Targeting Iron Deficiency Anemia in Heart Failure

    Targeting Iron Deficiency Anemia in Heart Failure Tajinderpal Saraon, Stuart D. Katz PII: DOI: Reference:

S0033-0620(15)30026-8 doi: 10.1016/j.pcad.2015.11.007 YPCAD 700

To appear in:

Progress in Cardiovascular Diseases

Please cite this article as: Saraon Tajinderpal, Katz Stuart D., Targeting Iron Deficiency Anemia in Heart Failure, Progress in Cardiovascular Diseases (2015), doi: 10.1016/j.pcad.2015.11.007

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ACCEPTED MANUSCRIPT Targeting Iron Deficiency Anemia in Heart Failure Running Title: Targeting ID Anemia in HF

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Stuart D. Katz MD, MS

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Tajinderpal Saraon, MD

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From the Leon H. Charney Division of Cardiology, New York University Langone Medical Center, New York, NY

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Disclosures /Conflicts of Interest: Stuart Katz: Luitpold Pharmaceuticals, consultant; Amgen Inc., consultant, speaker bureau

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Reprint request and correspondence: Stuart D. Katz, MD Helen L. and Martin S. Kimmel Professor of Advanced Cardiac Therapeutics New York University Langone Medical Center Leon H. Charney Division of Cardiology 530 First Avenue, Skirball 9R New York, NY 10016 Tel: 212-263-3946 Fax: 212-263-3988 Email: [email protected]

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Abstract Iron deficiency is common in heart failure (HF) patients, and is associated with increased risk of

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adverse clinical outcomes. Clinical trials of intravenous iron supplementation in iron-deficient HF

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patients have demonstrated short-term improvement in functional capacity and quality of life. In some trials, the benefits of iron supplementation were independent of the hemoglobin levels.

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Additional investigations of iron supplementation are needed to characterize the mechanisms

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contributing to clinical benefit and long-term safety in HF.

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Key words: iron homeostasis, intravenous iron, heart failure, clinical trials Abbreviations:

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6MWT – 6-minute walk test CV -Cardiovascular

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DMT-1 –Divalent metal transporter-1

HF-Heart failure

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FCM – Ferric carboxymaltose

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IRP – Iron regulatory proteins

KCCQ – Kansas City Cardiomyopathy Questionnaire LV –Left ventricular

LVEF –Left ventricular ejection fraction MLWHF- Minnesota Living With Heart Failure NT-pro BNP – N-terminal-pro brain natriuretic peptide NYHA –New York Heart Association QoL –Quality of life VO2 – Oxygen consumption or uptake WHO –World Health Organization

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Heart failure (HF) affects an estimated 5.7 million Americans and each year is

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associated with greater than 1 million hospital admissions and health care costs in excess of $30 billion (1,2). HF patients with concomitant anemia have increased morbidity and mortality

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risk when compared with non-anemic HF patients (3,4). Accordingly, anemia has been identified as a potential therapeutic target to improve clinical outcomes in the HF patient population (5).

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Since iron deficiency is common in HF patients, this review will focus on diagnostic testing and

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treatment strategies for HF patients with iron-deficiency anemia.

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Prevalence and etiology of anemia in HF

Reported estimates of the prevalence of anemia in HF patients vary broadly from 10 to

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49% (5,6). A meta-analysis of 153,180 HF patients derived from 34 published studies reported

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the mean prevalence of anemia to be 37.2% with range from 7% to greater than 50% (4). This variability in the estimate of prevalence of anemia is attributable in part to inconsistent

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definitions of anemia across published studies. The World Health Organization (WHO) defines anemia as hemoglobin concentration ˂13 g/dL in men and ˂12 g/dL in women; however, the National Kidney Foundation defines anemia as hemoglobin ˂12 g/dL in men and postmenopausal women and ˂11 g/dL in premenopausal women, with the 2006 updated guidelines changing the definition to ˂13.5 g/dL in men and ˂12 g/dL in women (7,8). Some studies in HF populations used these published definitions, while others defined anemia based on the population distribution of hemoglobin values, other arbitrary cut-off values, or diagnostic codes from claims data. The definition of iron-deficiency anemia is also inconsistent across published studies. The diagnosis of iron deficiency is based on blood biomarkers of iron homeostasis and reticulocyte and red blood cell measurements (9,10). Serum ferritin <30 ng/ml

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in association with low hemoglobin and microcytic hypochromic red blood cells is diagnostic of absolute iron deficiency anemia (severely reduced or absent bone marrow iron stores). In

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disease states with chronic inflammation, including HF, activation of pro-inflammatory cytokines

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is associated with increased serum ferritin values independent of iron stores. Inflammationmediated changes in iron homeostasis is often called functional iron deficiency, and may occur

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with or without anemia. In the presence of inflammation, iron deficiency anemia is more likely if serum ferritin is <100 ng/ml, transferrin saturation is <16%, soluble transferrin receptors are

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elevated, reticulocytes are reduced and hypochromic, and erythrocytes are microcytic. The ratio

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of soluble transferrin receptor to log serum ferritin has been proposed to be an accurate predictor of functional iron deficiency in patients with inflammation and anemia of chronic disease. In an observational study of 37 hospitalized anemic HF patients, bone marrow

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aspiration demonstrated that 73% of patients had absent iron staining in the bone marrow (11).

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Serum ferritin was lower in anemic patients with absent bone marrow iron staining when compared with other anemic patients (75±59 vs. 212±100 ng/ml, p<0.001). Absolute and

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functional iron deficiency anemia (severely reduced or absent iron stores) is common in HF populations. Based on ICD-9 discharge codes, anemia was present in 17% of a large cohort of

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hospitalized HF patients (n=12,065). Within the anemic subset (n=2082), 21% had iron deficiency and 58% were classified as anemia of chronic disease (12). In a pooled analysis of 5 European HF cohorts (n=1506), anemia was defined according to the above WHO criteria, and iron deficiency was defined as a ferritin level <100 ng/ml or serum ferritin 100–299 ng/ml in combination with transferrin saturation <20% (13). Based on these definitions, anemia was present in 28% of HF subjects, and iron deficiency was present in 50% of HF subjects. Independent clinical predictors of iron deficiency in this cohort included female sex, worse New York Heart Association (NYHA) functional class, lower red blood cell mean corpuscular volume, higher N-terminal-pro-brain natriuretic peptide (NT-pro BNP) levels, and presence of anemia. Iron deficiency is associated with clinical severity of HF and associated with greater mortality

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risk in patients with concomitant anemia (HR 1.71, 95% CI 1.24-2.36, P = .001) or without

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Pathophysiology of functional iron deficiency in inflammation

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concomitant anemia (HR 1.44, 95% CI 1.11-1.87, P = .006) (13-15).

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Iron is an essential dietary micronutrient that functions as a co-factor for hundreds of proteins and enzymes in the human body. Iron-containing proteins are key regulators of oxygen

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transport (hemoglobin), muscle iron storage (myoglobin), mitochondrial respiration, cellular

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redox regulation, vasomotor regulation as an essential co-factor of soluble guanylate cyclase, the downstream target of nitric oxide and other nitrosovasodilators in vascular smooth muscle, and as a transcription factor for signaling pathways involving neurotransmission, innate

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immunity, cell growth, and inflammation (16,17).

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Total body iron stores are regulated exclusively through control of iron absorption, as there are no known natural metabolic pathways for iron excretion (18,19). Hepcidin, a

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hepatocyte-derived peptide hormone, plays a critical role in a negative feedback loop regulation of iron absorption from the intestinal tract (20). Hepcidin is secreted in response to tissue

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sensors of increased body iron stores and tissue oxygenation, but is also regulated by other factors including pro-inflammatory cytokines, and gonadal hormones. Hepcidin inhibits transfer of dietary iron to the reticuloendothelial system by inducing degradation of the iron exporter protein ferroportin in enterocytes and macrophages. Dietary iron and recycled iron from senescent red blood cells is bound to transferrin for iron transport, and to ferritin for intracellular iron storage, in a complex regulated system that controls iron availability to the bone marrow for erythropoiesis. Functional iron deficiency occurs when inflammation-induced hepcidin production leads to increased degradation of ferroportin with consequent decreased dietary iron absorption and decreased delivery of macrophage iron to the erythrocyte precursors (9). The transferrin receptor is the primary receptor for transfer of iron into the various cell

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types, but other transporter proteins including divalent metal transporter-1 (DMT-1) and Zip-14, also contribute to intracellular transport of iron, especially in iron overload states (21).

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Transferrin-bound iron complexes are processed in endosomes and transferred via DMT-1 for

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intracellular iron storage (ferritin), or transport to mitochondria or other intracellular environments for incorporation into heme-containing and iron-sulfur cluster containing proteins.

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A small fraction of body iron stores is bound to citrate and other small molecules within the intracellular and extracellular compartments outside of the reticuloendothelial system (22). Low

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molecular weight iron is available for participation in redox reactions via Fenton Chemistry and

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interactions with nitric oxide and regulates synthesis and activity of iron-containing proteins (23). Iron regulatory proteins (IRP-1 and IRP-2) play an important role in maintaining iron homeostasis within non-heme tissues. In response to changes in iron availability and redox

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signals, IRP-1 and IRP-2 bind iron-response elements that regulate transcription of the

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transferrin receptor, ferritin, and other proteins (23).

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Treatment of iron-deficiency anemia in HF

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Oral Iron replacement

Oral iron salts are frequently used for iron replacement therapy due to the relative inexpensive cost and ease of administration. However, several important factors may limit success of oral iron therapy. First, gastrointestinal side effects are common and lead to poor compliance with oral iron therapy (24). Second, many common foods and medications interact with oral ferrous salts and can reduce gastrointestinal absorption (25,26). In addition, systemic venous congestion in HF patients may induce edema of the intestinal mucosa and reduce the absorption of oral iron (27). Finally, increased circulating hepcidin in HF and other inflammatory states reduces dietary iron absorption (28).

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IRON-HF was a multicenter randomized double-blind trial that was designed to compare the effects of oral iron therapy, intravenous iron therapy, and placebo on exercise capacity in

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anemic HF patients (hemoglobin 9-12 gm/dl) with functional iron deficiency (defined as

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transferrin saturation <20% and serum ferritin <500 ng/ml) (29). Due to recruitment shortfall and limited funding, the study only enrolled 23 subjects and thus did not have sufficient power to

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address its predetermined primary efficacy endpoint (change in peak oxygen uptake or peak VO2 over 3 months). Subjects were randomized to intravenous iron sucrose 200 mg once

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weekly for 5 weeks (n=10), ferrous sulfate 200 mg by mouth three times daily for 8 weeks (n=7),

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or placebo (n=6). At study entry, mean hemoglobin was 11.2±0.6 gm/dL and mean serum ferritin was 132±138 ng/ml. Hemoglobin levels increased in response to assigned treatment in all treatment groups with no significant differences between groups (iron sucrose +1.04 gm/dl,

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ferrous sulfate +1.69 gm/dl, and placebo +1.1 gm/dl, p=0.56 for group by time interaction).

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Serum ferritin increased in the intravenous iron group (+126 ng/ml) and oral iron groups (+103 ng/ml), but not the placebo group (-42 ng/ml). Despite similar changes in hemoglobin and serum

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ferritin in response to therapy, a non-significant difference of 4.36 ml/kg/min in peak VO2 between the iron sucrose and ferrous sulfate groups was noted.

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Another placebo-controlled clinical trial of oral iron study is currently underway (IRONOUT, NCT02188784, see clinicaltrials.gov). This trial is enrolling systolic HF subjects with and without anemia (Hemoglobin 9.0-13.5 g/dl) and functional iron deficiency (defined as serum ferritin between 15-100 ng/ml or serum ferritin between 100-299 ng/ml with transferrin saturation <20%). Eligible subjects will be randomized to oral iron therapy (iron polysaccharide 150 mg) twice daily or matching placebo for 16 weeks. The primary endpoint is peak VO2. Secondary endpoints include submaximal exercise, biomarkers, and quality of life (QoL).

Intravenous iron replacement

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Intravenous iron replacement is not dependent on gastrointestinal absorption and thus can deliver a much higher dose per administration compared to oral iron therapy, but requires

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travel to a health care facility for administration and is associated with rare hypersensitivity

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reactions, increased risk of infections, and higher in cost (30). Controlled clinical trials of intravenous iron therapy are summarized in Table 1 and the paragraphs below.

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In 2006, Bolger and colleagues conducted a prospective, uncontrolled, open-label study evaluating the effects of intravenous iron sucrose in 17 subjects with anemia and chronic stable

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NYHA II/III systolic HF [mean left ventricular (LV) ejection fraction (LVEF ) 26% ± 13%] (31). Patients were receiving treatment with guideline-recommended HF medications for ≥ 6 weeks

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and had anemia as defined by hemoglobin of ≤12 g/dl. Patients with serum ferritin >400 ng/ml were excluded. Patients received bolus intravenous injections of 200 mg undiluted iron sucrose

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on days 1, 3 and 5 in an outpatient setting. Serum ferritin was measured on day 12. If ferritin

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was <400 ng/ml on day 12, further doses of intravenous iron sucrose were administered on days 15 and 17. Most of the study subjects received all five doses of intravenous iron sucrose

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(total 1 g). Symptoms and exercise capacity were assessed by NYHA functional classification, the Minnesota Living with Heart Failure (MLHF) questionnaire and the 6-minute walk test

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(6MWT), respectively. After intravenous iron treatment and a mean follow up of 92 ± 6 days, hemoglobin, ferritin, serum iron and transferrin saturation all significantly increased from baseline values. At entry 9 patients were in NYHA class II symptoms and 8 patients were in class III. At follow-up all patients were in NYHA functional class II (p<0.02). The MLHF score also significantly improved (33 ± 19 to 19 ± 14, p=0.02). Mean 6MWT significantly increased from 242 ±78 m to 286 ±72 m (p=0.01). Changes in these later two outcome variables were strongly associated with increased hemoglobin levels (r=0.76, p=0.002 and r=0.56, p=0.03 respectively). Intravenous iron sucrose was well-tolerated in the study population.

In 2007, Toblli and colleagues conducted a randomized, double-blind, placebo controlled

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study, investigating the effects of intravenous iron sucrose (200 mg weekly for five weeks) in 40 subjects with anemia (hemoglobin <12.5 gm/dLin men or <11.5 gm/dLin women) and chronic

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NYHA class II-IV systolic HF (LVEF ≤35%) with evidence of iron deficiency (serum ferritin <100

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ng/ml and/or transferrin saturation ≤20%) and co-morbid renal insufficiency (estimated creatinine clearance ≤90 ml/min) (32). Primary endpoints were to determine the effects of study

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drug on iron stores, hemoglobin values, NT-ProBNP levels, systemic inflammation as assessed by C-reactive protein, and renal function at 6 months. Secondary endpoints were to determine

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the effects of study treatment on NYHA functional class, QoL (MLWHF questionnaire score),

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distance on the 6MWT, and LVEF assessed by transthoracic echocardiography. Intravenous iron significantly increased hemoglobin, ferritin and transferrin saturation when compared with placebo (all p<0.01). Intravenous iron significantly reduced NT-proBNP (p< 0.01) and C-reactive

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protein (p <0.01) when compared with placebo. There were also significant improvements in

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NYHA function class and MLHF questionnaire score (p< 0.01) and increased distance on the 6MWT (estimated mean treatment effect 54 m, p<0.01). LVEF significantly increased in

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response to intravenous iron when compared with placebo (p<0.01). Although not powered to detect difference in clinical event rates, there were no hospitalizations in the intravenous iron

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group and five hospitalizations in the placebo group over six months of follow-up. Intravenous iron sucrose was well-tolerated with no reported side effects.

Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Nonanemic Patients With Symptomatic Chronic Heart Failure and Iron Deficiency (FERRIC-HF) was a randomized, observer-blinded, placebo-controlled trial in 35 subjects with chronic NYHA II/III systolic HF (LVEF ≤45%) randomized in a 2:1 manner to intravenous iron sucrose vs. control (placebo or standard care depending on the enrolling center) (33). Eligibility criteria included exercise limitation characterized by a peak VO2 ≤18 ml/kg/min; hemoglobin concentration of <12.5 g/dL for anemic subjects and 12.5–14.5 g/dL for non-anemic subjects; serum ferritin of

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<100 ng/ml (or serum ferritin 100–300 ng/ml with transferrin saturation <20%). Patients in the intravenous iron group received weekly doses for 3 weeks (therapeutic phase) followed by

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doses at 4, 8, 12 and 16 weeks (maintenance phase). Iron therapy was withheld if ferritin was

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≥500 ng/ml or Hb ≥16.0 g/dL or transferrin saturation was ≥45% at any stage. The primary endpoint was the change in absolute peak VO2 (ml/min) from baseline to week 18. Secondary

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end points included changes in peak VO2 adjusted for body weight (ml/kg/min) from baseline to week 18, exercise duration, hemoglobin, biomarkers of iron stores, NYHA functional class,

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changes on 7-point patient Global Assessment scale, QoL (the MLWHF questionnaire score)

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and a fatigue score. The mean dose of iron sucrose administered during the study was 1,433±365 mg. For all enrolled subjects, the primary endpoint, absolute peak VO2 did not significantly increase in subjects randomized to iron sucrose when compared with placebo

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(mean treatment effect 96 ml/min, p=0.08) but peak VO2 normalized to body weight did

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significantly increase when compared with placebo (mean treatment effect 2.2 ml/kg/min, p=0.01). In the anemic subgroup (n=18), iron sucrose did not increase hemoglobin level

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(p=0.78), but did significantly increase absolute peak VO2 (mean treatment effect 205 ml/min, p=0.02) and a peak VO2 adjusted for body weight when compared with placebo (mean

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treatment effects 3.9 ml/kg/min, p=0.009). In the non-anemic subgroup, iron sucrose was not associated with change hemoglobin level or change in peak VO2. Changes in peak VO2 were associated with changes in transferrin saturation in anemic subjects (n=18, r=0.62, p=0.006) but not changes in hemoglobin concentration (r=0.37, p=0.08).

In a 2008 study, Usmanov and colleagues studied the effects of intravenous iron in 32 anemic patients (hemoglobin <11 gm/dl) with NYHA Class III–IV systolic HF and chronic renal insufficiency (serum creatinine 1.5–3.9 mg/dl) in an open-label observational longitudinal study over 6 months (34). The outcome variables were laboratory markers of anemia and iron stores, functional status and LV structure and function as assessed by transthoracic echocardiography.

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Intravenous iron sucrose was administered at a dose of 100 mg over 30 minutes three times weekly for 3 weeks followed by once weekly dosing for 23 weeks. The total dose was 3200 mg

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of elemental iron over the 26-week study. Intravenous iron sucrose significantly increased

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hemoglobin from pre-treatment mean of 10.7 mg/dL to post-treatment mean of 13.7 gm/dL in the NYHA Class III subjects (n=19, p<0.01) and from 9.4 to 12.7 gm/dL in the NYHA Class IV

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subjects (n=13, p<0.01). Intravenous iron sucrose improved symptoms to NYHA functional class II in nine of the subjects with baseline NYHA Class III symptoms (47.4%, p<0.01), but did not

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improve functional class in any of the 13 patients with NYHA IV symptoms at baseline.

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Echocardiographic parameters including posterior wall thickness, LV mass index, septal thickness, LV end-diastolic volume and end-systolic volumes, and LVEF improved significantly when compared with pre-treatment baseline in the NYHA Class III subjects. In the NYHA Class

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IV subjects, significant changes were observed in posterior wall thickness, LV mass index, LV

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end-diastolic volume and end-systolic volumes, but not LVEF.

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Anker and colleagues in 2009 conducted a multicenter, randomized, double blind, placebo controlled study entitled Ferric Carboxymaltose in Patients with Heart Failure and Iron

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Deficiency (FAIR-HF) to compare the effects of intravenous ferric carboxymaltose (FCM ) vs. placebo in 459 HF subjects with biomarkers of iron deficiency, with or without anemia (35). Study drug was randomly assigned in a 2:1 ratio: 304 subjects received FCM and 155 subjects received placebo. Key inclusion criteria included chronic NYHA functional class II or III symptoms, LV systolic function (LVEF ≤40% in patients with NYHA class II symptoms or ≤45% for NYHA class III symptoms), iron deficiency (defined as serum ferritin <100 ng/ml or serum ferritin 100–299 ng/ml with transferrin saturation <20%), and hemoglobin value 9.5–13.5 gm/dl. Intravenous bolus injection of FCM 200 mg or placebo was administered weekly until iron stores were repleted (correction phase, total number of weekly infusions based on estimated iron deficit derived from baseline hemoglobin values), followed by a dosing interval of 4 weeks

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starting week 8 or week 12 (maintenance phase). Study drug was administered in a doubleblind manner to maintain a transferrin saturation of 25–45% and a serum ferritin of 400–800

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ng/ml in the active treatment group. Primary endpoints for the study were a self-reported 7-point

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Patient Global Assessment Scale and Investigator-assessed NYHA functional class at week 24. Secondary end points included distance on the 6MWT and QoL (the overall score on the

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Kansas City Cardiomyopathy Questionnaire/KCCQ) at week 24. Intravenous FCM significantly increased serum ferritin and hemoglobin levels when compared with placebo at week 24 (mean

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treatment difference for serum ferritin was 246 ±20 ng/ml and mean treatment difference for

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hemoglobin, 0.6 gm/dL(both p< 0.001). For the primary end point at week 24, 50% of patients in the treatment group reported improvement on the patient global assessment scale compared to 28% in the placebo group (odds ratio; 2.51; 95% CI: 1.75 to 3.61, p<0.001). Likewise 47% of

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subjects receiving intravenous FCM improved to NYHA functional class I or II compared to 30 %

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in the placebo group (odd ratio 2.40, 95% CI: 1.55 to 3.71, p<0.001). For secondary endpoints at week 24, the distance on the 6MWT and KCCQ score significantly improved in subjects

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randomized to FCM when compared with placebo (mean study treatment effect for 35 ±8 m for 6MWT, and mean study treatment effect for KCCQ effect +7 points, both p<0.001). In a pre-

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specified subgroup analysis, the magnitude of the treatment effect did not differ in subjects with vs. without baseline anemia (defined as hemoglobin ≤12.0 g/dl), even though the hemoglobin level did not change in response to intravenous iron in the non-anemic subgroup (n=221) when compared with placebo (13.3±0.1 vs. 13.2±0.1 g/dl, p=0.21). The overall rate of adverse events was similar for both groups. Although not powered for assessment of clinical outcomes, but the rate of first hospitalization for cardiovascular (CV) events was numerically lower in the subjects randomized to receive intravenous FCM when compared with placebo (hazard ratio, 0.53; 95 % CI: 0.25 to 1.09; p=0.08).

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Ponikowski and colleagues, in a study entitled Beneficial effects of long-term intravenous iron therapy with FCM in patients with symptomatic HF and iron deficiency (CONFIRM-HF)

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performed a multicenter, randomized, double-blind, placebo-controlled trial in 304 ambulatory

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NYHA II/III class systolic HF (LVEF ≤45%) patients with elevated natriuretic peptides and iron deficiency (ferritin <100 ng/mL or 100–300 ng/mL if transferrin saturation <20%) (36). Patients

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were randomized 1:1 to treatment with FCM with 152 subjects or placebo in the remaining subjects for 52 weeks. The primary end point was the change in 6MWT distance from baseline

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to Week 24. Secondary end-points included changes in NYHA functional class, patient global

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assessment, health-related QoL (KCCQ), Fatigue Score at weeks 6, 12, 24, 36, and 52 and the effect of FCM on the rate of hospitalization for worsening HF. The mean total dose of FCM was 1500 mg during the 1-year study period (range of 500–3500mg). FCM significantly increased

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hemoglobin levels when compared with placebo (0.6±0.2 and 1.0±0.2 g/dl, at Weeks 24 and 52,

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respectively, all p<0.001). Treatment with FCM significantly prolonged 6MWT at Week 24 (difference FCM vs. placebo: 33 ±11 m, p=0.002). The treatment effect of FCM was consistent

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in all subgroups (although there was a trend for greater benefit in subjects with hemoglobin <12 gm/dL fat study entry, p=0.15 for interaction vs. hemoglobin ≥12 gm/dl) and was sustained to

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Week 52 (difference FCM vs. placebo: 36 ±11 m, p<0.001). FCM was associated with significant improvement in NYHA functional class, patient global assessment, QoL score, and Fatigue Score when compared with placebo from Week 24 to the end of the study. Treatment with FCM was associated with a significant reduction in the risk of hospitalizations for worsening HF [hazard ratio 0.39 (95% CI: 0.19–0.82), p=0.009].

Taken together, these clinical trials provide a consistent signal of improved submaximal exercise capacity, functional class, and QoL in response to intravenous iron therapy in patients with HF and iron-deficiency. However, there are several caveats to consider in the translation of these clinical trial findings to clinical practice. The improved clinical status associated with iron

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therapy was accompanied by a significant increase in hemoglobin values in the majority of the studies, but in the largest study to date (FAIR-HF), there was no significant change in

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hemoglobin levels in response to intravenous iron therapy, and no significant difference in

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response to iron therapy in subgroups based on baseline hemoglobin levels. This finding suggests that iron therapy may mediate its beneficial effects on functional capacity via effects

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on oxygen utilization in skeletal muscle, rather than increased oxygen delivery via increased hemoglobin levels. In experimental iron deficiency anemia in rats, exchange transfusion to

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normalize hematocrit increased peak VO2, but did not enhance submaximal exercise

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endurance, whereas iron repletion was closely coupled with improved submaximal exercise capacity, reduced lactate production, and increased skeletal muscle oxidative capacity (37-40). Studies of experimental iron-deficiency anemia and iron repletion in healthy human subjects

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(predominantly young athletes) have yielded mixed findings, but the majority of studies indicate

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that increased maximal exercise capacity in response to iron repletion is attributable to increased hemoglobin levels, with inconsistent effects of iron repletion on various measures of

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submaximal endurance (38,41-45). These findings are also consistent with a previous report in anemic HF subjects treated with erythropoietin, in which improved peak VO2 in response to

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therapy was significantly associated with increase in hemoglobin levels (46). Accordingly, additional investigation is needed to characterize the metabolic effects of iron supplementation and identify the subgroups most likely to benefit from therapy. The other caveat is the lack of long-term safety data in the HF trials of iron therapy. All the studies were of fairly short duration, and none were sufficiently powered to evaluate the effects of intravenous iron on clinical events. In the two largest trials (FAIR-HF and CONFIRM-HF), there were no signals of harm associated with intravenous iron therapy. However, there are known risks of iron therapy based on observations in chronic kidney populations. Besarab and colleagues reported increased incidence of myocardial infarctions in end-stage renal patients on dialysis whose hemoglobin was raised by epoetin to target of 42 % compared to a lower target of 30 % (HR 1.3 (0.9 to

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1.9)). Increased doses of iron dextran were used in the higher target hemoglobin group (47). In anemic HF patients, administration of darbepoetin alfa adjusted to increase hemoglobin levels

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1-2 gm/Dl did not improve primary endpoint of a composite of death from any cause or

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hospitalization for worsening HF (48). Risk of ischemic stroke was increased in subjects receiving darbepoetin when compared with placebo (4.5% vs. 2.8%, p=0.03). Intravenous iron

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use was uncommon and did not differ between treatment groups (4.9% in the darbepoetin group and 5.6% in the placebo group, p=0.47), but it remains uncertain whether the observed

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increased thrombotic risk is attributable to the erythropoietic agent or increased hemoglobin

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levels. Finally, there are additional theoretical concerns related to increased body iron stores. The iron hypothesis, first published in 1981, proposed that reduced iron stores secondary to menstrual blood loss protected against coronary heart disease in pre-menopausal women (49).

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Iron is a pro-oxidant factor that promotes atherosclerosis progression in experimental

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models,(50,51). but epidemiological studies of the association between various surrogate measures of iron stores (dietary iron intake, blood donation history, and serum biomarkers) and

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CV outcomes in male and female populations have reported inconsistent findings (52-54). Interpretation of existing studies is limited by methodological issues related to bias and

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misclassification in ascertainment of exposure and/or outcomes, and missing data on important potential confounding variables (reproductive history, inflammation, cancer, and bleeding). The iron hypothesis has been revised, based on advancements in knowledge of the regulation of iron homeostasis and macrophage biology, to propose that the association between body iron stores and CV outcomes depends on hepcidin-induced changes in macrophage phenotype (5557). Macrophages play a critical role in the normal regulation of iron stores, both in scavenging and recycling of iron from senescent red blood cells and transporting dietary iron from the enterocyte to the reticuloendothelial system (58). Macrophages also play a key role in the pathogenesis of atherosclerosis, through accumulation of oxidized low-density lipoprotein and foam cell formation within the blood vessel wall (59). The macrophage phenotype is modulated

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by the negative feedback effects of hepcidin on the iron exporter protein ferroportin (58). Low hepcidin levels increase macrophage ferroportin activity, with a resultant distinct non-foam cell

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macrophage phenotype (M(Hb)) characterized by decreased intracellular iron, increased

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cholesterol efflux, secretion of anti-inflammatory cytokines, and reduced atherogenic potential (60-62). Conversely, increased hepatic production of hepcidin in response to pro-

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inflammatory cytokines or increased iron stores is associated with a pro-atherogenic macrophage phenotype characterized by increased intracellular iron content, avid uptake of

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oxidized low density lipoprotein cholesterol, foam cell formation, and atherosclerotic plaque

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destabilization (63). This mechanistic link between hepcidin levels and macrophage phenotype may explain the apparent paradox related to the absence of increased CV risk in patients with hereditary hemochromatosis, as mutations associated with disruption of normal hepcidin

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signaling in these genetic syndromes would promote formation of the non-atherogenic, non-

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foam cell M(Hb) phenotype despite increases in tissue iron stores (55,64). In addition to potential increased risk of CV disease, excess iron stores may be associated with increased

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production of oxygen free radicals, nucleic acid damage, and increased apoptosis that contributes to the pathogenesis of many human diseases, including neurodegenerative

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diseases, chronic lung disease, acute and chronic kidney disease, osteoporosis, some cancers, and sarcopenia and frailty in the elderly (16,17,65-68).

Summary and Recommendations

In conclusion, the available short-term data for intravenous iron supplementation in iron deficient HF patients provide a consistent signal for beneficial effects on symptoms and submaximal exercise capacity, and no clear signal for harm, at least up to 6 months. Subgroup data has yielded mixed findings, but based on the preponderance of data in HF trials, existing data from healthy populations, and physiology of the Fick principle linking hemoglobin as a key

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regulator of peripheral oxygen delivery and aerobic capacity (46,69), it is reasonable to consider correction of iron deficiency with iron supplementation in anemic HF patients with biomarkers

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and erythrocyte morphology consistent with iron deficiency (Figure 1). Based on the available

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data from non-HF iron deficiency populations, it is recommended to begin therapy with a trial of oral iron supplementation for 8 weeks (70,71). Ferrous sulfate 325 mg provides 65 mg of

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elemental iron and is usually administered 3 times daily with meals. In the event of gastrointestinal intolerance, the frequency of dosing can be decreased or other oral formulations

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can be administered (ferrous fumarate or ferrous gluconate). If oral therapy is not well tolerated

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or does not sufficiently augment biomarkers of iron stores and hemoglobin, intravenous iron therapy is a reasonable alternative therapy. Intravenous iron therapy can also be considered as initial therapy for more severe anemia, or if reduced hemoglobin level is thought to be

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associated with acute exacerbation of HF symptoms. The total dose of the intravenous iron is

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usually based on an estimate of the deficit of body iron stores derived from the Ganzoni formula: Total body iron deficit (mg) = body weight (kg) x (target Hb – actual Hb in g/L) x 0.24 + 500 (72).

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There are limited comparative data for the available intravenous iron preparations (30,73). Iron dextran is thought to have a greater risk of allergic reactions, including anaphylaxis, when

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compared with newer preparations. Iron sucrose (Venofer®, American Regent, Inc., Shirley, NY), ferric gluconate (Ferrlecit®, Sanofi-Aventis, Bridgewater, NJ), and FCM (Injectafer®, American Regent, Inc., Shirley NY) have all been shown to be effective in the treatment of iron deficiency anemia. Iron sucrose and ferric gluconate are FDA-approved for use in dialysis populations, whereas FCM is FDA-approved for non-dialysis chronic kidney disease populations. The recommended dose for FCM (750 mg) is higher than that for iron sucrose (100-400 mg) or ferric gluconate (125 mg), so fewer injections of FCM are needed to replenish iron stores. In all patients with evidence of iron deficiency anemia, an evaluation to identify a source of blood loss is warranted. Some sources of blood loss are difficult to detect and may lead to recurrent anemia, so ongoing monitoring of hemoglobin and biomarkers of iron stores is

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recommended after completion of the intial course of iron replacement therapy.

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Figure Legend

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Figure 1. Recommendations for diagnosis and treatment of iron deficiency in anemic HF

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patients (adapted from reference 9). Treatment with iron therapy is not recommended for nonanemic HF patients with biomarkers of iron deficiency. Abbreviations: Hgb=hemoglobin in g/dL;

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Tsat=transferrin saturation (%); sTfr=soluble transferrin receptor (mg/L)

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Exercise Capacity Improved 6mwk test in treatment group. (p<0.01)

Ferritin

TSAT

Hb

Increased in treatment group. (p<0.01)

Increased in treatment group (p<0.01)

Increased in treatment group. (p<0.01)

Improved in treatment group. (p=0.03)

Nonsignificant improved 6mwk test in treatment group. (p=0.08)

Increased in treatment group (p<0.001)

Increased in treatment group (p<0.001)

No difference between groups. (p
Improved in treatment group. (p<0.001)

Improved 6mwk test in treatment group. (p<0.001)

Increased in treatment group. (p<0.001)

Increased in treatment group (p<0.001)

No difference between groups. (p
Improved in treatment group.

Improved 6mwk test in treatment

Increased in treatment group.

Increased in treatment group

Increased in treatment group.

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NYHA Class Improved in treatment group. (p<0.01)

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Table 1. Controlled trials of intravenous iron therapy in patients with ID anemia and HF Study name Design Duration ID anemia N Symptom/ Definition QOL Intravenous iron A prospective, 26 wks Hb <12.5 g/dlL, 40 MLHFQ reduces NT-prodouble-blind, transferrin improved in brain natriuretic randomized, saturation <20%, treatment peptide in anemic placeboferritin <100 ng/ml, group patients with controlled creatinine (p=0.01) chronic heart study in NYHA clearance (CrCl) failure and renal II-IV HF <90 ml/min insufficiency, patients, LVEF (reference 32) ≤35% Effect of A prospective, 18 wks Hb<12.5 35 PGAS intravenous iron randomized g/dL(anemic improved in sucrose on 2:1, opengroup) or 12.5 to treatment exercise tolerance label, 14.5 group. in anemic and observerg/dL(nonanemic (p<0.002) nonanemic blinded, group); ferritin patients with parallel, <100 ng/ml or symptomatic controlled trial between 100 chronic heart in NYHA II-III ng/ml and 300 failure and iron HF patients, ng/ml with a deficiency. LVEF ≤45% transferrin (reference 33) saturation <20% Ferric A prospective, 24 wks Hb 9.5-13.5 g/dL, 459 KCCQ and carboxymaltose in randomized ferritin <100 ng/ml PGAS patients with heart 2:1, doubleor ferritin 100-299 improved in failure and iron blind study, ng/ml with TSAT treatment deficiency. placebo<20% group (reference 35) controlled trial (p=0.001) in NYHA II (LVEF ≤40%) or III (LVEF ≤45%) HF patients Beneficial effects A prospective, 52 wks Hb <15g/dL, ferritin 304 KCCQ and of long-term randomized, <100 mcg/l or PGAS intravenous iron double-blind ferritin 100-300 improved in therapy with ferric study, mcg/l with TSAT treatment

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Targeting ID Anemia in HF

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group (p=0.001)

(p<0.001)

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Reduced Hospitalization for HF in treatment group . (p=0.009)

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<20%

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placebocontrolled trial in NYHA II-III (LVEF ≤45%) HF patients

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carboxymaltose in patients with symptomatic heart failure and iron deficiency. (reference 36)

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group. (p=0.002)

(p<0.001)

(p<0.001)

(p<0.001)

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Figure 1