Prognostic value of three iron deficiency definitions in patients with advanced heart failure
Authors: Papadopoulou C , Reinhold J , Gruner-Hegge N , Kydd A , Bhagra S , Parameshwar K J , Lewis C , Martinez L , Pettit S J 
Published: November 2023

Abstract

Background
Iron deficiency (ID) is a common co-morbidity in patients with chronic heart failure (HF) and is an independent predictor of adverse prognosis including quality of life and exercise capacity (1-3). Intravenous iron replacement improves outcomes in HF patients including exercise capacity, quality of life, rate of HF hospitalisation and possibly mortality (1-4). Different definitions of ID are used in clinical practice. European HF guidelines define ID as a serum ferritin concentration of &lt; 100 ng/ml, or a serum ferritin of concentration of 100-299 ng/ml with a transferrin saturation (TSAT) &lt; 20% (5) because this definition was used in most trials of iron replacement in HF (1-3). However, other criteria to diagnose ID have been proposed based on comparison to the gold standard of bone marrow biopsy including serum iron ≤ 13 µmol/L and TSAT &lt; 20% (6). Serum ferritin concentrations to diagnose ID has been criticised because inflammation can lead to increased serum ferritin concentrations even in patients who would fulfil ID criteria based on alternative definitions (7).

Purpose
The prognostic value of ID in patients with advanced HF, assessed for heart transplantation, is currently not well established. This patient population is characterised by relatively young age, single-organ pathology and prognosis is largely determined by the severity of heart disease rather than co-morbidities. In this study we investigated the prognostic value of various ID definitions in this patient cohort.

Methods and Results
Consecutive patients assessed for heart transplantation at a single UK centre between January 2010 and May 2022 were included. ID was defined as 1) serum ferritin concentration of &lt; 100 ng/ml, or 100-299 ng/ml with transferrin saturation &lt; 20% (guideline definition), 2) serum iron concentration ≤ 13 µmol/L, or 3) transferrin saturation &lt; 20%. The primary outcome measure was a composite of all-cause mortality, urgent heart transplantation or need for mechanical circulatory support. 801 patients were included, and the prevalence of ID was 39-55% depending on definition used. ID, defined by either serum iron or transferrin saturation, was an independent predictor of the primary outcome measure [HR 1.532 (95% CI 1.264 - 1.944) and HR 1.595 (95% CI 1.323 - 2.033), respectively], but the same association was not seen with the guideline definition of ID [HR 1.085 (95% CI 0.8827 - 1.333)]. These findings were robust in multivariable cox regression analysis. ID, by all definitions, was associated with lower six-minute walk distance, lower peak oxygen consumption, higher intra-cardiac filling pressures and lower cardiac output.

Conclusions
ID, when defined by serum iron concentration or transferrin saturation was associated with increased frequency of adverse clinical outcomes in patients with advanced HF. The same association was not seen with guideline definition of ID.