Assessment of biomarkers for iron deficiency following acute decompensated heart failure and its outcomes: a retrospective real-world clinical cohort study

Background Iron deficiency (ID) is a common comorbidity in heart failure (HF) with current guidelines defining it based on ferritin and transferrin saturation (TSAT). It is not fully understood which biomarker of ID is most strongly correlated with worse prognosis. Additionally, the ratios iron/soluble transferrin receptor (sTFR) and TSAT/sTFR have been suggested as metrics to better reflect ID in HF. Purpose To investigate the associations between iron, ferritin, TSAT and sTFR with the primary composite endpoint of HF hospitalisation (HHF) and all-cause mortality in HF as well as the secondary endpoints of HHF and all-cause mortality, and assess iron/sTFR and TSAT/sTFR as exploratory variables. Methods In this retrospective real-world clinical cohort study, we included all patients aged 18-85 years hospitalised in 2016-2020 with newly diagnosed HF with reduced ejection fraction (HFrEF). Patients were identified through medical records using ICD-10 code I50.0-I50.9 and were followed until 31 December 2021. Data on patient characteristics, medications, comorbidities, laboratory results and follow-up were collected. First ID screening, conducted from index hospitalisation to < 6 months post-discharge, was considered baseline. The association between ID markers and endpoints were analysed using Cox regression adjusted for age, sex, previous HF, EF, HF medications, malignancy and chronic kidney disease. Main analyses were adjusted for multiple testing with the Bonferroni-Holm method. A sensitivity analysis was performed with anemia at baseline and intravenous (iv) iron treatment during follow-up added as a time-updated variable. Results A total of 325 patients (70.2% male, 66 ± 13 years, EF 29 ± 7% and NT-proBNP 6875 ± 7626 ng/L) were included. Among them, 48.1% had ID (Table 1). Baseline sTFR were available for 224 (68.9%). Median follow-up was 2.2 years. The event rate per 100 person-years for the primary endpoint was 19.0 (20.6 for sTFR), for HHF 13.5 (14.4 for sTFR) and for all-cause mortality 8.4 (9.0 for sTFR). In the multivariable-adjusted model an increase per standard deviation in TSAT was significantly associated with a lower risk of HHF [hazard ratio (HR) 0.44, 95% confidence interval 0.27-0.72], but not with the combined endpoint or all-cause mortality (Figure 1). Iron, ferritin and sTFR were not significantly associated with the endpoints after adjustment for multiple testing. However, increased ratios TSAT/sTFR and iron/sTFR were significantly associated with a lower risk of HHF [HR 0.55 (0.37-0.83) and 0.58 (0.40-0.86) respectively]. Receiving iv iron during follow-up did not significantly alter the results. Concomitant anemia interacted significantly with the association between TSAT and HHF. Conclusions TSAT is significantly associated with the risk of HHF, although the role of concomitant anemia warrants further investigation. Iron/sTFR and TSAT/sTFR may serve as useful metrics for identifying patients at increased risk of HHF.Table 1 Figure 1