The FAIR-HF2-DZHK5 trial, a multicenter, randomized clinical study funded by the German Center for Cardiovascular Research (DZHK), has been published today in JAMA, a renowned medical journal. Co-financing was provided by the pharmaceutical company CSL Vifor, which also took responsibility for providing and distributing the study medication across Europe. The trial investigated whether intravenous iron supplementation using ferric carboxymaltose could reduce the risk of hospitalizations due to heart failure, or cardiovascular death.
The trial was led by Professor Stefan D. Anker of the German Heart Center at Charité (DHZC) and Professor Mahir Karakas of the University Medical Center Hamburg-Eppendorf (UKE). The University Medical Center Hamburg-Eppendorf served as the legal sponsor.
Half of all patients with heart failure are iron deficient
Iron deficiency is common in people with heart failure, affecting approximately half of all patients. An inadequate iron supply can significantly impair physical performance and quality of life and is associated with a worse overall prognosis. The aim of the FAIR-HF2 study was therefore to determine whether targeted iron supplementation in patients with heart failure would also impact the risk of hospitalizations and cardiovascular complications.
The study included 1,105 individuals with heart failure with reduced ejection fraction and iron deficiency from six European countries. Two laboratory parameters were used to diagnose iron deficiency: ferritin, which indicates the body’s iron stores, and transferrin saturation, which reflects how much iron in the blood is available for essential processes such as blood formation and energy metabolism.
Iron deficiency was defined as either a low ferritin level (below 100 nanograms per milliliter) or, if transferrin saturation was below 20 percent, a ferritin level between 100 and 299 nanograms per milliliter. Patients were medically monitored over a period of approximately 17 months.
Results: Well tolerated, with indications of benefit
The treatment reduced the number of cardiovascular deaths or first hospitalizations due to heart failure by 21 percent compared to placebo. However, this reduction was not statistically significant. No clear benefit was observed in the subgroup with especially low iron status (transferrin saturation below 20 percent). Overall, the therapy was well tolerated, and the rate of serious adverse events was not higher than in the placebo group.
“With FAIR-HF2 and the new meta-analysis, we confirm the existing Class I guideline recommendations for the treatment of patients with heart failure and iron deficiency using ferric carboxymaltose,” says Professor Anker. “Our goal is to improve symptoms and physical performance and reduce hospital admissions. Although FAIR-HF2 narrowly missed its primary endpoint, the study offers valuable insights into how iron deficiency should be defined and how targeted iron therapy can be used in heart failure.”
Additional analysis shows impact on hospitalizations and mortality
An international meta-analysis published in parallel in Nature Medicine underscores the clinical relevance of these findings. The analysis combines data from six randomized trials involving more than 7,000 patients, among them FAIR-HF, CONFIRM-HF, AFFIRM-AHF, IRONMAN, HEART-FID, and FAIR-HF2. The new evaluation shows that intravenous iron therapy significantly reduces the risk of recurrent hospitalizations due to heart failure and cardiovascular death, particularly during the first year of treatment. FAIR-HF2 thus makes an contribution to the current body of evidence and helps answer previously unresolved questions about the optimal timing and dosing of therapy.
“FAIR-HF2 is a crucial piece of the puzzle that advances our understanding of the role of iron in heart failure,” says Professor Tim Friede (DZHK, University Medical Center Göttingen), lead statistician of the FAIR-HF2 trial and senior author of the meta-analysis. “The combined analysis with other trials shows that the therapy may have the greatest clinical impact during the first year after treatment initiation.”
More than 40 institutions from Germany, Poland, Portugal, Italy, Hungary and Slovenia were involved in recruitment for the study, including several DZHK partner sites such as Berlin, Göttingen and Hamburg/Kiel/Lübeck. Data were collected via the DZHK clinical research platform.
Original publications:
Anker S. D. et al., Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency – The FAIR-HF2 DZHK05 Randomized Clinical Trial, JAMA, March 2025
Anker S. D., et al., Systematic review and meta-analysis of intravenous iron therapy for patients with heart failure and iron deficiency, Nature Medicine, March 2025
Scientific contact:
Prof. Dr. Stefan Anker, Klinik für Kardiologie (CVK) am Deutschen Herzzentrum der Charité, stefan.anker(at)dhzb-charite.de
Prof. Dr. Mahir Karakas, Klinik für Intensivmedizin am Universitätsklinikum Hamburg-Eppendorf, m.karakas(at)uke.de
