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Review
. 2024 Jul 9;150(2):151-161.
doi: 10.1161/CIRCULATIONAHA.124.068883. Epub 2024 May 11.

Redefining Iron Deficiency in Patients With Chronic Heart Failure

Milton Packer  1   2 , Stefan D Anker  3 , Javed Butler  4   1   5 , John G F Cleland  6 , Paul R Kalra  7   8   9 , Robert J Mentz  10   11 , Piotr Ponikowski  12   13 , Khawaja M Talha  5
Affiliations
Review

Redefining Iron Deficiency in Patients With Chronic Heart Failure

Milton Packer et al. Circulation. .

Abstract

A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20-100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%-30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted.

Keywords: ferritins; heart failure; iron; iron deficiencies; transferrin.

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Conflict of interest statement

Dr Packer reports personal fees for consulting from 89bio, AbbVie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Relypsa, and Salamandra, all outside the submitted work. Dr Anker reports grants from Vifor and Abbott Vascular; personal fees for consultancies, trial committee work, or lectures from Vifor, Abbott Vascular, Actimed, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GlaxoSmithKline, HeartKinetics, Impulse Dynamics, Occlutech, Pfizer, Regeneron, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave; and is a named co-inventor of 2 patent applications regarding MR-proANP (DE 102007010834 and DE 102007022367), but does not benefit personally from the patents, all outside the submitted work. Dr Butler reports personal consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Janssen, Daxor Edwards, Element Science, Eli Lilly, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, LivaNova, Medscape, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Secretome, Sequana, SQ Innovation, Tenex, Tricoq, and Vifor; and honoraria from Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Impulse Dynamics, and Vifor, all outside the submitted work. Dr Mentz reports grants from American Regent, AstraZeneca, Amgen, Bayer, Merck, Novartis, Zoll, and Cytokinetics; and personal consulting fees from Pharmacosmos, Vifor, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Abbott, Medtronic, Zoll, Boston Scientific, Cytokietics, Respicardia, Roche, Vifor, Sanofi, and Windtree, all outside the submitted work. Dr Cleland reports grants from Bristol Myers Squibb, British Heart Foundation, Medtronic, Pharma Nord, Vifor, and Pharmacosmos; personal consulting fees from Abbott, Biopeutics, Innolife, NI Medical, Novartis, and Servier; honoraria for committee or advisory boards from Idorsia and Medtronic; honoraria for lectures from AstraZeneca and Boehringer Ingelheim; and stock options or holdings in Heartfelt Limited and Viscardia, all outside the submitted work. Dr Kalra reports grants from Pharmacosmos and the British Heart Foundation; personal consulting fees from Amgen, Boehringer Ingelheim, Pharmacosmos, Servier, and CSL Vifor; and honoraria for lectures from AstraZeneca, Bayer, Novartis, Pfizer, Pharmacosmos, CLS Vifor, and Amgen, all outside the submitted work. Dr Ponikowski reports personal fees for consultancies, trial committee work, or lectures from Astra Zeneca, Bayer, Boehringer Ingelheim, Pfizer, Vifor Pharma, Amgen, Servier, Novartis, Novo Nordisk, Pharmacosmos, Abbott Vascular, Radcliffe Group, and Charite University, all outside the submitted work.

Figures

Figure.
Figure.
Iron regulatory proteins as potential biomarkers for an iron-deficiency state. The top row describes biologic function; the second row, triggers and biologic significance; the third row, diagnostic use; and the bottom row, assay limitations. IV indicates intravenous; and TSAT, transferrin saturation.
See this image and copyright information in PMC

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