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Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency: The FAIR-HF2 DZHK05 Randomized Clinical Trial - PMC

What are the efficacy and safety of intravenous ferric carboxymaltose in patients with heart failure and iron deficiency? In this randomized clinical trial that included 1105 patients, there was no significant between-group difference for ferric ...

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JAMA
. 2025 Mar 30;333(22):1965–1976. doi:
10.1001/jama.2025.3833

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Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency

The FAIR-HF2 DZHK05 Randomized Clinical Trial

Stefan D Anker

Stefan D Anker
,
MD, PhD

1
Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany

2
Institute of Health Centre for Regenerative Therapies, German Centre for Cardiovascular Research, partner site Charité Universitätsmedizin, Berlin, Germany

Find articles by
Stefan D Anker

1,
2,
✉
,
Tim Friede

Tim Friede
,
PhD

3
Department of Medical Statistics, University Medical Centre Göttingen, Göttingen, Germany

4
German Centre for Cardiovascular Research, partner site Lower Saxony, Germany

Find articles by
Tim Friede

3,
4
,
Javed Butler

Javed Butler
,
MD, MPH

5
Department of Medicine, University of Mississippi Medical Center, Jackson

6
Baylor Scott and White Research Institute, Dallas, Texas

Find articles by
Javed Butler

5,
6
,
Khawaja M Talha

Khawaja M Talha
,
MBBS

7
Department of Cardiology, Loyola University Medical Centre, Maywood, Illinois

Find articles by
Khawaja M Talha

7
,
Marius Placzek

Marius Placzek
,
PhD

3
Department of Medical Statistics, University Medical Centre Göttingen, Göttingen, Germany

Find articles by
Marius Placzek

3
,
Monika Diek

Monika Diek
,
MA

1
Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany

2
Institute of Health Centre for Regenerative Therapies, German Centre for Cardiovascular Research, partner site Charité Universitätsmedizin, Berlin, Germany

Find articles by
Monika Diek

1,
2
,
Anna Nosko

Anna Nosko
,
PhD

8
Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Find articles by
Anna Nosko

8
,
Adriane Stas

Adriane Stas
,
BA

4
German Centre for Cardiovascular Research, partner site Lower Saxony, Germany

9
Department of Medical Informatics, University Medical Centre Göttingen, Göttingen, Germany

Find articles by
Adriane Stas

4,
9
,
Stefan Kluge

Stefan Kluge
,
MD

8
Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Find articles by
Stefan Kluge

8
,
Dominik Jarczak

Dominik Jarczak
,
MD

8
Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Find articles by
Dominik Jarczak

8
,
Geraldine deHeer

Geraldine deHeer
,
MD

8
Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Find articles by
Geraldine deHeer

8
,
Meike Rybczynski

Meike Rybczynski
,
MD

10
University Heart and Vascular Centre Hamburg, Department of Cardiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

11
German Centre for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Hamburg, Germany

Find articles by
Meike Rybczynski

10,
11
,
Antoni Bayés-Genís

Antoni Bayés-Genís
,
MD, PhD

12
Heart Institute, Hospital Universitari Germans Trias i Pujol, CIBERCV, Barcelona, Spain

Find articles by
Antoni Bayés-Genís

12
,
Michael Böhm

Michael Böhm
,
MD

13
Department of Medicine III and Homburg Institute for Cardio, Renal, and Metabolic Medicine, Saarland University, Homburg, Germany

Find articles by
Michael Böhm

13
,
Andrew J S Coats

Andrew J S Coats
,
MD

14
Heart Research Institute, Sydney, Australia

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Andrew J S Coats

14
,
Frank Edelmann

Frank Edelmann
,
MD

15
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany

16
German Centre for Cardiovascular Research, partner site Berlin, Charité Universitätsmedizin, Berlin, Germany

Find articles by
Frank Edelmann

15,
16
,
Gerasimos Filippatos

Gerasimos Filippatos
,
MD

17
Department of Cardiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

Find articles by
Gerasimos Filippatos

17
,
Gerd Hasenfuß

Gerd Hasenfuß
,
MD

4
German Centre for Cardiovascular Research, partner site Lower Saxony, Germany

18
Department of Cardiology and Pneumology, University Medical Centre Göttingen, Georg August University of Göttingen, Göttingen, Germany

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Gerd Hasenfuß

4,
18
,
Wilhelm Haverkamp

Wilhelm Haverkamp
,
MD

1
Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany

2
Institute of Health Centre for Regenerative Therapies, German Centre for Cardiovascular Research, partner site Charité Universitätsmedizin, Berlin, Germany

Find articles by
Wilhelm Haverkamp

1,
2
,
Mitja Lainscak

Mitja Lainscak
,
MD, PhD

19
Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia

20
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

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Mitja Lainscak

19,
20
,
Ulf Landmesser

Ulf Landmesser
,
MD

16
German Centre for Cardiovascular Research, partner site Berlin, Charité Universitätsmedizin, Berlin, Germany

21
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany

22
Berlin Institute of Health, Berlin, Germany

Find articles by
Ulf Landmesser

16,
21,
22
,
Iain C Macdougall

Iain C Macdougall
,
MD

23
Department of Renal Medicine, King’s College Hospital, London, England

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Iain C Macdougall

23
,
Bela Merkely

Bela Merkely
,
MD, PhD, DSc

24
Heart and Vascular Centre, Semmelweis University, Budapest, Hungary

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Bela Merkely

24
,
Burkert M Pieske

Burkert M Pieske
,
MD

25
Division of Cardiology, Department of Internal Medicine, University Medicine Rostock, Rostock, Germany

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Burkert M Pieske

25
,
Fausto J Pinto

Fausto J Pinto
,
MD, PhD

26
Centro Academico de Medicina de Lisboa, CCUL@RISE, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

Find articles by
Fausto J Pinto

26
,
Tienush Rassaf

Tienush Rassaf
,
MD

27
West German Heart and Vascular Centre, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany

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Tienush Rassaf

27
,
Jennifer K Visser-Rogers

Jennifer K Visser-Rogers
,
PhD

28
Coronado Research, Newcastle, England

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Jennifer K Visser-Rogers

28
,
Giuseppe Rosano

Giuseppe Rosano
,
PhD

29
Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy

30
Cardiology, San Raffaele Cassino Hospital, Cassino, Italy

Find articles by
Giuseppe Rosano

29,
30
,
Maurizio Volterrani

Maurizio Volterrani
,
MD

29
Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy

31
IRCCS San Raffaele Roma, Rome, Italy

Find articles by
Maurizio Volterrani

29,
31
,
Stephan von Haehling

Stephan von Haehling
,
MD, PhD

4
German Centre for Cardiovascular Research, partner site Lower Saxony, Germany

18
Department of Cardiology and Pneumology, University Medical Centre Göttingen, Georg August University of Göttingen, Göttingen, Germany

Find articles by
Stephan von Haehling

4,
18
,
Markus S Anker

Markus S Anker
,
MD

16
German Centre for Cardiovascular Research, partner site Berlin, Charité Universitätsmedizin, Berlin, Germany

21
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany

22
Berlin Institute of Health, Berlin, Germany

32
School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland

Find articles by
Markus S Anker

16,
21,
22,
32
,
Wolfram Doehner

Wolfram Doehner
,
MD, PhD

33
Berlin Institute of Health-Centre for Regenerative Therapies and Department of Cardiology, Deutsches Herzzentrum der Charité and German Centre for Cardiovascular Research, partner site Charité-Universitätsmedizin Berlin, Berlin, Germany

Find articles by
Wolfram Doehner

33
,
Hüseyin Ince

Hüseyin Ince
,
MD

25
Division of Cardiology, Department of Internal Medicine, University Medicine Rostock, Rostock, Germany

Find articles by
Hüseyin Ince

25
,
Friedrich Koehler

Friedrich Koehler
,
MD

16
German Centre for Cardiovascular Research, partner site Berlin, Charité Universitätsmedizin, Berlin, Germany

34
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Charité Mitte, Berlin, Germany

35
Centre for Cardiovascular Telemedicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Find articles by
Friedrich Koehler

16,
34,
35
,
Gianluigi Savarese

Gianluigi Savarese
,
MD

36
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

Find articles by
Gianluigi Savarese

36
,
Muhammad Shahzeb Khan

Muhammad Shahzeb Khan
,
MD, MSc

6
Baylor Scott and White Research Institute, Dallas, Texas

37
Baylor Scott and White Health, Heart Hospital, Plano, Texas

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Muhammad Shahzeb Khan

6,
37
,
Ursula Rauch-Kröhnert

Ursula Rauch-Kröhnert
,
MD

16
German Centre for Cardiovascular Research, partner site Berlin, Charité Universitätsmedizin, Berlin, Germany

21
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany

22
Berlin Institute of Health, Berlin, Germany

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Ursula Rauch-Kröhnert

16,
21,
22
,
Tommaso Gori

Tommaso Gori
,
MD

38
Department of Cardiology, Cardiology I, University Medical Centre Mainz, Mainz, Germany

39
German Centre for Cardiovascular Research, Standort RheinMain, Frankfurt, Germany

Find articles by
Tommaso Gori

38,
39
,
Teresa Trenkwalder

Teresa Trenkwalder
,
MD

40
Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany

41
German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany

Find articles by
Teresa Trenkwalder

40,
41
,
Ibrahim Akin

Ibrahim Akin
,
MD

42
Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

43
German Centre for Cardiovascular Research, partner site Heidelberg/Mannheim, Mannheim, Germany

Find articles by
Ibrahim Akin

42,
43
,
Christina Paitazoglou

Christina Paitazoglou
,
MD

44
Department of Cardiology, Angiology, and Intensive Care Medicine, University Heart Centre Lübeck, Medical Clinic II, University Hospital Schleswig-Holstein, Lübeck, Germany

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Christina Paitazoglou

44
,
Iwona Kobielusz-Gembala

Iwona Kobielusz-Gembala
,
MD

45
Oświęcimskie Centrum Badań Klinicznych, Oświęcim, Poland

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Iwona Kobielusz-Gembala

45
,
Luca Kuthi

Luca Kuthi
,
MD

24
Heart and Vascular Centre, Semmelweis University, Budapest, Hungary

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Luca Kuthi

24
,
Norbert Frey

Norbert Frey
,
MD

46
Department of Cardiology, Angiology, and Pneumolgy, Clinical Trial Unit, University Hospital Heidelberg, Heidelberg, Germany

Find articles by
Norbert Frey

46
,
Manuela Licka

Manuela Licka
,
MD

46
Department of Cardiology, Angiology, and Pneumolgy, Clinical Trial Unit, University Hospital Heidelberg, Heidelberg, Germany

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Manuela Licka

46
,
Stefan Kääb

Stefan Kääb
,
MD

47
Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany

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Stefan Kääb

47
,
Karl-Ludwig Laugwitz

Karl-Ludwig Laugwitz
,
MD

41
German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany

48
Department of Internal Medicine I, Technical University Munich University Hospital, Munich, Germany

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Karl-Ludwig Laugwitz

41,
48
,
Piotr Ponikowski

Piotr Ponikowski
,
MD, PhD

49
Institute of Heart Diseases, Medical University and University Hospital, Wroclaw, Poland

Find articles by
Piotr Ponikowski

49
,
Mahir Karakas

Mahir Karakas
,
MD, PhD, MBA

8
Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

11
German Centre for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Hamburg, Germany

Find articles by
Mahir Karakas

8,
11,
✉

Author information

Article notes

Copyright and License information

1
Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany

2
Institute of Health Centre for Regenerative Therapies, German Centre for Cardiovascular Research, partner site Charité Universitätsmedizin, Berlin, Germany

3
Department of Medical Statistics, University Medical Centre Göttingen, Göttingen, Germany

4
German Centre for Cardiovascular Research, partner site Lower Saxony, Germany

5
Department of Medicine, University of Mississippi Medical Center, Jackson

6
Baylor Scott and White Research Institute, Dallas, Texas

7
Department of Cardiology, Loyola University Medical Centre, Maywood, Illinois

8
Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

9
Department of Medical Informatics, University Medical Centre Göttingen, Göttingen, Germany

10
University Heart and Vascular Centre Hamburg, Department of Cardiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

11
German Centre for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Hamburg, Germany

12
Heart Institute, Hospital Universitari Germans Trias i Pujol, CIBERCV, Barcelona, Spain

13
Department of Medicine III and Homburg Institute for Cardio, Renal, and Metabolic Medicine, Saarland University, Homburg, Germany

14
Heart Research Institute, Sydney, Australia

15
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany

16
German Centre for Cardiovascular Research, partner site Berlin, Charité Universitätsmedizin, Berlin, Germany

17
Department of Cardiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

18
Department of Cardiology and Pneumology, University Medical Centre Göttingen, Georg August University of Göttingen, Göttingen, Germany

19
Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia

20
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

21
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany

22
Berlin Institute of Health, Berlin, Germany

23
Department of Renal Medicine, King’s College Hospital, London, England

24
Heart and Vascular Centre, Semmelweis University, Budapest, Hungary

25
Division of Cardiology, Department of Internal Medicine, University Medicine Rostock, Rostock, Germany

26
Centro Academico de Medicina de Lisboa, CCUL@RISE, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

27
West German Heart and Vascular Centre, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany

28
Coronado Research, Newcastle, England

29
Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy

30
Cardiology, San Raffaele Cassino Hospital, Cassino, Italy

31
IRCCS San Raffaele Roma, Rome, Italy

32
School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland

33
Berlin Institute of Health-Centre for Regenerative Therapies and Department of Cardiology, Deutsches Herzzentrum der Charité and German Centre for Cardiovascular Research, partner site Charité-Universitätsmedizin Berlin, Berlin, Germany

34
Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Charité Mitte, Berlin, Germany

35
Centre for Cardiovascular Telemedicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

36
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

37
Baylor Scott and White Health, Heart Hospital, Plano, Texas

38
Department of Cardiology, Cardiology I, University Medical Centre Mainz, Mainz, Germany

39
German Centre for Cardiovascular Research, Standort RheinMain, Frankfurt, Germany

40
Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany

41
German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany

42
Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

43
German Centre for Cardiovascular Research, partner site Heidelberg/Mannheim, Mannheim, Germany

44
Department of Cardiology, Angiology, and Intensive Care Medicine, University Heart Centre Lübeck, Medical Clinic II, University Hospital Schleswig-Holstein, Lübeck, Germany

45
Oświęcimskie Centrum Badań Klinicznych, Oświęcim, Poland

46
Department of Cardiology, Angiology, and Pneumolgy, Clinical Trial Unit, University Hospital Heidelberg, Heidelberg, Germany

47
Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany

48
Department of Internal Medicine I, Technical University Munich University Hospital, Munich, Germany

49
Institute of Heart Diseases, Medical University and University Hospital, Wroclaw, Poland

Accepted for Publication:
March 10, 2025.

Published Online:
March 30, 2025. doi:
10.1001/jama.2025.3833

Correction:
This article was corrected April 8, 2025, to update the corresponding author information.

✉
Corresponding Authors:
Stefan D. Anker, MD, PhD, Deutsches Herzzentrum der Charite, Augustenburger Platz 1, Berlin 13353, Germany (
s.anker@cachexia.de
); Mahir Karakas, MD, PhD, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany (
m.karakas@uke.de
).

Author Contributions:
Dr S. Anker had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design:
S. Anker, Friede, Butler, Diek, Stas, Filippatos, Hasenfuß, Lainscak, Landmesser, Pieske, Pinto, Visser-Rogers, Rosano, Ince, Licka, Kääb, Laugwitz, Ponikowski, Karakas.

Acquisition, analysis, or interpretation of data:
S. Anker, Friede, Butler, Talha, Placzek, Nosko, Kluge, Jarczak, de Heer, Rybczynski, Bayés-Genís, Böhm, Coats, Edelmann, Filippatos, Haverkamp, Lainscak, Landmesser, Macdougall, Merkely, Pinto, Rassaf, Volterrani, von Haehling, M. Anker, Doehner, Koehler, Savarese, Khan, Rauch-Kröhnert, Gori, Trenkwalder, Akin, Paitazoglou, Kobielusz-Gembala, Kuthi, Frey, Kääb, Laugwitz, Karakas.

Drafting of the manuscript:
S. Anker, Friede, Butler, Talha, Pinto, Khan, Karakas.

Critical review of the manuscript for important intellectual content:
Butler, Talha, Placzek, Diek, Nosko, Stas, Kluge, Jarczak, de Heer, Rybczynski, Bayés-Genís, Böhm, Coats, Edelmann, Filippatos, Hasenfuß, Haverkamp, Lainscak, Landmesser, Macdougall, Merkely, Pieske, Pinto, Rassaf, Visser-Rogers, Rosano, Volterrani, von Haehling, M. Anker, Doehner, Ince, Koehler, Savarese, Khan, Rauch-Kröhnert, Gori, Trenkwalder, Akin, Paitazoglou, Kobielusz-Gembala, Kuthi, Frey, Licka, Kääb, Laugwitz, Ponikowski, Karakas.

Statistical analysis:
Friede, Placzek, Visser-Rogers, Kobielusz-Gembala.

Obtained funding:
S. Anker, Friede, Frey, Laugwitz, Karakas.

Administrative, technical, or material support:
Talha, Diek, Nosko, Stas, Kluge, Jarczak, de Heer, Rybczynski, Coats, Edelmann, Haverkamp, Merkely, Pinto, von Haehling, Doehner, Koehler, Savarese, Khan, Rauch-Kröhnert, Trenkwalder, Akin, Licka, Kääb, Laugwitz, Karakas.

Supervision:
S. Anker, Butler, Bayés-Genís, Lainscak, Landmesser, Pieske, Pinto, Rassaf, Rosano, von Haehling, Khan, Rauch-Kröhnert, Gori, Licka, Kääb, Laugwitz, Ponikowski, Karakas.

Conflict of Interest Disclosures:
Dr S. Anker reported receiving grants from Abbott Laboratories; receiving personal fees from Actimed Therapeutics, Alleviant, AstraZeneca, Bayer, Berlin Heals, BioVentrix, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior Pharmaceuticals GmbH, Cordio, CSL Vifor, CVRx, Cytokinetics, Edwards Lifesciences, Farraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Lilly, Mankind Pharma, Medtronic, Novartis, Novo Nordisk, Occlutech, Pfizer, Regeneron, Relaxera, Repairon GmbH, SCIRENT Clinical Research and Science, Sensible Medical, Servier, Vectorious Medical Technologies, Vivus, and V-Wave; and being a named co-inventor of 2 patent applications regarding midregional proatrial natriuretic peptide, but does not benefit personally from the related issued patents. Dr Friede reported receiving institutional grants from Abbott, the German Research Foundation, the Federal Joint Committee, and the European Commission; receiving personal fees from Actimed Therapeutics, Bayer, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, Fresenius Kabi, Galapagos, Immunic Therapeutics, Kyowa Kirin, LivaNova, Minoryx Therapeutics, Novartis, PINK! Activ gegen Brustkrebs, Recardio Inc, Relaxera, Roche, Servier, Viatris Inc, and CSL Vifor; being a data and safety monitoring committee member for Aslan, Bayer, Biosense Webster, Enanta Pharmaceuticals, Galapagos, IQVIA, Novartis, PPD, Recordati, Roche, and VICO Therapeutics; and being a trial steering committee member for SCL Behring. Dr Butler reported receiving personal fees from Abbott, Adaptyx Biosciences, American Regent, Amgen, Applied Therapeutic, AskBio (Asklepios BioPharmaceutical), Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell LLC, Cardior, Cardiorem, CSL Vifor, CVRx, Cytokinetics, Daxor Corporation, Diastol, Edwards Lifesciences, Element Science, Faraday Pharmaceuticals, Foundry, G3P, Idorsia, Innolife, Impulse Dynamics, Imbria Pharmaceuticals, Intellia, Inventiva Pharma, Ionis, Levator Therapeutics, Lexicon, Lilly, LivaNova, Janssen, Mankind, Medtronic, Merck, Occlutech, Owkin, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Pulnovo, Regeneron, Renibus Therapeutics, Reprieve, Roche, RyCarma Therapeutics, Salamandra, Saillant Therapeutics, Salubris, Sanofi, SC Pharma, Secretome Therapeutics, Sequana, SQ Innovation, TikkunLev Therapeutics, Tenex, Transmural, Tricog Health, Ultromics Ltd, Vera, Vifor, and Zoll. Dr Kluge reported receiving research support from CytoSorbents and Daiichi Sankyo; receiving grants from the German Ministry of Science and the German Heart Foundation; and receiving personal fees from ADVITOS, Biotest, CSL Behring, Daiichi Sankyo, Fresenius Medical Care, Gilead, Mitsubishi Tanabe Pharma, Merck Sharp and Dohme, Pfizer, Shionogi, and Zoll. Dr Bayés-Genís reported receiving personal fees from Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics, and CSL Vifor. Dr Böhm reported receiving grants from the German Research Foundation; receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Medtronic, Novartis, Pharmacosmos, Recor, Servier, and Vifor; serving on advisory boards for IQVIA, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, GSK, Medtronic, Novartis, Pharmacosmos, Recor, Servier, and CSL Vifor; and acting as a press spokesman and ex officio board member of the German Cardiac Society. Dr Coats reported receiving personal fees from Actimed Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, GSK, Menarini, Novartis, Novo Nordisk, Servier, CSL Vifor, Abbott, Actimed Therapeutics, Cardiac Dimensions, Corvia, CVRx, Enopace Biomedical Ltd, ESN Cleer, Faraday Pharmaceuticals, Impulse Dynamics, Respicardia, and Viatris. Dr Edelmann reported receiving personal fees from Vifor, Pharmacosmos, and Thieme. Dr Filippatos reported receiving personal fees from Novartis, Servier, Impulse Dynamics, Novo Nordisk, Medtronic, CSL Vifor, Boehringer Ingelheim, and Bayer and receiving grants from the European Union. Dr Lainscak reported receiving grants from the Slovenian Research Agency and receiving personal fees from Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Landmesser reported receiving grants from Abbott, Bayer, and Novartis. Dr Macdougall reported receiving personal fees from GlaxoSmithKline and Vifor Pharma. Dr Merkely reported receiving personal fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, Duke Clinical Research Institute, Medtronic, and Novartis and receiving institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Duke Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and CSL Vifor. Dr Pieske reported receiving personal fees from River BioMedics, AstraZeneca, Bayer, Merck Sharp and Dohme, Novartis, Bristol Myers Squibb, and Boehringer Ingelheim and having minor shares in Imaging in Clinical Trials GmbH. Dr Pinto reported receiving personal fees from Boehringer Ingelheim, Daichi Sankyo, Novartis, Servier, Vifor, and Zydus and serving on advisory boards for Medtronic, Novartis, Servier, and CSL Vifor. Dr Rassaf reported receiving personal fees from AstraZeneca, Bayer, Pfizer, and Daiichi-Sankyo and receiving grants from the German Research Foundation. Dr Visser-Rogers reported working for a consultancy company and receiving institutional payments and consulting fees from various pharmaceutical and biotech companies; being the current president of the International Biometric Society, British and Irish Region; and owning stock in Coronado Research. Dr Rosano reported receiving grants from the Ministero della Salute Ricerca Corrente and AstraZeneca and receiving personal fees from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Cipla, CSL Vifor, Novartis, Medtronic, Menarini, Servier, and Viatris. Dr von Haehling reported receiving grants from CTC North, Pharmacosmos, the Innovative Medicines Initiative, AstraZeneca, Amgen, IMI, and the German Centre for Cardiovascular Research and receiving personal fees from Vifor, Pharmacosmos, AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Edwards Lifesciences, Thermo Scientific BRAHMS Biomarkers, LumiraDx, Novartis, Novo Nordisk, and Merck Sharp and Dohme. Dr Doehner reported receiving personal fees from Ai Mediq, Bayer, Boehringer Ingelheim, Medtronic, and Vifor Pharma and receiving research support from the European Union (Horizon 2020), the German Ministry of Education and Research, the German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. Dr Ince reported serving on a data and safety monitoring board for RESHAPE-HF2. Dr Koehler reported receiving grants from the German Federal Ministry of Economics and Climate Protection and receiving personal fees from Biotronik, Boehringer-Ingelheim, Sanofi Germany GmbH, Novartis Germany (until 2022), and Amgen Germany (in 2021). Dr Savarese reported receiving personal fees from Boston Scientific, Merck, Novartis, CSL Vifor, Bayer, Cytokinetics, Pharmacosmos, AstraZeneca, Boehringer Ingelheim, Servier, Medtronic, Teva Pharmaceuticals, Abbott, Edwards Lifesciences, Intas Pharmaceuticals, and Abbott and receiving grants from Abbott, AstraZeneca, Boehringer Ingelheim, Servier, CSL Vifor, Novartis, Boston Scientific, Edwards Lifesciences, Teva Pharmaceuticals, Medtronic, Merck, Pharmacosmos, Roche, Cytokinetics, Menarini, Intas Pharmaceuticals, Getz, and Bayer. Dr Khan reported receiving personal fees from Bayer and Novartis. Dr Gori reported receiving personal fees and grant support from Abbott Vascular, Shockwave Medical, Bristol-Myers Squibb/Pfizer, Bayer, AstraZeneca, Novartis, ZOLL Medical/TherOx Inc, SMT, and Insight Lifetech. Dr Trenkwalder reported receiving grants from Pfizer; receiving personal fees from Pfizer, Alnylam, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Novartis, and Alexion; and receiving travel support from Alnylam, Bayer, and Boehringer Ingelheim. Dr Kuthi reported receiving personal fees from Boehringer Ingelheim and receiving nonfinancial support from Novartis and Novo Nordisk. Dr Frey reported receiving personal fees from AstraZeneca, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Pfizer. Dr Ponikowski reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Amgen, Servier, Novartis, Bayer, Merck Sharp and Dohme, Pfizer, Cibiem, Impulse Dynamics, Renal Guard Solutions, Bristol Myers Squibb, Berlin-Chemie, Novo Nordisk, Pharmacosmos, Moderna, Relaxera, and Abbott Vascular. Dr Karakas reported receiving grants from Adrenomed AG, the German Ministry of Health, Vifor, the German Heart Foundation, and the Else Kröner-Fresenius Foundation; receiving personal fees from Adrenomed AG, SphingoTec GmbH, CSL Vifor, Daiichi-Sankyo, Pharmacosmos, and 4TEEN4 Pharmaceuticals GmbH; and being a part-time employee of 4TEEN4 Pharmaceuticals GmbH. No other disclosures were reported.

Funding/Support:
The study was financed by the German Center for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung eV), CSL Vifor (an unrestricted scientific grant and free provision of 0.9% saline and ferric carboxymaltose), and the German Heart Foundation (Deutsche Herzstiftung eV).

Role of the Funder/Sponsor:
The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation:
Presented in part at the American College of Cardiology annual meeting; March 30, 2025; Chicago, Illinois.

Data Sharing Statement:
See
Supplement 7
.

✉
Corresponding author.

Received 2025 Feb 17; Accepted 2025 Mar 10; Issue date 2025 Jun 10.

Copyright 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.

PMC Copyright notice

PMCID: PMC11955906 PMID:
40159390

See "
Iron Deficiency in Adults: A Review.
" with doi: 10.1001/jama.2025.0452.

Key Points

Question

What are the efficacy and safety of intravenous ferric carboxymaltose in patients with heart failure and iron deficiency?
Findings

In this randomized clinical trial that included 1105 patients, there was no significant between-group difference for ferric carboxymaltose compared with placebo in the occurrence of time to cardiovascular death or first heart failure hospitalization in the overall cohort, in the subset of patients with a transferrin saturation less than 20%, or in total (first and recurrent) heart failure hospitalizations.
Meaning

Ferric carboxymaltose was well tolerated, but did not significantly improve outcomes compared with placebo in patients with heart failure and iron deficiency.
Abstract

Importance

Uncertainty remains about the efficacy of intravenous iron in patients with heart failure and iron deficiency.
Objective

To assess the efficacy and safety of ferric carboxymaltose in patients with heart failure and iron deficiency.
Design, Setting, and Participants

This multicenter, randomized clinical trial enrolled 1105 patients with heart failure (defined as having a left ventricular ejection fraction of ≤45%) and iron deficiency (serum ferritin level <100 ng/mL; or if transferrin saturation was <20%, a serum ferritin level between 100 ng/mL and 299 ng/mL) at 70 clinic sites in 6 European countries from March 2017 to November 2023. The median follow-up was 16.6 months (IQR, 7.9-29.9 months).
Intervention

Administration of ferric carboxymaltose (n = 558) initially given at an intravenous dose of up to 2000 mg that was followed by 500 mg every 4 months (unless stopping criteria were met) vs a saline placebo (n = 547).
Main Outcomes and Measures

The primary end point events were (1) time to cardiovascular death or first heart failure hospitalization, (2) total heart failure hospitalizations, and (3) time to cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation less than 20%. All end point events were measured through follow-up. The end points would be considered statistically significant if they fulfilled at least 1 of the following conditions: (1)
P
≤ .05 for all 3 of the end point comparisons, (2)
P
≤ .025 for 2 of the end point comparisons, or (3)
P
≤ .0167 for any of the 3 end point comparisons (Hochberg procedure).
Results

Of the 1105 participants (mean age, 70 years [SD, 12 years]; 33% were women), cardiovascular death or first heart failure hospitalization (first primary outcome) occurred in 141 in the ferric carboxymaltose group vs 166 in the placebo group (hazard ratio, 0.79 [95% CI, 0.63-0.99];
P
= .04). The second primary outcome (total heart failure hospitalizations) occurred 264 times in the ferric carboxymaltose group vs 320 times in the placebo group (rate ratio, 0.80 [95% CI, 0.60-1.06];
P
= .12). The third primary outcome (cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation <20%) occurred in 103 patients in the ferric carboxymaltose group vs 128 patients in the placebo group (hazard ratio, 0.79 [95% CI, 0.61-1.02],
P
= .07). A similar amount of patients had at least 1 serious adverse event in the ferric carboxymaltose group (269; 48.2%) vs in the placebo group (273; 49.9%) (
P
= .61).
Conclusions and Relevance

In patients with heart failure and iron deficiency, ferric carboxymaltose did not significantly reduce the time to first heart failure hospitalization or cardiovascular death in the overall cohort or in patients with a transferrin saturation less than 20%, or reduce the total number of heart failure hospitalizations vs placebo.
Trial Registration

ClinicalTrials.gov Identifier:
NCT03036462

This randomized clinical trial compares the efficacy and safety of ferric carboxymaltose vs placebo in patients with heart failure and iron deficiency.
Introduction

Iron deficiency is prevalent in up to half of patients with heart failure, and is associated with worse symptoms, reduced exercise capacity, and increased mortality vs patients without iron deficiency.
1
,
2
,
3
,
4
However, the benefit of intravenous iron supplementation for patients with heart failure and iron deficiency remains uncertain.
5
,
6
The AFFIRM-AHF (A Randomized, Double-blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalizations and Mortality in Iron Deficient Subjects Admitted for Acute Heart Failure) trial
7
did not meet its primary end point of total heart failure hospitalizations and cardiovascular death in patients with worsening heart failure treated with ferric carboxymaltose, but reported a significant reduction in total heart failure hospitalizations.

The IRONMAN (Intravenous Ferric Derisomaltose in Patients with Heart Failure and Iron Deficiency) trial
8
showed similar results to the AFFIRM-AHF trial
7
using a different iron preparation. The HEART-FID (Ferric Carboxymaltose in Heart Failure with Iron Deficiency) trial
9
also did not show a significant benefit of intravenous iron supplementation in patients with chronic stable heart failure; however, the population of patients recruited had the highest transferrin saturation values at baseline compared with all other relevant trials. The HEART-FID trial
9
also used the most stringent approach
10
to guide longer-term therapy with intravenous iron. These heterogeneous results may be related to the COVID-19 pandemic and its effects on the conduct of trials and on the differences in cumulative iron dosing
10
across the trials. The definition of iron deficiency used in prior trials relied mainly on serum ferritin level, but transferrin saturation less than 20% has emerged as a potentially more specific marker of iron deficiency.
11

A meta-analysis
12
suggested a benefit on clinical outcomes with intravenous iron supplementation among patients with a transferrin saturation less than 20%, irrespective of the serum ferritin test used. However, there remains uncertainty regarding the role of intravenous iron and optimal dosage in patients with heart failure and iron deficiency. We performed the FAIR-HF2 (Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality) trial to evaluate the effects of more intensive and consistent supplementation of intravenous iron in patients with heart failure and iron deficiency.
Methods

Study Design

The current study was a prospective, investigator-initiated, multicenter randomized clinical trial that included patients with chronic, stable heart failure and iron deficiency and was conducted at 70 clinic sites in 6 European countries. The trial protocol was designed by the principal investigators and the financial sponsor and was approved by the institutional review boards or ethics committees at each participating site (
Supplements 1-4
). Details of the trial design and protocol have been published.
13
Additional information about the study design appears in eFigure 1 in
Supplement 5
.

An independent data and safety monitoring committee (
Supplement 5
) evaluated patient safety during the trial. The legal sponsor of the study was the University Hospital Hamburg-Eppendorf. The SecuTrial of the German Centre for Cardiovascular Research was used for the data collection. The monitoring of the trial was initially coordinated by CTC North, but later coordinated and completed by GKM Gesellschaft für Therapieforschung mbH. The Consolidated Standards of Reporting Trials (
CONSORT
) reporting guideline was used for this trial.
Patients, Randomization, and Follow-Up

Eligible patients had chronic heart failure with reduced ejection fraction for at least 3 months, a left ventricular ejection fraction of 45% or less, and evidence of serum iron deficiency (had a serum ferritin level <100 ng/mL; or if transferrin saturation was <20%, had a serum ferritin level between 100 ng/mL and 299 ng/mL). At the time of screening, eligible patients were considered (1) restabilized and eligible for hospital discharge within 24 hours, (2) as stable and ambulatory among those with a heart failure hospitalization within the past 12 months, or (3) as stable and ambulatory with elevated natriuretic peptide levels. All participants provided written informed consent for inclusion in the study.

Patients were excluded if they had (1) a known hypersensitivity to any component of ferric carboxymaltose, (2) a ferritin concentration of 300 μg/L or greater or a hemoglobin concentration of less than 9.5 g/dL, (3) a history of treatment with an erythropoietin-stimulating agent, or (4) received any intravenous iron or a blood transfusion within the 6 weeks prior to randomization. The complete list of inclusion and exclusion criteria appears in eTable 1 in
Supplement 5
.

Patients were randomly assigned in a 1:1 ratio to either intravenous ferric carboxymaltose (treatment group) or placebo (control group) in addition to medical therapy (
Figure 1
). Randomization was carried out using a block randomization with random block sizes and stratified by the following 4 baseline variables: hemoglobin concentration (>12.0 g/dL vs ≤12.0 g/dL), country, status at inclusion (outpatient vs inpatient), and serum ferritin level (>100 ng/mL vs ≤100 ng/mL).

Figure 1. Recruitment, Randomization, and Follow-Up in the FAIR-HF2 Trial.

Open in a new tab

FAIR-HF2 indicates Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality.

a
The precise reasons are unknown.

b
Included adverse effects, COVID-19 restrictions, medical reasons that prohibit further participation at the discretion of the investigator or patient, heart transplant, and patient felt overstrained.

c
Included intake of a medication forbidden per the study participation rules, COVID-19 restrictions, medical reasons that prohibit further participation at the discretion of the investigator or patient, heart transplant, and patient felt overstrained.

d
Four patients in the ferric carboxymaltose group and 2 patients in the placebo group did not receive any therapy.
Intervention

The treatment dosing phases were divided into a repletion and a maintenance phase (eTable 2 in
Supplement 5
). The repletion dose of ferric carboxymaltose followed the European Medicines Agency summary of product characteristics based on hemoglobin concentration and body weight. Ferric carboxymaltose was initially administered up to a maximum dose of 2000 mg during the first 2 visits at baseline and at week 4; the subsequent fixed maintenance doses of 500 mg were administered every 4 months unless the hemoglobin concentration exceeded 16 g/dL or the serum ferritin level exceeded 800 ng/mL. Saline was administered at all visits for patients in the placebo group.

Unblinded site personnel prepared and administered the ferric carboxymaltose or saline placebo. The participants and all other staff were blind to the administration of the allocated treatment. The study treatment was prepared using black syringes or other appropriate measures, and then administered using a curtain to maintain patient blinding. Unblinded site personnel were not involved in performing any patient assessments at their site.
Outcomes and Assessment

The trial initially planned to include 1 primary end point (composite outcome of cardiovascular death and first and recurrent heart failure hospitalizations). However, the trial was partly performed during the COVID-19 pandemic, and given the blinded nature of the study, we were unable to determine the exact quantity and duration of intravenous iron therapy that each patient received. Moreover, when the blinded event rate analyses were conducted, the overdispersion parameter for the rate of total cardiovascular deaths and heart failure hospitalizations was found to be higher than originally planned, and it was decided in March 2024 (ie, well before database closure on December 23, 2024) to use 3 distinct primary end points: (1) the time to first event of either cardiovascular death or heart failure hospitalization; (2) the composite rate of first and recurrent heart failure hospitalizations; and (3) the time to first event of either cardiovascular death or heart failure hospitalization in the subgroup of patients with a transferrin saturation less than 20% at baseline. The decision to change from a single primary end point to 3 primary end points was not entirely a statistical one and included clinical and methodological considerations that have been described elsewhere.
13

Deaths and hospitalization events were adjudicated by a clinical events committee (
Supplement 5
). The secondary end points included the change from baseline to 12 months in New York Heart Association functional class, EQ-5D score, and 6-minute walk distance as well as the change in patient-reported global assessment of subjective well-being score during follow-up until 12 months. The original primary end point (composite outcome of cardiovascular death and first and recurrent heart failure hospitalizations) was included as an exploratory end point. The rates of the occurrence for the first 2 primary end points (censored at 12 months) were also included as exploratory analyses (end points). The safety end points included all-cause mortality and cardiovascular mortality at 3 years of follow-up.
Statistical Analysis

The sample size was planned for the original primary composite outcome of total heart failure hospitalizations and cardiovascular death. Assuming negative binomial distributions, a sample size of 545 patients per group who were followed up for, on average, 2 years was estimated to provide power of at least 80% at a 1-sided significance level of .025 as long as the reduction in the event rate was at least 30%. No changes to the planned sample size were made during the study period. Information on the blinded sample size review and additional sample size considerations have been published.
13

The complete statistical analysis plan appears in
Supplement 6
. The statistical analyses were performed according to the intention-to-treat principle. The analysis of the primary end points related to time to cardiovascular death or first heart failure hospitalization (in the full population and in the population of patients with a transferrin saturation <20% at baseline) was performed using the Cox proportional hazards model (adjusted for stratification variables of the randomization) to derive hazard ratios (HRs) with 95% CIs. The analysis for the primary end point of total (first and recurrent) heart failure hospitalizations was based on the semiparametric regression model for the mean and rate functions of recurrent events proposed by Lin et al
14
(adjusted for stratification variables of the randomization) and reported as rate ratios (RRs) with 95% CIs.

Recurrent event outcomes were illustrated by cumulative incidence functions and time to event outcomes were illustrated by Kaplan-Meier curves and stratified by treatment group. Repeated assessments of New York Heart Association classification and patient-reported global assessment of subjective well-being were analyzed using mixed-effects proportional odds models; the treatment differences are reported as odds ratios (ORs) with 95% CIs. The Hochberg procedure was used to analyze the 3 primary hypotheses to control the family-wise type I error rate at the prespecified 2-sided significance level of .05.
15

The 3 primary end points were considered statistically significant if the corresponding 2-sided
P
values fulfilled at least 1 of the following conditions: (1)
P
≤ .05 for all 3 of the end point comparisons, (2)
P
≤ .025 for 2 of the end point comparisons, or (3)
P
≤ .0167 for any of the 3 end point comparisons (Hochberg procedure). The Hochberg procedure controls for the family-wise type I error rate and should not be confused with the Benjamini-Hochberg procedure, which controls for the false discovery rate and is a weaker criterion than the type I error rate. Further explanation of the Hochberg procedure and examples of its application in heart failure trials are provided elsewhere.
16
The family-wise type I error rate across the 4 secondary end points, which is formally tested only if all primary hypotheses are rejected, was also controlled for using the Hochberg procedure.

Two-sided
P
values are reported. The statistical analyses were performed using R version 4.3.1 (R Foundation for Statistical Computing).
Results

Between March 7, 2017, and November 29, 2023, 1824 patients were screened and 1105 participants (mean age, 70 years [SD, 12 years], 33% were women, and 78% had ischemic cardiomyopathy) were enrolled and randomized at 70 clinic sites in 6 European countries. A total of 558 patients were randomly assigned to the ferric carboxymaltose group and 547 to the placebo group (
Figure 1
). The median duration of follow-up was 16.6 months (IQR, 7.9-29.9 months).

The baseline characteristics
17
appear in
Table 1
. A comparison of the baseline characteristics with other major clinical trials may be published later. At enrollment, the mean hemoglobin level was 12.5 g/dL (SD, 1.1 g/dL) and 68% of participants had a transferrin saturation less than 20%.

Table 1. Patient Characteristics at Baseline.

Ferric carboxymaltose (n = 558)

Placebo (n = 547)

Age, mean (SD), y

70.1 (11.4)

69.7 (12.0)

Sex, No. (%)

Male

359 (64.3)

378 (69.1)

Female

199 (35.7)

169 (30.9)

Medical history, No. (%)

Diabetes

248 (44.4)

255 (46.6)

Hypertension

446 (79.9)

426 (77.9)

Myocardial infarction

264 (47.3)

262 (47.9)

Percutaneous coronary intervention

277 (49.6)

291 (53.2)

Coronary artery bypass graft surgery

111 (19.9)

96 (17.6)

Stroke or transient ischemic attack

82 (14.7)

95 (17.4)

Atrial fibrillation or flutter

282 (50.5)

290 (53.0)

Ischemic cause of cardiomyopathy

428 (76.7)

430 (78.6)

Heart failure hospitalization within previous 12 mo, No. (%)

193 (34.6)

209 (38.2)

New York Heart Association classification, No. (%)
a

II

369 (66.1)

359 (65.6)

III

186 (33.3)

184 (33.6)

IV

1 (0.2)

3 (0.6)

Body mass index, mean (SD)
b

28.1 (5.7)

28.2 (5.5)

Systolic blood pressure

Mean (SD), mm Hg

120 (19)

119 (18)

<90 mm Hg, No. (%)

27 (5.0)

24 (4.3)

>140 mm Hg, No. (%)

51 (9.4)

66 (11.9)

N-terminal pro-brain natriuretic peptide

Median (IQR), pg/mL

1734 (834-5007)

2022 (841-4825)

>400 pg/mL, No. (%)

350 (93.8)

321 (90.4)

>1000 pg/mL, No. (%)

258 (69.2)

244 (68.7)

Distance for 6-min walk test, mean (SD), m

315 (120)

313 (116)

Estimated glomerular filtration rate,
c
median (IQR), mL/min/1.73 cm
2

58 (42-77)

57 (42-77)

EQ-5D score, mean (SD)

0.81 (0.21)

0.82 (0.20)

Heart failure therapy, No. (%)

Angiotensin-converting enzyme inhibitor

240 (43.0)

215 (39.3)

Angiotensin receptor blocker

100 (17.9)

90 (16.5)

Angiotensin receptor-neprilysin inhibitor

200 (35.8)

219 (40.0)

β-Blocker

504 (90.3)

512 (93.6)

Mineralocorticoid receptor antagonist

386 (69.2)

393 (71.9)

Sodium-glucose cotransporter-2 inhibitor

130 (23.3)

131 (24.0)

Diuretics

461 (82.6)

445 (81.4)

Iron indices, mean (SD)

Hemoglobin, g/dL

12.5 (1.1)

12.4 (1.1)

Ferritin, μg/L

72 (52)

74 (58)

Iron, μg/dL

68 (33)

66 (30)

Transferrin, mg/dL

267 (53)

269 (53)

Transferrin saturation, %

18.6 (9.3)

17.9 (9.0)

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SI conversion factors: To convert iron to μmol/L, multiply by 0.179; transferrin to μmol/L, multiply by 0.123.

a

Assesses severity of physical limitation in patients with heart failure. Class I indicates no symptoms with ordinary activity; class II, mild limitation with ordinary activity; class III, limitation with mild activity; and class IV, limitation at rest.

b

Calculated as weight in kilograms divided by height in meters squared.

c

Calculated using the creatinine equation.
17

The mean ferric carboxymaltose dose was 2040 mg (SD, 448 mg) during year 1 (visits 1-4), 925 mg (SD, 423 mg) during year 2 (visits 5-7), and 750 mg (SD, 440 mg) during year 3 (visits 8-10) (eTables 3-4 in
Supplement 5
). Four patients in the ferric carboxymaltose group and 2 patients in the placebo group did not receive any therapy. In the ferric carboxymaltose group, 189 patients (34%) discontinued treatment vs 206 patients (38%) in the placebo group.

Primary Outcomes

The first primary end point of time to cardiovascular death or first heart failure hospitalization occurred in 141 patients in the ferric carboxymaltose group compared with 166 patients in the placebo group (HR, 0.79 [95% CI, 0.63-0.99],
P
= .04, which is not formally significant when applying the Hochberg procedure;
Figure 2
and
Table 2
). The second primary end point of total heart failure hospitalizations occurred 264 times in the ferric carboxymaltose group compared with 320 times in the placebo group (RR, 0.80 [95% CI, 0.60-1.06],
P
= .12). The third primary end point of time to cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation less than 20% occurred in 103 patients in the ferric carboxymaltose group compared with 128 patients in the placebo group (HR, 0.79 [95% CI, 0.61-1.02],
P
= .07).

Figure 2. Cumulative Incidence of the Primary End Points.

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The overall median follow-up was 16.6 months (IQR, 7.9-29.9 months). For parts A-C, the median follow-up was 17.3 months (IQR, 8.2-30.9 months) in the ferric carboxymaltose group vs 16.0 months (IQR, 8.7-28.7 months) in the placebo group.
Table 2. Primary, Secondary, and Safety End Points.

Ferric carboxymaltose
(n = 558)

Placebo
(n = 547)

Absolute
difference, %

Estimate (95% CI)

P
value

Primary end points

Time to first hospitalization for heart failure or cardiovascular death, No. of patients (rate/100 patient-years)

141 (16.7)

166 (21.9)

−25 (−5.2)

HR, 0.79 (0.63 to 0.99)

.04

Total (first and recurrent) hospitalizations for heart failure, No. of occurrences (rate/100 patient-years)

264 (26.4)

320 (33.4)

−56 (−7.0)

RR, 0.80 (0.60 to 1.06)

.12

Time to first hospitalization for heart failure or cardiovascular death in patients with transferrin saturation <20%, No. of patients (rate/100 patient-years)

103 (18.9)

128 (25.6)

−25 (−6.7)

HR, 0.79 (0.61 to 1.02)

.07

Secondary end points

New York Heart Association classification, change from baseline to 12 mo
a

OR, 0.69 (0.37 to 1.29)

EQ-5D score, change from baseline to 12 mo, mean (SD)
b

0.02 (0.18)

−0.02 (0.19)

0.04 (0.26)

MD, 0.03 (0.01 to 0.06)

Distance on 6-min walk test, change from baseline to 12 mo, mean (SD), m

27.2 (91.1)

19.7 (84.7)

7.5 (124)

MD, 10.7 (−1.44 to 22.9)

Patient-reported global assessment of well-being during follow-up until 12 mo

OR, 0.25 (0.17 to 0.37)

Safety end points within 36 mo, No. of patients (rate/100 patient-years)

All-cause mortality

104 (9.0)

111 (10.0)

−7 (−1)

HR, 0.94 (0.72 to 1.24)

Cardiovascular mortality

54 (5.8)

65 (7.5)

−11 (−1.7)

HR, 0.80 (0.55 to 1.14)

Open in a new tab

Abbreviations: HR, hazard ratio; MD, mean difference; OR, odds ratio; RR, rate ratio.

a

Assesses severity of physical limitation in patients with heart failure.

b

Ranges from −0.594 to 1; a score of 1 indicates perfect health; 0, death; and negative values, health status considered worse than death.

Secondary Outcomes

The secondary end point results appear in
Table 2
. For the 6-minute walk test, the mean change in distance from baseline to 12 months was 27.2 m (SD, 91.1 m) in the ferric carboxymaltose group vs 19.7 m (SD, 84.7 m) in the placebo group (between-group mean difference, 10.7 [95% CI, −1.44 to 22.9];
Figure 3
,
Table 2
, and eFigure 2 in
Supplement 5
). For the EQ-5D score, the between-group mean difference in the change from baseline to 12 months was 0.03 (95% CI, 0.01 to 0.06) (
Figure 3
,
Table 2
, and eFigure 2 in
Supplement 5
). There was an improvement in the mean patient-reported global assessment of well-being from baseline to 12 months in the ferric carboxymaltose group compared with the placebo group (OR, 0.25 [95% CI, 0.17 to 0.37];
Figure 3
,
Table 2
, and eTable 5 in
Supplement 5
). The change in New York Heart Association functional class was similar in both treatment groups (OR, 0.69 [95% CI, 0.37 to 1.29];
Figure 3
,
Table 2
, and eTable 6 in
Supplement 5
).

Figure 3. Secondary End Points.

Open in a new tab

OR indicates odds ratio. See eFigure 2 in
Supplement 5
for corresponding data for parts A and B of this figure and eTables 5-6 for corresponding data for parts C and D.

a
New York Heart Association classification is used to assess the severity of physical limitation in patients with heart failure. Class I indicates no symptoms with ordinary activity; class II, mild limitation with ordinary activity; class III, limitation with mild activity; and class IV, limitation at rest.
Safety Outcomes

The overall incidence of investigator-reported adverse events, serious adverse events, and adverse events leading to discontinuation of study participation or drug withdrawal were similar in both groups (eTables 7-8 in
Supplement 5
). A similar amount of patients had at least 1 serious adverse event in the ferric carboxymaltose group (269; 48.2%) and in the placebo group (273; 49.9%) (χ
2
test,
P
= .61). The number of deaths due to any cause within 36 months was 104 in the ferric carboxymaltose group and 111 in the placebo group (HR, 0.94 [95% CI, 0.72-1.24],
P
= .68). The number of deaths due to cardiovascular causes within 36 months was 54 in the ferric carboxymaltose group and 65 in the placebo group (HR, 0.79 [95% CI, 0.55-1.14],
P
= .21; eFigures 3-4 in
Supplement 5
).
Exploratory End Points

The rate of total (first and recurrent) heart failure hospitalizations and cardiovascular deaths within 36 months was 27.2 per 100 patient-years in the ferric carboxymaltose group vs 35.1 per 100 patient-years in the placebo group (RR, 0.76 [95% CI, 0.59-0.98]). The end point results for the entire follow-up period appear in eFigure 5 in
Supplement 5
. In an exploratory analysis censored at 12-month follow-up, the HR was 0.71 (95% CI, 0.53-0.94) for the first primary end point of time to cardiovascular death or first heart failure hospitalization and the RR was 0.65 (95% CI, 0.47-0.90) for the second primary end point of total heart failure hospitalizations.
Subgroup Analyses

There were no significant differences in the rate of the first primary end point between the ferric carboxymaltose group and the placebo group (
Figure 4
). Changes in transferrin saturation, serum ferritin level, and hemoglobin level from baseline appear in eFigures 6-8 in
Supplement 5
.

Figure 4. Subgroup Analyses of Composite of Time to First Event of Cardiovascular Death or Hospitalization for Heart Failure (HF) in Study Population.

Open in a new tab

The dashed reference line corresponds to the overall effect. LVEF indicates left ventricular ejection fraction.

a
Calculated as weight in kilograms divided by height in meters squared.

b
Used to assess the severity of physical limitation in patients with heart failure. Class I indicates no symptoms with ordinary activity; class II, mild limitation with ordinary activity; class III, limitation with mild activity; and class IV, limitation at rest.
Discussion

The current randomized clinical trial showed that ferric carboxymaltose did not reduce the rate of time to cardiovascular death or first heart failure hospitalization, compared with placebo, in patients with chronic stable heart failure with reduced ejection fraction. Ferric carboxymaltose was not more effective in reducing clinical events in patients with a transferrin saturation less than 20% vs the other included patients. The results from the current trial were consistent across almost all subgroups and with prior trials.

For the first primary outcome, the treatment effect estimate showed a 21% reduction in event rates (
P
= .04), but did not meet statistical significance. The effect estimate was similar to that observed in prior clinical trials of intravenous iron in patients with heart failure that also did not reach statistical significance (eTable 9 in
Supplement 5
). For example, in the IRONMAN trial,
8
the treatment effect was estimated with an HR of 0.84 (95% CI, 0.70-1.02) for the secondary end point of cardiovascular death or heart failure hospitalization. Similarly, in the AFFIRM-AHF trial,
7
the treatment effect was estimated with an RR of 0.79 (95% CI, 0.62-1.01) for the primary end point of total heart failure hospitalizations and cardiovascular deaths. For the second primary end point in the current trial (total heart failure hospitalizations), the treatment effect estimate was similar to the effect estimate reported in the IRONMAN trial
8
(RR, 0.80 [95% CI, 0.62-1.03]) and in the AFFIRM-AHF trial
7
(RR, 0.74 [95% CI, 0.58-0.94]).

The current trial is the first, to our knowledge, to report a primary outcome in a subset of patients with a transferrin saturation less than 20%, which is considered a more specific marker of iron deficiency compared with conventional criteria based on serum ferritin level.
11
,
18
We report a similar relative treatment effect estimate for the time to cardiovascular death or first hospitalization for heart failure among patients in the ferric carboxymaltose group with a transferrin saturation less than 20% compared with all patients in this study. The larger absolute difference in patients with a transferrin saturation less than 20% compared with all patients in this study (despite a similar relative treatment effect) is likely due to higher event rates in the former group of patients. These results support the potential use of transferrin saturation as a standalone criterion for diagnosing iron deficiency in patients with heart failure, but they also refute prior claims that patients with a transferrin saturation less than 20% may experience a greater therapeutic benefit than the population with iron deficiency recruited in recent trials.

The original definition of iron deficiency (as used in the FERRIC-HF trial
19
and in the FAIR-HF trial
5
is now recommended in guidelines), but this definition is proving to be challenging in clinical practice, particularly with regard to the measurement of ferritin. In future trials (eg, in trials planned for patients with heart failure with preserved ejection fraction), a simplified definition of iron deficiency (ie, a transferrin saturation <20%) may be considered. However, when using this approach, we believe it will be prudent to exclude patients with a clinical or subclinical infection as evidenced, for instance, by elevated blood levels of C-reactive protein.

It has been postulated that the lack of clear efficacy of intravenous iron supplementation on clinical events may be attributed to inadequate repletion and maintenance of iron stores during the trial.
10
For example, in the HEART-FID trial,
9
82% of the patients did not receive additional ferric carboxymaltose during the maintenance phase due to reported adequacy of iron stores and hemoglobin levels.
10
,
20
Similarly, in the IRONMAN and AFFIRM-AHF trials,
7
,
8
approximately 80% of patients received only 2 infusions of iron supplementation during the study period. The current trial used a somewhat higher dose of ferric carboxymaltose during years 2 and 3 (eFigure 9 in
Supplement 5
) than in previous trials.
12
,
21
This had no adverse safety consequences.

Future clinical trials could also evaluate full-dose administration of intravenous iron therapy (1000-2000 mg based on body weight and hemoglobin level at the time) at the start of the second and third year of follow-up to assess whether redosing with a more aggressive regimen (within the regulatory-approved ranges) further enhances the favorable effects of intravenous iron therapy. This is especially of interest because the sensitivity analyses in the current study showed encouraging results during the first year after full correction of iron deficiency with ferric carboxymaltose (eFigure 10 in
Supplement 5
); these results were similar to those reported in the IRONMAN trial.
8

Limitations

This study has several limitations. First, the rate of treatment discontinuation was high in the trial (34% in the ferric carboxymaltose group and 38% in the placebo group). We believe this was due to the COVID-19 pandemic in 2020-2022, budgetary constraints, evolving international guidelines recommending use of intravenous iron therapy, and challenges pertaining to maintenance of blinded intravenous infusions in a long-term treatment setting. The higher than expected dropout rates resulted in a loss of power.

Second, the total length of follow-up was shorter than originally planned and was negatively affected by the COVID-19 pandemic because patients were not allowed to visit clinics and experienced delays in receiving their study medications. Third, even though there is a class 2a recommendation for use of intravenous iron in patients with heart failure and iron deficiency per contemporary chronic heart failure guidelines,
22
,
23
there was a propensity among patients toward prematurely discontinuing with treatment. Fourth, observed differences between treatment groups were less than originally predicted, but closely resemble those of prior clinical trials and meta-analyses.
12
,
21
Conclusions

In patients with heart failure and iron deficiency, ferric carboxymaltose did not significantly reduce the time to first heart failure hospitalization or cardiovascular death in the overall cohort or in patients with a transferrin saturation less than 20%, or reduce the total number of heart failure hospitalizations vs placebo.

Supplement 1.

Original trial protocol

jama-e253833-s001.pdf
(2.1MB, pdf)

Supplement 2.

Final protocol

jama-e253833-s002.pdf
(1.2MB, pdf)

Supplement 3.

Summary of changes to the trial protocol

jama-e253833-s003.pdf
(75.7KB, pdf)

Supplement 4.

Final charter

jama-e253833-s004.pdf
(1.9MB, pdf)

Supplement 5.

FAIR-HF2-DZHK05 study group

eFigure 1.
Study design

eFigure 2.
Boxplots of 6-minute walk test and EQ5D

eFigure 3.
Safety endpoint of all-cause mortality

eFigure 4.
Safety endpoint of cardiovascular mortality

eFigure 5.
Recurrent heart failure hospitalizations and cardiovascular deaths

eFigure 6.
Change from baseline in transferrin saturation

eFigure 7.
Change from baseline in serum ferritin

eFigure 8.
Change from baseline in hemoglobin

eFigure 9.
Mean intravenous iron dose across major heart failure trials

eFigure 10.
Key outcomes censored at 12, 24, and 36 months

eTable 1.
FAIR-HF 2 – complete inclusion and exclusion criteria

eTable 2.
Dosing regimen in the treatment group

eTable 3.
Drug dosing in the ferric carboxymaltose group

eTable 4.
Drug dosing in the placebo group

eTable 5.
Comparison of NYHA at 12 months between treatment groups

eTable 6.
Comparison of patient global assessment (PGA) at 12 months between treatments

eTable 7.
Adverse events of all randomized patients

eTable 8.
Serious adverse events of all randomized patients

eTable 9.
Event rates for cardiovascular death or heart failure hospitalization and total heart failure hospitalizations in control group across different trials

jama-e253833-s005.pdf
(2MB, pdf)

Supplement 6.

Statistical analysis plan

jama-e253833-s006.pdf
(279.1KB, pdf)

Supplement 7.

Data sharing statement

jama-e253833-s007.pdf
(15KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Original trial protocol

jama-e253833-s001.pdf
(2.1MB, pdf)

Supplement 2.

Final protocol

jama-e253833-s002.pdf
(1.2MB, pdf)

Supplement 3.

Summary of changes to the trial protocol

jama-e253833-s003.pdf
(75.7KB, pdf)

Supplement 4.

Final charter

jama-e253833-s004.pdf
(1.9MB, pdf)

Supplement 5.

FAIR-HF2-DZHK05 study group

eFigure 1.
Study design

eFigure 2.
Boxplots of 6-minute walk test and EQ5D

eFigure 3.
Safety endpoint of all-cause mortality

eFigure 4.
Safety endpoint of cardiovascular mortality

eFigure 5.
Recurrent heart failure hospitalizations and cardiovascular deaths

eFigure 6.
Change from baseline in transferrin saturation

eFigure 7.
Change from baseline in serum ferritin

eFigure 8.
Change from baseline in hemoglobin

eFigure 9.
Mean intravenous iron dose across major heart failure trials

eFigure 10.
Key outcomes censored at 12, 24, and 36 months

eTable 1.
FAIR-HF 2 – complete inclusion and exclusion criteria

eTable 2.
Dosing regimen in the treatment group

eTable 3.
Drug dosing in the ferric carboxymaltose group

eTable 4.
Drug dosing in the placebo group

eTable 5.
Comparison of NYHA at 12 months between treatment groups

eTable 6.
Comparison of patient global assessment (PGA) at 12 months between treatments

eTable 7.
Adverse events of all randomized patients

eTable 8.
Serious adverse events of all randomized patients

eTable 9.
Event rates for cardiovascular death or heart failure hospitalization and total heart failure hospitalizations in control group across different trials

jama-e253833-s005.pdf
(2MB, pdf)

Supplement 6.

Statistical analysis plan

jama-e253833-s006.pdf
(279.1KB, pdf)

Supplement 7.

Data sharing statement

jama-e253833-s007.pdf
(15KB, pdf)

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</reference>

<statements>
1. Conversely, absolute or functional iron depletion starves cardiomyocyte mitochondria of essential iron-sulfur clusters, degrading electron transport chain complexes I, II, and III, and impairing myocardial contractility and cellular energetics
2. In heart failure with reduced ejection fraction (HFrEF), approximately half of all patients experience absolute or functional iron deficiency, defined as serum ferritin <100 ug/L or ferritin 100--299 ug/L with a transferrin saturation (TSAT) <20%
3. Landmark randomized controlled trials—including AFFIRM-AHF, IRONMAN, and HEART-FID—have demonstrated the efficacy of high-dose intravenous iron formulations, such as ferric carboxymaltose (FCM) and ferric derisomaltose (FDI)
4. While individual trials differed in meeting composite primary endpoints, systematic reviews confirm that parenteral iron restores cardiomyocyte mitochondrial respiration, improves functional performance (measured by 6-minute walk distance), elevates quality of life, and reduces recurrent hospitalizations for heart failure
5. Intravenous Iron (FCM/FDI): Mitochondrial electron transport chain; cellular energetics in HFrEF
6. Intravenous Iron (FCM/FDI): AFFIRM-AHF, IRONMAN, HEART-FID
7. Intravenous Iron (FCM/FDI): Reduced recurrent HF hospitalizations; improved 6MWD and QoL; neutral on all-cause death
8. Conversely, targeted biometal modulation demonstrates success when addressing specific intracellular metabolic deficiencies
9. Parenteral iron repletion in heart failure bypasses inflammatory absorption blocks to restore cardiomyocyte mitochondrial energetics, alleviating symptoms and lowering rehospitalization rates
</statements>

Begin the assessment now. Output only the JSON list, without any conversational text or explanations.