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

Author(s): Stefan D. Anker, MD, PhD^1,2; Tim Friede, PhD^3,4; Javed Butler, MD, MPH^5,6; Khawaja M. Talha, MBBS⁷; Marius Placzek, PhD³; Monika Diek, MA^1,2; Anna Nosko, PhD⁸; Adriane Stas, BA^4,9; Stefan Kluge, MD⁸; Dominik Jarczak, MD⁸; Geraldine deHeer, MD⁸; Meike Rybczynski, MD^10,11; Antoni Bayés-Genís, MD, PhD¹²; Michael Böhm, MD¹³; Andrew J. S. Coats, MD¹⁴; Frank Edelmann, MD^15,16; Gerasimos Filippatos, MD¹⁷; Gerd Hasenfuß, MD^4,18; Wilhelm Haverkamp, MD^1,2; Mitja Lainscak, MD, PhD^19,20; Ulf Landmesser, MD^16,21,22; Iain C. Macdougall, MD²³; Bela Merkely, MD, PhD, DSc²⁴; Burkert M. Pieske, MD²⁵; Fausto J. Pinto, MD, PhD²⁶; Tienush Rassaf, MD²⁷; Jennifer K. Visser-Rogers, PhD²⁸; Giuseppe Rosano, PhD^29,30; Maurizio Volterrani, MD^29,31; Stephan von Haehling, MD, PhD^4,18; Markus S. Anker, MD^16,21,22,32; Wolfram Doehner, MD, PhD³³; Hüseyin Ince, MD²⁵; Friedrich Koehler, MD^16,34,35; Gianluigi Savarese, MD³⁶; Muhammad Shahzeb Khan, MD, MSc^6,37; Ursula Rauch-Kröhnert, MD^16,21,22; Tommaso Gori, MD^38,39; Teresa Trenkwalder, MD^40,41; Ibrahim Akin, MD^42,43; Christina Paitazoglou, MD⁴⁴; Iwona Kobielusz-Gembala, MD⁴⁵; Luca Kuthi, MD²⁴; Norbert Frey, MD⁴⁶; Manuela Licka, MD⁴⁶; Stefan Kääb, MD⁴⁷; Karl-Ludwig Laugwitz, MD^41,48; Piotr Ponikowski, MD, PhD⁴⁹; Mahir Karakas, MD, PhD, MBA^8,11;

Source: JAMA. 2025;333(22):1965–1976

Dr. Maen Hussein's Thoughts

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%.

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

Author Affiliations

¹Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany; ²Institute of Health Centre for Regenerative Therapies, German Centre for Cardiovascular Research, partner site Charité Universitätsmedizin, Berlin, Germany; ³Department of Medical Statistics, University Medical Centre Göttingen, Göttingen, Germany; ⁴German Centre for Cardiovascular Research, partner site Lower Saxony, Germany; ⁵Department of Medicine, University of Mississippi Medical Center, Jackson; ⁶Baylor Scott and White Research Institute, Dallas, Texas; ⁷Department of Cardiology, Loyola University Medical Centre, Maywood, Illinois; ⁸Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; ⁹Department of Medical Informatics, University Medical Centre Göttingen, Göttingen, Germany; ¹⁰University Heart and Vascular Centre Hamburg, Department of Cardiology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; ¹¹German Centre for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Hamburg, Germany; ¹²Heart Institute, Hospital Universitari Germans Trias i Pujol, CIBERCV, Barcelona, Spain; ¹³Department of Medicine III and Homburg Institute for Cardio, Renal, and Metabolic Medicine, Saarland University, Homburg, Germany; ¹⁴Heart Research Institute, Sydney, Australia; ¹⁵Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, Berlin, Germany; ¹⁶German Centre for Cardiovascular Research, partner site Berlin, Charité Universitätsmedizin, Berlin, Germany; ¹⁷Department of Cardiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; ¹⁸Department of Cardiology and Pneumology, University Medical Centre Göttingen, Georg August University of Göttingen, Göttingen, Germany; ¹⁹Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia; ²⁰Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; ²¹Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany; ²²Berlin Institute of Health, Berlin, Germany; ²³Department of Renal Medicine, King’s College Hospital, London, England; ²⁴Heart and Vascular Centre, Semmelweis University, Budapest, Hungary; ²⁵Division of Cardiology, Department of Internal Medicine, University Medicine Rostock, Rostock, Germany; ²⁶Centro Academico de Medicina de Lisboa, CCUL@RISE, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; ²⁷West German Heart and Vascular Centre, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany; ²⁸Coronado Research, Newcastle, England; ²⁹Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy; ³⁰Cardiology, San Raffaele Cassino Hospital, Cassino, Italy; ³¹IRCCS San Raffaele Roma, Rome, Italy; ³²School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland; ³³Berlin 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; ³⁴Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Charité Mitte, Berlin, Germany; ³⁵Centre for Cardiovascular Telemedicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; ³⁶Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; ³⁷Baylor Scott and White Health, Heart Hospital, Plano, Texas; ³⁸Department of Cardiology, Cardiology I, University Medical Centre Mainz, Mainz, Germany; ³⁹German Centre for Cardiovascular Research, Standort RheinMain, Frankfurt, Germany; ⁴⁰Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany; ⁴¹German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany; ⁴²Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; ⁴³German Centre for Cardiovascular Research, partner site Heidelberg/Mannheim, Mannheim, Germany; ⁴⁴Department of Cardiology, Angiology, and Intensive Care Medicine, University Heart Centre Lübeck, Medical Clinic II, University Hospital Schleswig-Holstein, Lübeck, Germany; ⁴⁵Oświęcimskie Centrum Badań Klinicznych, Oświęcim, Poland; ⁴⁶Department of Cardiology, Angiology, and Pneumolgy, Clinical Trial Unit, University Hospital Heidelberg, Heidelberg, Germany; ⁴⁷Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany; ⁴⁸Department of Internal Medicine I, Technical University Munich University Hospital, Munich, Germany; ⁴⁹Institute of Heart Diseases, Medical University and University Hospital, Wroclaw, Poland;

Efficacy and Safety of Aspirin for Primary Cardiovascular Risk Prevention in Younger and Older Age: An Updated Systematic Review and Meta-analysis of 173,810 Subjects from 21 Randomized Studies

The debate insofar as aspirin in primary prevention of death has raged for decades. This very large study demonstrates potential benefit for younger population (7% benefit), but in general there is no significant impact in all-cause mortality and risk of major bleeding was noticeable. In my opinion, it is reasonable to consider low dose aspirin for individuals 50-60 years of age, especially with risk factors for CV disease.