Iron supplementation in acute heart failure: energize your life

This editorial refers to ‘The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study’, by E.A. Jankowska et al., doi:10.1093/eurheartj/ehab234. Diagnosis and treatment of iron deficiency (ID) in patients with acute heart failure and potential mechanisms how ID may aggravate heart failure severity. Hb, haemoglobin; LVEF, left ventricular ejection fraction; TSAT, transferrin saturation. Diagnosis and treatment of iron deficiency (ID) in patients with acute heart failure and potential mechanisms how ID may aggravate heart failure severity. Hb, haemoglobin; LVEF, left ventricular ejection fraction; TSAT, transferrin saturation. Iron deficiency (ID) is a frequent comorbidity in heart failure (HF).1 In chronic HF, ID worsens symptoms, impairs exercise tolerance, reduces health-related quality of life (HRQoL), and is associated with poor prognosis independent of the presence of anaemia.2,3 The European Society of Cardiology (ESC) HF guidelines recommend assessing systemic iron status and treating ID with i.v. ferric carboxymaltose (FCM) to alleviate symptoms and improve HRQoL in symptomatic patients with HF with reduced ejection fraction (HFrEF).2 Compared with other HF therapies, i.v. iron appears particularly effective in improving HRQoL.4 Unfortunately, clinical uptake of this treatment option remains rather poor, leaving ID underdiagnosed and undertreated in the majority of patients. Whether we should assess and treat ID in patients with acute HF (AHF), up to 80% of whom are diagnosed with ID, is an open question.1 In small-scale clinical trials, iron supplementation in iron-deficient patients stabilized after an episode of acute HF (AHF) appeared safe.5,6 Whether this therapy impacts outcome remains unclear. AFFIRM-AHF is a multicentre, double-blind, randomized trial evaluating the effect of pre-discharge i.v. FCM on outcomes in iron-deficient patients with a left ventricular ejection fraction of less than 50% who were stabilized after an episode of AHF.7 ID was defined as a serum ferritin concentration <100 μg/L, or between 100 and 299 μg/L with a transferrin saturation (TSAT) <20%, as determined at any time during the index hospitalization. Compared with placebo, FCM significantly reduced the risk of hospitalization for HF, with no apparent effect on the risk of cardiovascular death.7 Jankowska et al. have now assessed the effects of i.v. FCM on HRQoL in a pre-specified substudy of AFFIRM-AHF, published in this issue of the European Heart Journal.8 HRQoL was assessed with the 12-item version of the Kansas City Cardiomyopathy Questionnaire (KCCQ), which quantifies HF symptoms, physical challenges, social limitations, and quality of life.9 Patients had severe HF: >50% of them had class III and IV symptoms, a median N-terminal probrain natriuretic peptide concentration >4500 ng/L, and a KCCQ overall summary score of 38 points. The median total FCM dose administered before discharge and, if necessary, in week 6 was 1352 mg, calculated based on body weight and haemoglobin. From randomization to week 2, the KCCQ score in both groups improved substantially, reflecting successful treatment of AHF. From week 4 to 24, the FCM group showed greater score improvements. With no additional iron application(s) beyond 24 weeks, treatment effects were attenuated thereafter. FCM treatment effects appeared to be independent of baseline haemoglobin and additive to HF treatment with renin–angiotensin–aldosterone system inhibitors and beta-blockers. AFFIRM-AHF thus strongly suggests that iron status assessment and pre-discharge iron supplementation should become part of routine work-up for patients hospitalized with AHF. However, some aspects deserve further consideration. The definition of ID in AHF has been the subject of considerable debate. AFFIRM-AHF used the current ESC definition, established to guide iron treatment in chronic HF.2 Other definitions and/or surrogate markers, such as TSAT <20% or soluble transferrin receptor, may be more accurate for diagnosing ID in AHF.3 Detecting ID in AHF has many pitfalls. Inflammatory stress and acute renal failure may elevate ferritin; malnutrition and a catabolic state may reduce transferrin and, thus, artificially increase TSAT.10 Moreover, acute plasma volume changes may render these markers unsuitable for detecting ID. In AFFIRM-AHF, a ferritin concentration <100 μg/L, but not a TSAT <20%, appeared to identify those patients who responded best to iron supplementation.7,8 Following admission with AHF, ferritin concentrations and TSAT may ‘spontaneously’ increase during hospitalization and over a period of 30 days.11 Indeed, in AFFIRM-AHF, ferritin and TSAT in the placebo group increased within 6 weeks after randomization.7 Consequently, fewer patients are classified as having ID at discharge and during short-term follow-up. Whether such increases in ferritin and TSAT reflect iron status or other pathomechanisms is uncertain. This could be further explored by relating these changes to patient characteristics and outcome events. The magnitude of KCCQ improvement with FCM treatment vs. placebo compares favourably with other HF therapies.9 To assess clinically meaningful changes in KCCQ, the authors performed a responder analysis. The proportion of FCM-treated patients with small, moderate, and large improvements was numerically larger compared with the placebo group, but these results did not reach statistical significance. However, the thresholds tested here derive from chronic HF and may not be useful for assessing treatment effects in AHF.9 Hence, the clinical significance of improved KCCQ with iron supplementation observed in AFFIRM-AHF remains somewhat unclear. How does iron supplementation improve health status and outcome in patients with HF? Iron is an essential cofactor in haem and iron–sulfur cluster-containing proteins required for oxygen transport (haemoglobin) and storage (myoglobin) as well as cellular energy metabolism (e.g. components of the mitochondrial electron transport chain).12 Systemic ID, induced by malabsorption, blood loss, and/or iron sequestration due to chronic low-grade inflammation, limits iron supply for tissues.1,3 In most trials, the benefits of iron supplementation were independent of its haematopoietic effects.3 Instead, repleting cardiac and/or skeletal muscle iron stores may account for the beneficial effects of iron supplementation. Both organs have high energy demands and depend on proper mitochondrial function for continuous provision of ATP. Patients with longer HF duration or more advanced disease may have lower (tissue) iron concentrations and might therefore derive greater benefit from iron supplementation, as also indicated by subgroup analyses from AFFIRM-AHF.7,8,13,14 Mechanistically, transgenic mice engineered to develop cardiac-specific ID display mitochondrial dysfunction and develop HF.15,16 Correcting this iron deficit prevents the cardiac phenotype in these animals.15,16 So far, only a few studies have investigated cardiac iron status in patients with HF. For example, low cardiac iron content is associated with greater disease severity in chronic HF.13 In explanted terminally failing hearts, iron content is lower than in non-failing hearts and associates with mitochondrial dysfunction.14,16,17 Replenishing cardiac iron by FCM may improve heart function, as suggested by non-invasive imaging.18 Of note, systemic iron status cannot predict cardiac ID, indicating that HF may alter cardiac iron uptake and release.13,17 Finally, HF and ID act synergistically to induce skeletal myopathy and worsen exercise capacity.19 As indicated by magnetic resonance spectroscopy, skeletal muscle function is impaired in iron-deficient HFrEF patients, leading to lower muscle strength, greater energetic depletion, and more pronounced muscle tissue acidification during exercise.20 Iron supplementation may enhance skeletal muscle energetic recovery after exercise, suggesting improved mitochondrial function.21 Thus, iron supplementation may improve health status and outcome by restoring cardiac and skeletal muscle energetics in HF. In conclusion, AFFIRM-AHF identifies ID as a treatment target in patients stabilized after an episode of AHF. The in-hospital setting provides an excellent opportunity to administer FCM prior to discharge, thereby enhancing clinical uptake of this safe, simple, and effective therapy (Graphical Abstract). HF networks need to ensure that a second dose is infused after 6 weeks, if necessary, and that iron status is re-assessed every 3–4 months. Future studies should explore the regulation and functional implications of cardiac and skeletal muscle ID in HF patients to design individualized iron supplementation strategies. This work was supported by the German Research Foundation [Clinical Research Unit (KFO311) to T.K.]. Conflict of interest: T.K. has received an unrestricted research grant and advisory board and speaker fees from Vifor Pharma Ltd, and advisory board fees from Pharmocosmos Ltd. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.