Introduction
Iron deficiency (ID) is prevalent in more than 50% of patients with chronic heart failure (HF)1–4 and is associated with reduced peak oxygen consumption, diminished exercise capacity, poor quality of life, as well as higher mortality and increased risk of hospitalization for worsening HF, irrespective of anaemia status.1,3,5,6
Clinicians should actively screen for and treat ID, as reflected in current guidelines.7 However, there is an ongoing controversy on how ID should be defined in HF.8 The European Society of Cardiology (ESC) guidelines define ID as ferritin level below 100 ng/mL or a ferritin level between 100 and 299 ng/mL combined with a transferrin saturation (TSAT) below 20%.7 However, this definition lacks validation against the gold standard of bone marrow iron staining.9 The present definition is mainly based on inclusion criteria for clinical trials for iron repletion strategies in HF patients.10
A recent study suggests alternatives like TSAT < 20% or serum iron of ≤13 μmol/L as criteria for ID as they offer higher sensitivity and specificity in detecting ID in the bone marrow compared with ESC guidelines.11 To date, studies investigating the clinical outcomes associated with various definition of ID in patients with chronic HF remain limited and relatively small.8,12 Thus, the aim of this study was to explore the prevalence of ID, as defined by different criteria, in patients with new-onset chronic HF across the spectrum of left ventricular ejection fraction (LVEF), who have undergone iron biomarker testing, and to assess its association with all-cause and cardiovascular mortality, as well as first hospitalization for HF. The criteria for ID we explored included the current ESC guideline, ferritin <100 ng/mL, TSAT < 20% and serum iron ≤13 μmol/L.
Methods
Data source
This study was designed as a nationwide cohort study. The Danish Heart Failure Registry (DHFR) is a nationwide clinical quality database enrolling patients with new-onset HF since 2003. Detailed information regarding the registry, including inclusion and exclusion criteria, has previously been described elsewhere.13 DHFR has recently been validated, demonstrating a positive predictive value ranging from 93% to 99.5% across all variables.14
The unique personal identifier assigned to all Danish residents at birth or upon immigration enables exact individual-level linkage between registers. The following databases were used in the current study: the clinical laboratory information system,15 the Danish Civil Registration System,16 the Danish National Patient Registry,17 Danish Register of Causes of Death18 and the Danish National Registry of Medicinal Product Statistics.19
For details on the International Classification of Diseases, Tenth Revision (ICD-10), the Anatomical Therapeutic Chemical (ATC) classification and the Nordic Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedures used throughout this study, see Table S1.
Patient selection and study period
The present study included all patients with new-onset HF registered in the DHFR who had accessible laboratory data via the clinical laboratory information system from April 2003 to December 2019. Only patients with available iron-related parameters between 60 days before and up to 1 year after the HF diagnosis were included. Index date was defined as the date of available iron biomarker data and continued until 31 December 2019. Patients with missing data on left ejection fraction, estimated glomerular filtration rate (eGFR) <15 mL/min, iron biomarkers obtained during hospitalization for worsening HF, as well as received treatment with erythropoietin-stimulating agents, intravenous (IV) iron therapy and received blood transfusion within 2 months were excluded from consideration in this study.
Definition
Over the years, the definition of HF in DHFR has aligned with the recommendation of ESC guidelines. Currently, for a patient to be diagnosed with HF, they must have symptoms and signs of HF. HF is then further classified into three distinct phenotypes based on the measurement of LVEF: HF with reduced ejection fraction (HFrEF) is defined as LVEF ≤ 40%; HF with mildly reduced ejection fraction (HFmrEF) is defined as LVEF between 41% and 49%; and HF with preserved ejection fraction (HFpEF) is defined as LVEF ≥ 50%. Additionally, for a diagnosis of HFpEF, there must be evidence of structural and/or functional cardiac abnormalities and/or elevated natriuretic peptide levels.7
In this study, we exploited four distinct definitions to classify ID. Firstly, ID according to ESC guidelines was defined as a serum ferritin level below 100 ng/mL or a ferritin level ranging from 100 to 299 ng/mL with a TSAT below 20%.7 The second definition classified ID solely by a ferritin <100 ng/mL. The third definition used a TSAT threshold of <20%. The fourth definition determined ID by a serum iron concentration ≤13 μmol/L. TSAT was calculated by using the formula: [iron (μmol/L)/(transferrin [g/L] × 25.2) × 100].20 Anaemia was defined based on the criteria established by the World Health Organization, which identifies haemoglobin levels below 12.0 g/dL in women and below 13.0 g/dL in men as indicative of anaemia.7
Baseline characteristics
Baseline characteristics for patients were identified at the time of inclusion for the study. Comorbidities were defined binarily and considered present if registered (overnight stay or outpatient visits) up to 5 years prior to inclusion. Data regarding HF phenotype, hypertension and the New York Heart Association (NYHA) functional classification were collected from DHFR. Diabetes was defined by redeeming one or more prescriptions of insulin or non-insulin glucose-lowering treatment within 6 months before inclusion in the study. Hyperlipidaemia was similarly defined by redeeming any lipid-lowering medication within the same time frame. Medication treatment was considered as any redeemed prescription up to 1 year before inclusion. For further details, see Table S1.
Outcome and follow-up
The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality (defined as any cause of death associated with ICD-10 Codes I00–I99) and first hospitalization for HF. Follow-up began from the date the ID status was determined and continued until 5 years or until death, emigration or end of follow-up (31 December 2019).
Statistics
Baseline characteristics are presented as frequencies and percentages for categorical variables and median with inter-quartile range (IQR) for age. Categorical variables were compared between patients included and excluded from the study using the chi-squared test, while age, due to its non-normal distribution, was compared using the Wilcoxon rank-sum test.
We calculated the prevalence of ID according to each of the previously mentioned definitions. For our analysis, patients were included if their laboratory data were sufficient to determine their ID status based on at least one of the four definitions. This implies that a patient's data would be included in a specific analysis related to the ID definition that their available laboratory results support. Consequently, it is possible for the same patient to be included in multiple analyses, depending on which ID definitions their laboratory data meet. If a patient had multiple values of the same iron biomarker or haemoglobin available, the first value close to the time of HF diagnosis was used for the analysis. To evaluate the association between the different definitions for ID and outcomes, we used Cox proportional hazard models. All models were adjusted for gender, age groups (categorical), HF phenotype, NYHA, hypertension, diabetes, atrial fibrillation/flutter, ischaemic heart disease, myocardial infarction, stroke, stages of chronic kidney disease (G1–G4), chronic obstructive pulmonary disease, prior HF admission (defined as more than one admission for HF prior to the time of inclusion), and the use of anticoagulant, antiplatelet, beta-blockers, loop diuretic, mineralocorticoid receptor antagonist, and renin–angiotensin system inhibitor based on prior research.7,21 Furthermore, we accounted for the probability of ID testing by integrating the inverse probability weights into our Cox models. The proportional hazard assumption for all models was verified using the Schoenfeld residual plot. The results are reported as hazard ratios (HRs) with 95% confidence intervals (CIs) for each ID definition in relation to the outcome, after adjustments. CI that does not encompass 1.0 was considered statistically significant. Kaplan–Meier curves for cumulative all-cause mortality were used to compare differences in mortality based on ID status as defined by various ID definitions. Furthermore, we calculated and illustrated Aalen–Johansen cumulative incidence for cardiovascular mortality and first hospitalization for HF, considering all-cause mortality as a competing risk. All analyses were performed using R Version 4.0.3.22
Results
Prevalence of ID according to definition and baseline characteristics according to HF phenotype
A flow chart of the included population in the study is shown in Figure S1. In total, 9477 patients were included in the study. The distribution of characteristics in patients with available iron biomarkers by HF phenotype is summarized in Table 1. The median duration of follow-up in the analysis for all-cause mortality of the total included population was 27 (25th and 75th percentile: 11–47 months). There were no participants lost to follow-up due to immigration or any other reasons. The median age of the total included population was 72 years (IQR: 63–80), and the majority of patients were male (66.3%). Compared with patients with HFrEF, patients with HFpEF and HFmrEF were more likely to have diabetes mellitus, hypertension and atrial fibrillation/flutter and more likely to be female. When comparing patients included with the patients excluded from the study, the included patients were more likely to be female and older; have HFrEF, anaemia and NYHA Class III–IV; possess more comorbidities; and were more likely to be treated with loop diuretics and oral anticoagulants. Only 76 of the included patients received treatment with IV iron during the follow-up period. The majority of patients included in this study were diagnosed with HF during the years 2015 to 2017 (Table S2).
Table 1 Characteristics of patients according to heart failure phenotype.
| HFrEF ( |
HFmrEF ( |
HFpEF ( |
Total ( |
|
| Age (years), median [Q1–Q3] | 72 [63–80] | 73 [64.0–80.5] | 73 [65–81] | 72 [63–80] |
| Gender, n (%) | ||||
| Male | 5665 (66.9) | 320 (63.1) | 299 (59.4) | 6284 (66.3) |
| Laboratory findings, n (%) | ||||
| Iron deficiency according to ESC guidelines | 3667 (54.3) | 236 (58.1) | 253 (62.5) | 4156 (54.9) |
| Ferritin <100 ng/mL | 2677 (35.8) | 179 (40.1) | 178 (39.9) | 3034 (36.3) |
| Serum iron ≤13 μmol/L | 4399 (59.1) | 253 (58.8) | 284 (64.3) | 4936 (59.4) |
| Transferrin saturation <20% | 3271 (53.7) | 186 (52.7) | 218 (57.2) | 3675 (53.8) |
| NYHA classification, n (%) | ||||
| I | 889 (11.4) | 90 (20.6) | 84 (20.0) | 1063 (12.3) |
| II | 4705 (60.3) | 263 (60.2) | 242 (57.8) | 5210 (60.2) |
| III | 2055 (26.3) | 76 (17.4) | 84 (20.0) | 2215 (25.6) |
| IV | 154 (2.0) | 8 (1.8) | 9 (2.1) | 171 (2.0) |
| Medical history, n (%) | ||||
| Atrial fibrillation/flutter | 2025 (23.9) | 130 (25.6) | 163 (32.4) | 2318 (24.5) |
| Cancer | 1139 (13.5) | 79 (15.6) | 66 (13.1) | 1284 (13.5) |
| Chronic kidney disease | 646 (7.6) | 44 (8.7) | 43 (8.5) | 733 (7.7) |
| Chronic obstructive pulmonary disease | 1011 (11.9) | 74 (14.6) | 68 (13.5) | 1153 (12.2) |
| Diabetes | 1954 (23.1) | 130 (25.6) | 136 (27.0) | 2220 (23.4) |
| Hypertension | 3858 (45.6) | 274 (54.0) | 270 (53.7) | 4402 (46.4) |
| Hyperlipidaemia | 5268 (62.2) | 333 (65.7) | 305 (60.6) | 5906 (62.3) |
| Ischaemic heart disease | 3116 (36.8) | 220 (43.4) | 197 (39.2) | 3533 (37.3) |
| Peripheral artery disease | 381 (4.5) | 22 (4.3) | 25 (5.0) | 428 (4.5) |
| Previous myocardial infarction | 1843 (21.8) | 129 (25.4) | 117 (23.3) | 2089 (22.0) |
| Previous stroke | 675 (8.0) | 39 (7.7) | 43 (8.5) | 757 (8.0) |
| Prior admission for heart failure | 933 (11.0) | 43 (8.5) | 37 (7.4) | 1013 (10.7) |
| Treatment, n (%) | ||||
| ACE-I or ARB | 7933 (93.7) | 442 (87.2) | 426 (84.7) | 8801 (92.9) |
| Beta-blocker | 7726 (91.2) | 426 (84.0) | 404 (80.3) | 8556 (90.3) |
| MRA | 4491 (53.0) | 151 (29.8) | 164 (32.6) | 4806 (50.7) |
| SGLT2 inhibitor | 187 (2.2) | 9 (1.8) | 11 (2.2) | 207 (2.2) |
| Loop diuretics | 6694 (79.1) | 357 (70.4) | 368 (73.2) | 7419 (78.3) |
| Antiplatelet | 5154 (60.9) | 309 (60.9) | 291 (57.9) | 5754 (60.7) |
| Oral anticoagulant | 3459 (40.9) | 205 (40.4) | 221 (43.9) | 3885 (41.0) |
| Stratified by year of heart failure diagnosis | ||||
| 2003–2005 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| 2006–2008 | 109 (1.3) | 11 (2.2) | 15 (3.0) | 135 (1.4) |
| 2009–2011 | 745 (8.8) | 110 (21.7) | 78 (15.5) | 933 (9.8) |
| 2012–2014 | 1659 (19.6) | 118 (23.3) | 123 (24.5) | 1900 (20.0) |
| 2015–2017 | 3752 (44.3) | 155 (30.6) | 183 (36.4) | 4090 (43.2) |
| 2018–2019 | 2202 (26.0) | 113 (22.3) | 104 (20.7) | 2419 (25.5) |
Figure 1 illustrates the prevalence of ID according to different criteria. The overall prevalence of ID in the total population ranged between 35.8% and 64.3% depending on the ID definition (Figure 1A). The highest prevalence of ID was observed in all HF phenotypes when using serum iron ≤13 μmol/L as the definition for ID (Figure 1A). When comparing patients with and without anaemia, those with anaemia had a higher prevalence of ID regardless of the applied criteria for ID (Figure 1B,C).
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The relationship between ID defined by ESC guidelines, ferritin <100 ng/mL, TSAT < 20% and serum iron ≤13 μmol/L is presented in Figure 2. Among patients with ID defined by iron ≤13 μmol/L or TSAT < 20%, irrespective of their anaemia status, 26% and 15.5%, respectively, did not meet the diagnostic criteria for ID according to the ESC guidelines. Conversely, 11% of patients meeting the ESC guideline criteria for ID exhibited serum iron >13 μmol/L and TSAT > 20%.
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Mortality and ID according to different defnitions
During the follow-up period, a total of 2820 (29.7%) patients died. Among these, 1268 (44.9%) were due to cardiovascular causes. No significant interaction was found in the adjusted models between definitions of ID and HF phenotypes for all three outcomes. However, there were significant interactions between all definitions of ID and anaemia status for all-cause mortality. In the analysis, we therefore stratified the population into anaemic and non-anaemic groups (Figures S7 and S8). In the multivariable Cox regression analysis, in non-anaemic patients, ID defined by ESC guideline, TSAT < 20% or serum iron ≤13 μmol/L was independently associated with both higher all-cause and cardiovascular mortality compared with patients without ID defined by ESC guideline, TSAT > 20% or serum iron >13 μmol/L, respectively (Figure 3). In anaemic patients, only ID defined as TSAT < 20% or serum iron ≤13 μmol/L was independently associated with higher all-cause and cardiovascular mortality (Figure 3). No association between ferritin <100 ng/mL and all-cause and cardiovascular mortality was seen, irrespective of anaemia status (Figure 3). Cumulative incidence curves for all-cause mortality according to the different ID definitions are shown in Figures 4 and 5. Corresponding curves showing cumulative incidence of cardiovascular mortality can be found in Figure S2.
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First hospitalization for HF and ID according to different definitions
In our analyses,ID defined by ESC guidelines, TSAT < 20% or serum iron ≤13 μmol/L were all independently associated with an increased risk for first hospitalization for HF, irrespective of anaemia status (Figure 3). Regardless of anaemia status, ID defined by ferritin <100 ng/mL was not significantly associated with an increased risk of first hospitalization for HF (Figure 3). The cumulative incidences of first hospitalization for HF by ID, defined by the different definitions, can be found in Figure S3.
Discussion
Studies exploring the prognostic value of ID as defined by the current ESC guideline definition on ID in HF have yielded inconsistent results. To our knowledge, this is the first nationwide study to investigate the prevalence and prognostic implications of the ESC guideline definition and other proposed definitions for ID in patients newly diagnosed with chronic HF across the spectrum of LVEF. Notably, this study stands as the largest study to date elaborating on this topic. Three key observations were made. Firstly, the prevalence of ID varied significantly, ranging from 39.3% to 67.3%, depending on the definition applied. Secondly, serum iron ≤13 μmol/L and TSAT < 20% were associated with all-cause and cardiovascular mortality, as well as first hospitalization for HF, irrespective of anaemia status. Thirdly, ID defined by ESC guidelines was associated with all-cause and cardiovascular mortality only in non-anaemic patients. However, this definition was associated with an increased risk of first hospitalization for HF, irrespective of anaemia status.
A recent study by Masini et al. showed that ID defined by TSAT < 20% and serum iron ≤13 μmol/L, but not ID defined by ESC guidelines, was associated with higher all-cause mortality.8 Previous observational studies have shown that ID according to the ESC guideline definition was an independently associated with higher risk of all-cause mortality and hospitalization for HF.3,5,6,23–25 Subsequent studies with larger populations do not support these findings.2,8,12,26,27 Several recent studies, including this, have shown that TSAT < 20% and serum iron ≤13 μmol/L were independently associated with all-cause mortality.8,12,28,29 In this study, ID as defined by ESC guidelines was only associated with all-cause and cardiovascular mortality in non-anaemic patients. Contrary to the study by Masini et al., who did not separate anaemic from non-anaemic patients or investigate the interaction between the prognostic values of the different ID definitions and anaemia status, our results might be driven primarily by TSAT < 20%, which showed the highest HR for non-anaemic patients. Consistent with prior research, isolated ferritin <100 ng/mL was not associated with all-cause mortality.6,26,30
The lack of consensus on the definition of ID in HF stems from the limited studies that validate serum biomarkers against bone marrow assessment to identify ID in HF patients.8 ID in bone marrow does not necessarily mean intracellular iron depletion within skeletal cells and cardiac myocytes. However, prolonged reduction of iron delivery due to systemic ID will eventually reduce the intracellular iron levels in these cells.31 A study applying iron staining to bone marrow in HF patients with LVEF ≤ 45% found that the ESC guideline definition for ID exhibited lower sensitivity and specificity in comparison with TSAT ≤ 19.8% and serum iron of 13 μmol/L. Moreover, TSAT ≤ 19.8% and serum iron of 13 μmol/L were associated with a higher risk of all-cause mortality.11 The lower sensitivity and specificity of the ESC guideline for detecting ID in the bone marrow may stem from its reliance primarily on ferritin levels. Ferritin can increase during states of cell damage, inflammation and infection. Consequently, elevated ferritin levels can be observed even when actual ID exists within the bone marrow, potentially masking the true ID status.
Interestingly, HFpEF had the highest prevalence of ID, regardless of the definition used, with the exception of the ferritin 100 ng/mL criterion. Compared with those with HFrEF, those with HFpEF were older and had a greater burden of comorbidities, including chronic kidney disease and atrial fibrillation, which all increase the risk of developing ID.7
In our study, 26% and 15.5% of patients classified with ID based on serum iron ≤13 μmol/L or TSAT < 20% criteria, respectively, did not meet the guidelines criteria for ID. Conversely, 11% of patients meeting the ESC guideline criteria for ID exhibited serum iron >13 μmol/L and TSAT > 20%. Notably, patients with HFrEF and HFmrEF in this latter subgroup would still be recommended with IV iron supplementation, despite the possibility that it may not significantly impact their prognosis.7 As shown in this study, the current ESC guideline definition of ID may result in a subset of HF patients missing out on the potential benefits of IV iron supplement. By excluding a large subgroup of patients with serum iron ≤13 μmol/L or TSAT < 20% who do not meet the ESC guidelines criteria for ID from clinical trials on iron repletion, the results of these studies may have been affected. There is a strong correlation between TSAT and serum iron.30 However, in our study, only 4% had serum iron >13 μmol/L and TSAT < 20%, while 13% had serum iron ≤13 μmol/L and TSAT > 20%. This discrepancy may be attributed to the state of inflammation, where transferrin levels decrease and ferritin levels increase. Because TSAT is calculated based on transferrin and serum iron ([iron (μmol/L)/(transferrin [g/L] × 25.2) × 100]), a higher decrease in transferrin due to inflammation can lead to normal TSAT values in some cases, even when serum iron levels are low.30 Resolution of ID after 1 year according to serum iron ≤13 μmol/L criterion for ID was associated with a better survival but not when ID was defined by ESC guidelines and TSAT < 20%.30 These findings suggest that ID, defined solely by serum iron ≤13 μmol/L in HF patients, may perform better as both diagnostic and prognostic markers. However, whether treatment with IV iron in patients with serum iron ≤13 μmol/L can reduce mortality remains to be explored.
To date, meta-analyses of clinical trials on IV iron repletion, using ESC guidelines to define ID, have shown a reduction in the composite endpoint of hospitalization for HF or cardiovascular death. This reduction was mainly due to a reduction in hospitalization for HF.32 This finding aligns with our observation that ID, as defined by ESC guidelines, was associated with increased risk of hospitalization for HF, irrespective of anaemia status. Subgroup analysis of a recent meta-analysis suggests that those with TSAT < 20% may benefit more from IV iron compared with those with TSAT > 20%.32,33 Therefore, clinical trials on iron repletion in patients with HF might be targeting a group of patients who may not all have true ID. Further trials testing IV iron supplement and applying the proposed new definitions of ID (TSAT < 20% or serum ≤13 μmol/L) in HF across the ejection fraction are needed to demonstrate the effect on prognosis.
Strength and limitation
A major strength of this nationwide observational study was the large sample size and long follow-up time. This was possible due to the access to the DHFR and ability to link with other validated registries, which reduces detection bias. However, several limitations exist in this study. Firstly, the observational nature does not allow us to draw any conclusion about the cause–effect relationship. Secondly, screening for ID was first included in the ESC guidelines in 2016. Therefore, it was not standard clinical practice to screen for ID prior to 2016. This is reflected in our study, as most patients included were diagnosed with HF between 2015 and 2017. Additionally, compared with patients not included in the study, those who were included tended to be sicker. This introduced a selection bias, and therefore, the prevalence of ID presented in this study may not reflect the true prevalence of ID in Danish patients with new-onset chronic HF. However, we tried to account for this in our analysis. Thirdly, our study did not account for changes in iron status over time. Additionally, we did not consider whether patients received iron supplementation (both IV and oral) after inclusion, which could potentially introduce residual confounding. The Danish national guideline does not recommend routine treatment of ID in chronic HF. This is reflected in the fact that only 76 patients received IV iron during follow-up, which is unlikely to have a significant influence on the main findings. Fourthly, testing for iron biomarkers is often prompted by the presence of anaemia, thus raising the possibility of confounding by indication. Lastly, the use of the ESC definition was based on trials including patients with LVEF ≤ 45% who were stable on guideline-directed medical therapy. The underperformance of this definition in our registry cohort might be due to the inclusion of HFpEF and HFmrEF patients, as well as HFrEF patients not yet established on guideline-directed medical therapy.
Conclusions
ID defined by TSAT < 20% or serum iron ≤13 μmol/L was associated with all-cause and cardiovascular mortality. ID, as defined by the current ESC guidelines, was associated with all-cause and cardiovascular mortality in non-anaemic patients. However, it was associated with first hospitalization for HF regardless of their anaemia status. These findings suggest that a serum iron ≤13 μmol/L or TSAT < 20% might be better prognostic markers than the current guideline definition. However, there is a need for further trials to test IV iron supplementation using these newly proposed ID definitions.
Conflict of interest statement
Dr. Køber received personal fees from Novo Nordisk, AstraZeneca, Novartis and Boehringer Ingelheim unrelated to this work. Dr. Torp-Pedersen received grants from Bayer and Novo Nordisk unrelated to this work. Dr. Schou received personal fees for lectures from Novo Nordisk, AstraZeneca, Boehringer Ingelheim and Novartis unrelated to this work. Dr. Biering-Sørensen received either or both personal fees and grants from Amgen, Novo Nordisk, Boston Scientific, Sanofi Pasteur, CSL Seqirus, GlaxoSmithKline, Bayer, Novartis, GE Healthcare and AstraZeneca unrelated to this work. The other authors report no conflicts of interest.
Funding
This study was supported by the Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte Hospital.
Data availability statement
The data in this study cannot be made publicly available as access must be granted to institutions by the Danish Data Protection Agency and the Danish Health Data Authority.
von Haehling S, Gremmler U, Krumm M, Mibach F, Schön N, Taggeselle J, et al. Prevalence and clinical impact of iron deficiency and anaemia among outpatients with chronic heart failure: the PrEP Registry. Clin Res Cardiol 2017;106:436‐443. doi:
González‐Costello J, Comín‐Colet J, Lupón J, Enjuanes C, de Antonio M, Fuentes L, et al. Importance of iron deficiency in patients with chronic heart failure as a predictor of mortality and hospitalizations: insights from an observational cohort study. BMC Cardiovasc Disord 2018;18:206. doi:
IjT K, Comin‐Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575‐582.e3. doi:
Bekfani T, Pellicori P, Morris D, Ebner N, Valentova M, Sandek A, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2019;108:203‐211. doi:
Martens P, Nijst P, Verbrugge FH, Smeets K, Dupont M, Mullens W. Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid‐range and preserved ejection fraction. Acta Cardiol 2018;73:115‐123. doi:
Becher PM, Schrage B, Benson L, Fudim M, Corovic Cabrera C, Dahlström U, et al. Phenotyping heart failure patients for iron deficiency and use of intravenous iron therapy: data from the
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2021; [eLocator: ehab368]. doi:
Masini G, Graham FJ, Pellicori P, Cleland JGF, Cuthbert JJ, Kazmi S, et al. Criteria for iron deficiency in patients with heart failure. J Am Coll Cardiol 2022;79:341‐351. doi:
Beavers CJ, Ambrosy AP, Butler J, Davidson BT, Gale SE, PIÑA IL, et al. Iron deficiency in heart failure: a scientific statement from the Heart Failure Society of America. J Card Fail 2023;29:1059‐1077. doi:
Jankowska EA, Tkaczyszyn M, Suchocki T, Drozd M, von Haehling S, Doehner W, et al. Effects of intravenous iron therapy in iron‐deficient patients with systolic heart failure: a meta‐analysis of randomized controlled trials. Eur J Heart Fail 2016;18:786‐795. doi:
Grote Beverborg N, IjT K, Meijers WC, Voors AA, Vegter EL, van der Wal HH, et al. Definition of iron deficiency based on the gold standard of bone marrow iron staining in heart failure patients. Circ Heart Fail 2018;11: [eLocator: e004519]. doi:
Tada A, Nagai T, Koya T, Nakao M, Ishizaka S, Mizuguchi Y, et al. Applicability of new proposed criteria for iron deficiency in Japanese patients with heart failure. ESC Heart Fail 2023;10:985‐994. doi:
Schjødt I, Nakano A, Egstrup K, Cerqueira CS. The Danish Heart Failure Registry. CLEP 2016;8:497‐502. doi:
Andersen C, Schjødt I, Nakano A, Johnsen SP, Egstrup K, Løgstrup BB. The Danish Heart Failure Registry: a validation study of content. CLEP 2022;14:1585‐1594. doi:
Grann ER, Nielsen F, Thomsen R. Existing data sources for clinical epidemiology: the clinical laboratory information system (LABKA) research database at Aarhus University, Denmark. CLEP 3:133‐138. doi:
Schmidt M, Pedersen L, Sørensen HT. The Danish civil registration system as a tool in epidemiology. Eur J Epidemiol 2014;29:541‐549. doi:
Schmidt M, Schmidt SAJ, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. CLEP 2015;7:449‐490. doi:
Helweg‐Larsen K. The Danish Register of Causes of Death. Scand J Public Health 2011;39:26‐29. doi:
Pottegård A, Schmidt SAJ, Wallach‐Kildemoes H, Sørensen HT, Hallas J, Schmidt M. Data resource profile: the Danish National Prescription Registry. Int J Epidemiol, 2016;46:798‐798f. doi:
Beilby J, Olynyk J, Ching S, Prins A, Swanson N, Reed W, et al. Transferrin index: an alternative method for calculating the iron saturation of transferrin. Clin Chem 1992;38:2078‐2081. doi:
Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol 2020;76:2982‐3021. doi:
RStudio Team (2022). RStudio: integrated development environment for R. RStudio, PBC, Boston, MA http://www.rstudio.com/. Accessed 5 September 2023.
Rangel I, Gonçalves A, de Sousa C, Leite S, Campelo M, Martins E, et al. Iron deficiency status irrespective of anemia: a predictor of unfavorable outcome in chronic heart failure patients. Cardiology 2014;128:320‐326. doi:
Docherty KF, Welsh P, Verma S, de Boer RA, O'Meara E, Bengtsson O, et al. Iron deficiency in heart failure and effect of dapagliflozin: findings from DAPA‐HF. Circulation 2022;146:980‐994. doi:
Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010;31:1872‐1880. doi:
Fitzsimons S, Yeo TJ, Ling LH, Sim D, Leong KTG, Yeo PSD, et al. Impact of change in iron status over time on clinical outcomes in heart failure according to ejection fraction phenotype. ESC Heart Fail 2021;8:4572‐4583. doi:
Graham FJ, Pellicori P, Masini G, Cuthbert JJ, Clark AL, Cleland JGF. Influence of serum transferrin concentration on diagnostic criteria for iron deficiency in chronic heart failure. ESC Heart Fail, 2023;10:2826‐2836. doi:
Graham FJ, Friday JM, Pellicori P, Greenlaw N, Cleland JG. Assessment of haemoglobin and serum markers of iron deficiency in people with cardiovascular disease. Heart 2023;109:1294‐1301. doi:
Okonko DO, Mandal AKJ, Missouris CG, Poole‐Wilson PA. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241‐1251. doi:
Moliner P, Jankowska EA, Van Veldhuisen DJ, Farre N, Rozentryt P, Enjuanes C, et al. Clinical correlates and prognostic impact of impaired iron storage versus impaired iron transport in an international cohort of 1821 patients with chronic heart failure. Int J Cardiol 2017;243:360‐366. doi:
Packer M, Anker SD, Butler J, Cleland JGF, Kalra PR, Mentz RJ, et al. Identification of three mechanistic pathways for iron‐deficient heart failure. Eur Heart J, 2024;45:2281‐2293. doi:
Ponikowski P, Mentz RJ, Hernandez AF, Butler J, Khan MS, van Veldhuisen, DJ, et al. Efficacy of ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta‐analysis. Eur Heart J, 2023;44:5077‐5091. doi:
Graham FJ, Pellicori P, Kalra PR, Ford I, Bruzzese D, Cleland JGF. Intravenous iron in patients with heart failure and iron deficiency: an updated meta‐analysis. Eur J Heart Fail, 2023;25:528‐537. doi:
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Abstract
Aims
Iron deficiency (ID) is prevalent in chronic heart failure (HF) but lacks a consensus definition. This study evaluates the prevalence and the prognostic impact of ID using different criteria on all‐cause and cardiovascular mortality, as well as first hospitalization for HF in patients with new‐onset chronic HF.
Methods
In this nationwide registry‐based cohort, we explored four definitions of ID: the current European Society of Cardiology (ESC) guidelines [ferritin <100 ng/mL or ferritin 100–299 ng/mL and transferrin saturation (TSAT) <20%], ferritin level <100 ng/mL, TSAT < 20% and serum iron ≤13 μmol/L. Patients were identified through the Danish Heart Failure Registry.
Results
Of 9477 new‐onset chronic HF patients registered in the Danish Heart Failure Registry from April 2003 to December 2019, we observed ID prevalence rates ranging from 35.8% to 64.3% depending on the ID definition used. Among patients with ID defined by iron ≤13 μmol/L or TSAT < 20%, 26% and 15.5%, respectively, did not meet the ESC guidelines definition for ID. Conversely, 11% of patients meeting the ESC criteria exhibited serum iron >13 μmol/L and TSAT > 20%. Regardless of anaemia status, ID defined by TSAT < 20% or serum iron ≤13 μmol/L was associated with all‐cause mortality [non‐anaemic, hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.30–1.89 and HR: 1.47, 95% CI: 1.24–1.73; anaemic, HR: 1.22, 95% CI: 1.07–1.38 and HR: 1.25, 95% CI: 1.09–1.44, respectively] and cardiovascular mortality (non‐anaemic, HR: 2.21, 95% CI: 1.59–3.06 and HR: 1.47, 95% CI: 1.12–1.95; anaemic, HR: 1.37, 95% CI: 1.11–1.69 and HR: 1.28, 95% CI: 1.02–1.61, respectively), as well as increased risk of first hospitalization for HF (non‐anaemic, HR: 1.28, 95% CI: 1.09–1.1.50 and HR: 1.27, 95% CI: 1.10–1.46; anaemic, HR: 1.25, 95% CI: 1.08–1.44 and HR: 1.22, 95% CI: 1.05–1.42, respectively). ID defined by ESC guidelines was associated with all‐cause and cardiovascular mortality only in non‐anaemic patients (HR: 1.41, 95% CI: 1.18–1.1.70 and HR: 1.58, 95% CI: 1.18‐2.12.). Furthermore, the ESC guideline definition was associated with increased risk of first hospitalization for HF, regardless of anaemia status (non‐anaemic, HR: 1.26, 95% CI: 1.08–1.1.47; anaemic, HR: 1.34, 95% CI: 1.17–1.53).
Conclusions
ID, when defined by TSAT < 20% or serum iron ≤13 μmol/L, is associated with increased risk of all‐cause and cardiovascular mortality, as well as first hospitalization for HF in patients with new‐onset chronic HF, regardless of anaemia status. Conversely, ID defined as ESC guidelines is associated with all‐cause and cardiovascular mortality only in non‐anaemic patients.
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Details
1 Department of Cardiology, Copenhagen University Hospital ‐ Herlev and Gentofte Hospital, Copenhagen, Denmark
2 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
3 Department of Cardiology, Copenhagen University Hospital ‐ Nordsjællands Hospital, Hillerød, Denmark, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
4 Department of Cardiology, Copenhagen University Hospital ‐ Rigshospitalet, Copenhagen, Denmark
5 Department of Cardiology, Copenhagen University Hospital ‐ Herlev and Gentofte Hospital, Copenhagen, Denmark, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Department of Cardiology, Copenhagen University Hospital ‐ Rigshospitalet, Copenhagen, Denmark, Steno Diabetes Center Copenhagen, Copenhagen, Denmark
6 Department of Cardiology, Copenhagen University Hospital ‐ Herlev and Gentofte Hospital, Copenhagen, Denmark, Duke Clinical Research Institute, Durham, North Carolina, USA
7 Department of Cardiology, Copenhagen University Hospital ‐ Herlev and Gentofte Hospital, Copenhagen, Denmark, Center for Advanced Heart Disease, Section of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA