systolic chronic heart failure. Eur. Heart J. 2010;31:1872–1880.
33. Cohen-Solal A, Damy T, Terbah M, et al. High prevalence of iron deficiency in patients with acute decompen- sated heart failure. Eur. J. Heart Fail.
2014;16:984–991.
Part I
Anemia and erythropoietin
2 Anemia in heart failure:
still relevant?
Niels Grote Beverborg, Dirk J. van Veldhuisen, Peter van der Meer
Adapted from JACC Heart Failure. 2018 Mar;6(2):201-208.
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 patho-
physiological mechanisms and both conditions share several risk factors, see figure 1.
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 VO 2 max) or NT-pro BNP. 31 In exploratory analyses, changes in TSAT correlated with changes in VO 2 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 VO 2 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 %, VO
2max <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)
VO
2max ↑ (P=0.08) VO
2max/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. Placebo 13.0 ± 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 %, VO
2max 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)
VO
2max ↑ 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 deficiency 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
1. van Veldhuisen DJ, Anker SD, Ponikows- ki P, Macdougall IC. Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches. Nat. Rev.
Cardiol. 2011;8:485–93.
2. Adlbrecht C, Kommata S, Hülsmann M, et al. Chronic heart failure leads to an expanded plasma volume and pseudoanaemia, but does not lead to a reduction in the body’s red cell volume.
Eur. Heart J. 2008;29:2343–2350.
3. Grote Beverborg N, Verweij N, Klip IjT, et al. Erythropoietin in the general population: Reference ranges and clini- cal, biochemical and genetic correlates.
PLoS One 2015;10:e0125215.
4. Groenveld HF, Januzzi JL, Damman K, et al. Anemia and Mortality in Heart Failure Patients. A Systematic Review and Meta-Analysis. J. Am. Coll. Cardiol.
2008;52:818–827.
5. Tang WHW, Tong W, Jain A, Francis GS, Harris CM, Young JB. Evaluation and long-term prognosis of new-onset, transient, and persistent anemia in am- bulatory patients with chronic heart fail- ure. J. Am. Coll. Cardiol. 2008;51:569–76.
6. Waldum B, Westheim AS, Sandvik L, et al. Baseline anemia is not a predictor of all-cause mortality in outpatients with advanced heart failure or severe renal dysfunction. Results from the Norwe- gian Heart Failure Registry. J. Am. Coll.
Cardiol. 2012;59:371–8.
7. Klip IT, Comin-Colet J, Voors AA, et al.
Iron deficiency in chronic heart failure:
an international pooled analysis. Am.
Heart J. 2013;165:575–582.e3.
8. Okonko DO, Mandal AKJ, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure:
Prevalence, predictors, and relation to
anemia, exercise capacity, and survival.
J. Am. Coll. Cardiol. 2011;58:1241–1251.
9. Nanas JN, Matsouka C, Karageorgop- oulos D, et al. Etiology of Anemia in Patients With Advanced Heart Failure. J.
Am. Coll. Cardiol. 2006;48:2485–2489.
10. van der Meer P, Lok DJ, Januzzi JL, et al. Adequacy of endogenous erythro- poietin levels and mortality in anaemic heart failure patients. Eur. Heart J.
2008;29:1510–1515.
11. Westenbrink BD, Visser FW, Voors AA, et al. Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well. Eur. Heart J. 2007;28:166–171.
12. Westenbrink BD, Voors AA, De Boer RA, et al. Bone marrow dysfunction in chronic heart failure patients. Eur. J.
Heart Fail. 2010;12:676–684.
13. van der Meer P, Voors AA, Lipsic E, Smilde TDJ, van Gilst WH, van Veld- huisen DJ. Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure. J. Am. Coll.
Cardiol. 2004;44:63–7.
14. Grote Beverborg N, van der Wal HH, Klip IjT, et al. High serum erythropoi- etin levels are related to heart failure development in subjects from the general population with albuminuria:
data from PREVEND. Eur. J. Heart Fail.
2016;18:814–821.
15. van der Meer P, Lipsic E, Westenbrink BD, et al. Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl- proline partially explain the occurrence of anemia in heart failure. Circulation 2005;112:1743–7.
16. Ishani A, Weinhandl E, Zhao Z, et al.
Angiotensin-converting enzyme inhibi-
tor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J. Am. Coll.
Cardiol. 2005;45:391–9.
17. Komajda M, Anker SD, Charlesworth A, et al. The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET. Eur.
Heart J. 2006;27:1440–6.
18. Weiskopf RB, Viele MK, Feiner J, et al.
Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998;279:217–21.
19. Ebner N, Jankowska EA, Ponikowski P, et al. The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Ag- gravating Heart Failure. Int. J. Cardiol.
2016;205:6–12.
20. Klip IT, Jankowska EA, Enjuanes C, et al.
The additive burden of iron deficiency in the cardiorenal-anaemia axis: Scope of a problem and its consequences. Eur.
J. Heart Fail. 2014;16:655–662.
21. Garty M, Cohen E, Zuchenko A, et al.
Blood transfusion for acute decompen- sated heart failure--friend or foe? Am.
Heart J. 2009;158:653–8.
22. Kao DP, Kreso E, Fonarow GC, Krantz MJ.
Characteristics and outcomes among heart failure patients with anemia and renal insufficiency with and without blood transfusions (public discharge data from California 2000-2006). Am. J.
Cardiol. 2011;107:69–73.
23. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P, Clinical Guide- lines Committee of the American Col- lege of Physicians. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American
College of Physicians. Ann. Intern. Med.
2013;159:770–9.
24. Swedberg K, Young JB, Anand IS, et al.
Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure. N. Engl. J.
Med. 2013;368:1210–1219.
25. Bello NA, Lewis EF, Desai AS, et al. In- creased risk of stroke with darbepoetin alfa in anaemic heart failure patients with diabetes and chronic kidney disease.
Eur. J. Heart Fail. 2015;17:1201–1207.
26. Bennett CL. Venous Thromboembolism and Mortality Associated With Recom- binant Erythropoietin and Darbepo- etin Administration for the Treatment of Cancer-Associated Anemia. JAMA 2008;299:914.
27. Singh AK, Szczech L, Tang KL, et al. Cor- rection of Anemia with Epoetin Alfa in Chronic Kidney Disease. N. Engl. J. Med.
2006;355:2085–2098.
28. Kleijn L, Belonje AMS, Voors AA, et al.
Inflammation and anaemia in a broad spectrum of patients with heart failure.
Heart 2012;98:1237–41.
29. Borovka M, Teruya S, Alvarez J, Helmke S, Maurer MS. Differences in blood volume components between hyporesponders and responders to erythropoietin alfa:
The heart failure with preserved ejection fraction (HFPEF) anemia trial. J. Card.
Fail. 2013;19:685–691.
30. van der Meer P, Grote Beverborg N, Pfeffer MA, et al. Hyporesponsiveness to Darbepoetin Alfa in Patients With Heart Failure and Anemia in the RED-HF Study (Reduction of Events by Darbepo- etin Alfa in Heart Failure): Clinical and Prognostic Associations. Circ. Heart Fail.
2018;11:e004431.
31. Lewis GD, Semigran MJ, Givertz MM, et
al. Oral Iron Therapy for Heart Failure
With Reduced Ejection Fraction: Design
and Rationale for Oral Iron Repletion Ef-
fects on Oxygen Uptake in Heart Failure.
Circ. Heart Fail. 2016;9:e000345.
32. Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous Iron Reduces NT-Pro-Brain Natriuretic Peptide in Anemic Patients With Chronic Heart Failure and Renal Insufficiency. J. Am.
Coll. Cardiol. 2007;50:1657–1665.
33. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J. Am. Coll. Car- diol. 2008;51:103–12.
34. Anker SD, Comin Colet J, Filippatos G, et al. Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency.
N. Engl. J. Med. 2009;361:2436–2448.
35. Ponikowski P, Van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron de- ficiency. Eur. Heart J. 2015;36:657–668.
36. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of Ferric Carboxymaltose on Exercise Capac- ity in Patients With Chronic Heart Failure and Iron Deficiency. Circulation 2017;136:1374–1383.
37. Grote Beverborg N, Klip IjT, Meijers WC, et al. Definition of Iron Deficiency Based on the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients.
Circ. Heart Fail. 2018;11:e004519.
38. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: An individual patient data meta-analysis.
Eur. J. Heart Fail. 2017.
39. Ponikowski P, Voors AA, Anker SD, et al.
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2016;37:2129–
2200m.
40. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am.
Coll. Cardiol. 2013;62:e147-239.
41. Vadhan-Raj S, Abonour R, Goldman JW, et al. A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated ane- mia. J. Hematol. Oncol. 2017;10:73.
42. van Eijk LT, John ASE, Schwoebel F, et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans.
Blood 2014;124:2643–6.
43. Georgiev P, Lazaroiu M, Ocroteala L, et al. Abstract 3847: The anti-hepcidin Spiegelmer{®} Lexaptepid Pegol (NOX- H94) as treatment of anemia of chronic disease in patients with multiple my- eloma, low grade lymphoma, and CLL: A phase II pilot study (abstr). Cancer Res.
2014;74:3847 LP-- 3847.
44. Ruckle J, Jacobs M, Kramer W, et al.
Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal wom- en. J. Bone Miner. Res. 2009;24:744–752.
45. Havill J, Kopyt N, Coyne D, Weiswasser M, Smith W. Sotatercept improves anemia, vascular calcification, and bone loss in patients with end-stage kidney disease on hemodialysis. (Abstr. TH-PO038). J Am Soc Nephrol. 2015;26:310A–311A.
46. Paulson RF. Targeting a new regulator of erythropoiesis to alleviate anemia. Nat.
Med. 2014;20:334–335.
47. Iancu-Rubin C, Mosoyan G, Wang J, Kraus T, Sung V, Hoffman R. Stromal cell-mediated inhibition of erythropoi- esis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap. Exp. Hematol. 2013;41:155–
166.e17.
48. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis.
Curr. Opin. Genet. Dev. 1998;8:588–94.
49. Bonomini M, Del Vecchio L, Sirolli V, Locatelli F. New Treatment Approaches for the Anemia of CKD. Am. J. Kidney Dis. 2016;67:133–42.
50. Chen N, Qian J, Chen J, et al. Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China. Nephrol.
Dial. Transplant. 2017;32:1373–1386.
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