Iron is an essential trace element that is needed in all organ systems and key biochemical pathways, e.g. erythropoiesis, mitochondrial function, oxygen transport, myocardial and skeletal muscle metabolism, immune and nervous system. Iron deficiency (ID) is one of the most common conditions in clinical medicine, with an estimated prevalence of 30%; in Slovenian adult population, the prevalence is >40%. Similarly, the prevalence is 40-50% in heart failure following diagnostic criteria of ferritin concentration <100 µg/L OR transferrin saturation (TSAT <20%.

ID is associated with worse patient performance, quality of life, and outcome in terms of hospitalisations and mortality. Therefore, it is an important therapeutic target and has been in spotlight of HF research in particular. Within HF, the subpopulation with reduced ejection fraction (HFrEF) is most investigated; randomized placebo controlled trials and individual patient data metaanalyses have clearly demonstrated the efficacy of intravenous iron to improve exercise capacity and quality of life, and to reduce hospitalisations. This has resulted in European Society of Cardiology guidelines that intravenous iron supplementation is recommended in patients with HFrEF.

There however are several aspects (“blind spots”) that are less well not investigated at all:

• What is the prevalence of ID in heart failure in a nationwide sample

• What is the reason for ID in HF

• What are the mechanisms of ID related effects in HF

• Is intravenous iron effective to improve quality of life and patient outcome in patients with HF with preserved ejection fraction (HFpEF)

To address these challenges, we have conceived the “Ferric carboxymaltose for iron deficiency in heart failure with preserved ejection fraction: multicentre, double-blind, randomised, clinical trial (SIDEROS)” project which will focus on interventional randomized trial in HFpEF.

All Slovenian hospitals will screen for ID in consecutive patients with HF to obtain prevalence data. In those with ID, we will investigate whether occult gastrointestinal bleeding that requires additional diagnostic work-up, is present. Patients will then be invited to participate in prospective observational and randomized trials as per patient characteristics. HFpEF patients will be randomized to placebo versus intravenous iron to investigate whether iron supplementation reduces HF hospitalisation and cardiovascular mortality; within this study, there will be sub-studies focusing on quality of life and patient performance. Within randomized trial, patients will be invited to substudies investigating the ID cause (iron absorption testing, detailed dietary intake analysis, drug interaction analysis) and mechanisms of ID related effects (bone marrow biopsy, skeletal muscle biopsy, serum biomarkers).

The novelty and relevance of the research is guaranteed through consortia set-up as there is no randomized controlled trial about ID in a nationally representative sample. Additionally, we will include three key opinion leaders from abroad who are first/last authors of the landmark trials/metaanalyses in the field and ESC guidelines for management of heart failure. The results of this project therefore are expected to be the game changer for HF guidelines and clinical practice worldwide.