Introduction

Heart failure (HF) is a very prevalent disease associated with high morbidity and mortality,1 prompting research into new therapeutic avenues to improve prognosis and quality of life (QoL) for patients with this condition. Existing evidence points to iron deficiency (ID) as one of the most common comorbidities in HF.2-6 Reduced iron stores in the body have been linked to major pathophysiological problems, because iron is an essential micronutrient in mitochondrial function and energy production in cells and tissues. Basic research studies have confirmed that ID has adverse effects on the contractile function of cardiomyocytes and that this effect can be reversed by replenishing iron stores.7

The 2012 European Society of Cardiology (ESC) guidelines for HF were based on the results of a clinical trial that examined the effect of administering iron in patients with HF and ID8, 9 and suggested that intravenous (i.v.) iron may be considered for the treatment of ID. In the light the scientific evidence available to date, subsequent editions of the guidelines (2021) finally established the recommendation for the routine use of i.v. iron [ferric carboxymaltose (FCM)] for the treatment of HF and improvement of QoL and functional status (FS) in patients with ID.10 Since then, this treatment option has been included in the routine pharmacopoeia for outpatient treatment of symptomatic patients with HF and reduced left ventricular ejection fraction (LVEF). Additionally, magnetic resonance imaging (MRI) techniques (T2-weighted scans) have shown that the iron administered is taken up by the myocardium11 and can improve LVEF 30 days after administration.12

The administration of FCM in patients with decompensated HF has been effective in reducing long-term hospitalizations.13 However, most studies have included patients with HF and reduced ejection fraction (EF) (HFrEF) and mid-range LVEF (40–50%), but no trials have been conducted to date on patients with HF and preserved LVEF (HFpEF).

This retrospective study evaluated the real-world effectiveness of outpatient administration of FCM in repleting the body's iron stores, and its effect on the patient's FS and echocardiographic parameters of ventricular function. All results were analysed in terms of functional class, ventricular systolic function, type of heart disease (HFrEF vs. HFpEF), reversal of ID as assessed by restoration of iron status parameters and haemoglobin levels, and the effects of FCM treatment on kidney and liver function.

Methods Study and patient cohort

A retrospective study was conducted in 565 consecutive patients referred from cardiology outpatient clinics to the day hospital for outpatient administration of i.v. FCM between January 2016 and December 2020. During selection of the study population, admissions due to decompensation, death during the observation time (within 3 months of treatment administration), and patients undergoing major medical or surgical procedures during that period were excluded. In total, 484 patients were finally included, of whom 288 had HFrEF and 196 HFpEF (Figure 1). Clinical, laboratory, and echocardiographic variables were compared prior to administration (baseline) and 3 months after administration of FCM.

Flow chart of study patient selection. HF, heart failure; LVEF, left ventricular ejection fraction.

Heart failure with preserved ejection fraction was described according to European Guidelines for the diagnosis and treatment of acute and chronic HF.10 Patients were diagnosed with HFpEF if they had symptoms and signs of HF with normal or near-normal LVEF (LVEF ≥ 50%), elevated levels of natriuretic peptides [BNP > 35 pg/mL or N-terminal pro-brain natriuretic peptide (NT-proBNP) > 125 pg/mL], and at least one additional criterion (either relevant structural heart disease or diastolic dysfunction).

The diagnosis of ID was based on the standard criteria defined in the consensus document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine on the diagnosis and treatment of ID in HF14 [laboratory diagnosis of ID: ferritin iron allergy; uncontrolled hypertension (HT) (blood pressure > 160/100 mmHg) at the time of FCM administration; infection, inflammatory disease, or active neoplastic disease; severe liver dysfunction (transaminases ≥3 times the upper limit of normal); and polycythaemia (haemoglobin > 16 g/dL). The FCM dose15 administered was 1000 mg diluted in 250 cc of 9% saline infused over 30 min or the same dose diluted in 100 cc infused over 15 min. For patients weighing  14 g/dL, the dose administered was 500 mg. Among HT patients, only those who achieved normal controlled blood pressure values after anti-hypertensive treatment were treated with FCM.

Evaluation of the patients' FS was based on the New York Heart Association (NYHA) functional classification,16 which was slightly adapted, establishing a set of criteria included in a questionnaire designed by nursing staff specialized in HF (Supporting Information, Appendix S1). Assessment of left ventricular function was quantitative; assessment of right ventricular (RV) function was qualitative and was performed by echocardiogram. Renal failure was defined as the presence of an at least moderately decreased glomerular filtration rate (GFR) calculated using the abbreviated MDRD equation (GFR ≤ 59 mL/min/1.73 m2).17, 18

Systolic function and iron metabolism parameters were assessed by echocardiography and blood tests, respectively, in all patients before and after FCM administration (3 months after treatment initiation). FS was also assessed at each visit.

All follow-up assessments were performed 2 months after iron administration (range 1 to 3 months).

This study was carried out in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Hospital Universitario y Politécnico La Fe, Valencia (Spain).

Statistical analysis

Qualitative variables were expressed as percentages and quantitative variables as means and standard deviation or as medians and interquartile ranges (IQRs; 25–75%) in case of P < 0.05 after confirming normality with the Kolmogorov–Smirnov (Z) test. The association between quantitative variables with normal distribution was analysed using the Student's t-test, while we used the χ2 test or Wilcoxon rank test for two related samples for the remaining variables. A P-value of <0.05 was taken as significant. Statistical analysis was performed using SPSS Statistics software Version 27® and Stata Statistics/Data analysis 16.1 serial number 501606323439.

Results Baseline clinical characteristics

The baseline characteristics of the study population are shown in Table 1. The mean number of patients treated per year was 96.8. Mean age in the study series was 68 years, with a higher percentage of men (59%). The most common aetiologies in patients were ischaemic heart disease, idiopathic cardiomyopathy, and valvular heart disease. Other aetiologies present in the study population were mainly hypertensive heart disease and hypertrophic and restrictive cardiomyopathy in the HFpEF group, and chemotherapy-induced cardiomyopathy and arrhythmogenic RV dysplasia in the HFrEF group. In the overall patient series, there was a higher prevalence of HFrEF (60%). This patient subgroup had a lower mean age (65 vs. 71 years on average in patients with HFpEF) and a higher frequency of ischaemic heart disease and dilated cardiomyopathy compared with valvular heart disease.

Table 1. Baseline characteristics of study patients

HF according to LVEF

N (%)

Statistical significance

Total patients

N (%)

HFpEF

196 (40%)

HFrEF

288 (60%)

P-value P-value

All patients

484 (100%)

Men, n (%) 82 (42) 204 (71) <0.0001 286 (59) Age (years), mean ± SD 71 ± 14 65 ± 13 <0.0001 68 ± 14 FS (NYHA), n (%) 0.39 I 0 (0) 0 (0) 0.655 0 (0) I–II 54 (28) 60 (21) 0.087 114 (24) II 58 (30) 99 (34) 0.270 157 (32) II–III 49 (25) 62 (22) 0.372 111 (23) III 29 (14) 61 (20) 0.076 90 (18) III–IV 4 (2) 4 (2) 0.850 8 (2) IV 2 (1) 2 (1) 0.902 4 (1) Baseline heart disease, n (%) <0.0001 IHD 51 (26) 122 (42) 0.0001 173 (36) DCM 19 (10) 96 (33) 0.0001 115 (14) VHD 88 (45) 32 (12) 0.0001 120 (25) CHD 13 (7) 8 (3) 0.041 21 (4) Other 25 (12) 30 (10) 0.426 55 (11) History (n, %) CVS 39 (20) 63 (22) 0.6 102 (21) HT 159 (81) 210 (73) 0.04 369 (76) Dyslipidaemia 100 (51) 150 (52) 0.8 250 (52) DM 84 (43) 135 (47) 0.4 219 (45) Smoking 88 (45) 144 (50) 0.3 232 (48) Alcoholism 6 (3) 26 (9) 0.01 32 (7) COPD 18 (9) 81 (28) 0.0001 99 (20) Obesity (BMI > 30) 31 (16) 35 (12) 0.2 66 (14) Renal failurea 49 (25) 72 (25) 1 121 (25) Hypothyroidism 14 (7) 34 (12) 0.09 48 (10) AF 139 (71) 138 (48) 0.0001 277 (57) Treatment (n, %) ACE/ARA-II inhibitors 123 (37) 199 (69) 0.1 322 (67) ARNI 2 (1) 46 (16) 0.0001 48 (10) Beta-blockers 123 (63) 187 (65) 0.6 310 (64) MRA 49 (25) 112 (39) 0.001 161 (33) Ivabradine 25 (13) 49 (17) 0.2 74 (15) Loop diuretics 145 (74) 198 (69) 0.2 343 (71) Thiazides 33 (17) 35 (12) 0.1 68 (14) Tolvaptan 4 (2) 12 (4) 0.2 16 (3) Antiplatelet agents 57 (29) 124 (43) 0.002 181 (37) Anticoagulants 96 (49) 101 (35) 0.002 197 (41) Nitrates 14 (7) 32 (11) 0.1 46 (10) Digoxin 8 (4) 6 (2) 0.2 14 (3) OAD 55 (28) 84 (29) 0.8 139 (29) SGLT2i 10 (5) 55 (19) 0.0001 65 (13) ACE/ARA-II inhibitors, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists; AF, atrial fibrillation; ARNI, angiotensin receptor-neprilysin inhibitors; BMI, body mass index; CHD, congenital heart disease; COPD, chronic obstructive pulmonary disease; CVS, cardiovascular surgery; DCM, dilated cardiomyopathy; DM, diabetes mellitus; FS, functional status; HF, heart failure; HFpEF, heart failure with preserved left ventricular ejection fraction; HFrEF, heart failure with reduced left ventricular ejection fraction; HT, hypertension; IHD, ischaemic heart disease; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association functional classification of the HF; OAD, oral antidiabetics; SD, standard deviation; SGLT2i, sodium-glucose co-transporter inhibitors type 2; VHD, valvular heart disease.

There were differences in history and concomitant treatments between both groups of patients with HF. A history of HT and atrial fibrillation (AF) was more frequent among patients with HFpEF, while alcoholism and chronic obstructive pulmonary disease (COPD) reached a significantly higher percentage among patients with HFrEF. In terms of treatment, anticoagulant therapy was more prevalent among patients with HFpEF, which may be explained by the higher prevalence of valvular heart disease and AF in this patient profile, while in the subgroup with HFrEF, combined neprilysin and renin-angiotensin-aldosterone system inhibitors (such as angiotensin receptor-neprilysin inhibitors, ARNI), mineralocorticoid receptor agonists (MRA), antiplatelet agents, and sodium-glucose co-transporter 2 inhibitors (SGLT2i) were the most widely used therapeutic agents due to their proven efficacy in this patient profile.16, 19

Effectiveness and toxicity of ferric carboxymaltose

Laboratory tests for ferritin and TSAT levels post-FCM administration showed an up to 5-fold increase in ferritin and 1.6-fold increase in TSAT relative to baseline values, both statistically significant (Table 2). Furthermore, this result was confirmed in both patient subgroups (HFpEF and HFrEF), although the changes were of a different magnitude. Larger increases were found in ferritin and TSAT levels in patients with preserved LVEF (6-fold and 2-fold, respectively) compared with patients with reduced LVEF (4.4-fold and 1.6-fold, respectively) (Table 2 and Figure 2).

Table 2. Effectiveness and toxicity parameters in the total population and according to type of heart failure (with preserved or reduced left ventricular ejection fraction) Parameters Total study population Baseline Follow-up P-value Fera (μg/L) 55 (27–99) 278 (131–418) <0.0001 TSATa (%) 15 (10–19) 24 (18–32) <0.0001 Hbb (g/L) 12.8 ± 2.1 13.6 ± 2.1 <0.0001 ASTa (U/L) 19 (16–25) 20 (18–26) 0.07 ALTa (U/L) 16 (12–22) 17 (12–24) 0.06 Cra (mg/dL) 1.1 (0.9–1.4) 1.1 (0.9–1.4) 0.68 Parameters HF with preserved EF HF with reduced EF Baseline Follow-up P-value Baseline Follow-up P-value Fera (μg/L) 38 (17–36) 217 (95–401) 0.0001 67 (35–131) 293 (169–424) <0.0001 TSATa (%) 12 (8–19) 23 (17–30) 0.0001 16 (11–21) 25 (19–33) <0.0001 Hbb (g/L) 12.2 ± 2.2 12.9 ± 2.2 0.0001 13.3 ± 1.9 14.0 ± 2.0 <0.0001 ASTa (U/L) 19 (16–23) 20 (16–27) 0.09 19.5 (16–26) 20 (17–26) 0.25 ALTa (U/L) 15 (11–20) 16 (11–23) 0.07 17 (13–23) 18 (13–26) 0.06 Cra (mg/dL) 1.0 (0.8–1.4) 1.0 (0.8–1.4) 0.8 1.2 (0.9–1.5) 1.2 (0.9–1.5) 0.6 ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cr, creatinine; EF, ejection fraction; Fer, ferritin; Hb, haemoglobin; HF, heart failure; TSAT, transferrin saturation.

Effectiveness of treatment with ferric carboxymaltose in iron repletion. Hb, haemoglobin; HFpEF, heart failure with preserved left ventricular ejection fraction; HFrEF, heart failure with reduced left ventricular ejection fraction; TSAT, transferrin saturation. aMedian and interquartile range 25–75%. bMean ± standard deviation.

After administration, no significant differences were found in levels of markers for liver necrosis and kidney dysfunction. Liver parameters showed a non-statistically significant increase, with no clinical relevance (the increase was only one point above baseline values). These results were similar for both types of HF (Table 2 and Figure 3).

Impact of treatment with ferric carboxymaltose at the hepatic or renal level. All values correspond to median and interquartile range 25–75%. ALT, alanine aminotransferase; AST, aspartate aminotransferase; HFpEF, heart failure with preserved left ventricular ejection fraction; HFrEF, heart failure with reduced left ventricular ejection fraction.

Effects of the administration of ferric carboxymaltose on systolic function and functional status

A significant increase in LVEF of 8 percentage points was confirmed in the overall patient series (baseline LVEF vs. follow-up LVEF) (Table 3). RV contractility was qualitatively assessed and classified as normal RV contractility, or mildly, moderately, or severely depressed RV function. Follow-up showed an increase of almost 5 percentage points in the number of patients with normal RV contractility, mainly due to the number of patients with previous moderately depressed function who achieved normal contractility. These changes were significant for patients with both HFpEF and HFrEF (Table 3 and Figure 4). The effect of treatment on cardiac stress was assessed by measurement of the injury marker NT-proBNP. No differences were found in the levels of this marker after iron administration, either in the overall study population or according to the type of HF (Table 3 and Figure 4).

Table 3. Functional and ventricular function parameters in the total population and according to type of heart failure (with preserved or reduced left ventricular ejection fraction) Parameters Total study population Baseline Follow-up P-value NYHA-HF scorea 2.4 (2–2.7) 1.9 (1.5–2.5) <0.0001 LVEF (%)a 40 (29–53) 48 (30–57) <0.0001 RVEF (%) <0.0001 Normal 61.9 66.7 Mildly depressed 12.5 11.8 Moderately depressed 13.2 8.1 Severely depressed 12.5 13.4 NT-proBNPa (pg/mL) 1532 (591–3021) 1442 (593–3409) 0.29 Parameters HF with preserved EF HF with reduced EF Baseline Follow-up P-value Baseline Follow-up P-value NYHA-HF scorea 2.2 (1.5–2.5) 2.0 (1.4–2.4) <0.0001 2.4 (2.0–2.5) 2.0 (1.5–2.5) <0.0001 LVEF (%)a 54 (52–56) 57 (55–61) <0.0001 30 (25–39) 35 (26–40) <0.0001 RVEF (%) <0.0001 <0.0001 Normal 74.1 81 53