WHAT IS ALREADY KNOWN ON THIS TOPIC
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Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with worse outcomes; however, the optimal diagnostic criteria for ID in patients with atrial fibrillation/flutter (AF), both with and without concurrent HF, remain uncertain.
WHAT THIS STUDY ADDS
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This study shows that ID defined by transferrin saturation (TSAT)
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In contrast, the European Society of Cardiology guideline definition of ID for patients with HF or ferritin
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Introduction
The prognostic implications of iron deficiency (ID) in patients with atrial fibrillation/flutter (AF) remain largely underexplored.1 Patients with AF are susceptible to ID and anaemia, primarily due to the increased risk of bleeding associated with anticoagulation therapy for stroke prophylaxis.2 In heart failure (HF), ID is prevalent in up to 50% of patients and is associated with reduced quality of life and increased risk of hospitalisation due to HF and mortality, regardless of anaemia status.3–5 Despite its importance, there is a lack of consensus on the definition for ID in HF.6 Current HF guidelines define ID as a ferritin level 7 8 This definition is primarily based on the inclusion criteria used in clinical trials evaluating iron repletion therapies for chronic HF.6 7 However, this definition is controversial, and alternatives such as TSAT 9
The optimal diagnostic criteria for ID in patients with AF remain uncertain. Previous studies have applied the same ID criteria used for patients with HF to those with AF.10 The rational for using the same criteria is that both AF and HF are associated with chronic inflammation.11
The aim of this study was to explore the association between ID, as defined by various criteria, and all-cause and cardiovascular mortality, as well as all-cause hospitalisation in patients with AF, both with and without HF.
Methods
Data source
The present study is a Danish nationwide real-world study, and was designed and reported in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.12 In Denmark, all Danish residents are assigned a unique personal identification, which allows individual-level linkage between various healthcare registers. The following databases were used in the current study: the clinical laboratory information system13; the Danish Civil Registration System14; the Danish National Patient Registry15; The Danish Cancer Register16; the Danish National Registry of Medicinal Product Statistics17 and the Danish Register of Causes of Death.18 For details on the International Classification of Diseases, 10th revision (ICD-10) and the Anatomical Therapeutic Chemical, see online supplemental table 1.
Patient selection and follow-up
We identified all patients with available iron-related parameters following an established diagnosis of AF, regardless of the AF type, during the period from 1 January 2008 to 31 December 2019. The patients were then stratified into two groups: those with AF and concurrent HF and those with AF without HF. Patients with an estimated glomerular filtration rate 2 were excluded from the study. The patients were followed from the date of the first available iron biomarker after the established diagnosis of AF, and for up to 5 years, or until immigration, death or the end of the study (31 December 2019), whichever occurred first.
Exposure definitions
In this study, we examined four different definitions for diagnosing ID. First, we defined ID as in current European Society of Cardiology (ESC) guidelines for HF, which is a serum ferritin level 19 Anaemia was defined based on the criteria established by WHO, which define anaemia as haemoglobin levels 20 Estimated glomerular filtration rate was calculated using serum creatinine levels, measured either on the same day or within the same week as the iron biomarkers.
Baseline characteristics
Baseline characteristics of the study population were reported at the time of their inclusion in the study. Comorbidities were deemed present if registered (overnight stay or outpatient visits) within 5 years preceding their inclusion in the study. HF was defined as having been diagnosed at any time prior to inclusion in the study. Diabetes mellitus was defined based on the patients having filled at least one or more prescriptions of insulin or non-insulin glucose-lowering treatment within 6 months prior to the study entry.21 Medicine use within 6 months before inclusion was identified. For further details, see online supplemental table 1.
Study outcomes
The primary outcome was all-cause mortality, and secondary outcomes were cardiovascular mortality and all-cause hospitalisation. Cardiovascular mortality was defined as death due to a cardiovascular cause as the primary cause of death (ICD-10: I00-99).
Statistics
Baseline characteristics were summarised as frequencies and percentages for categorical variables, while continuous variables were presented as means±SD or medians with IQR, depending on their distribution. Comparisons between groups were conducted using the t-test or the Wilcoxon rank-sum test for continuous variables (based on their distribution) and the χ2 test for categorical variables. The prevalence of ID was calculated according to each definition.
For our analyses, patients were included if their laboratory data were sufficient to determine their ID status based on at least one of the four definitions. This meant that a patient’s data would be included in a specific analysis related to the ID definition that their available laboratory results supported. Consequently, the same patient could be included in multiple analyses, depending on which ID definitions their laboratory data met. If a patient had multiple values of the same iron biomarker or haemoglobin available, the first value after an established AF diagnosis was used in the analyses.
To evaluate the association between the different ID definitions and outcomes, we used Cox proportional hazards models. All models were adjusted for gender, age groups (categorical), anaemia status, diabetes, stages of chronic kidney disease, chronic liver disease, chronic obstructive pulmonary disease, ischaemic heart disease, previous ischaemic stroke, cancer and the use of oral anticoagulants and antiplatelet treatment.22 The proportional hazards assumption for all models was verified using Schoenfeld residual plots. The results are reported as adjusted HRs with 95% CIs for each ID definition in relation to the outcome. 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. Additionally, we calculated and illustrated Aalen-Johansen cumulative incidences for cardiovascular mortality and all-cause hospitalisation, considering all-cause mortality as a competing risk. All analyses were performed using R V.4.0.3.23
Supplementary analyses
To account for the potential impact of the duration of AF prior to inclusion had on outcomes, we conducted supplementary analyses including only those patients with available iron indices within 12 months from AF diagnosis.
Patient and public involvement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.
Results
Baseline characteristics
A flow chart of the selection process for the included patients is shown in online supplemental figure 1. In total, 10 834 patients with AF were included in the study, with 7621 patients having AF with HF and 3213 patients having AF without HF. The median follow-up duration for the total included population was 31 months (IQR 12–52 months). Baseline characteristics of the included patients, stratified by HF status, are summarised in table 1. The median age of the population was 76 years (IQR 69–82 years), and 69.6% were male. Compared with patients having AF without HF, those patients having AF with HF were more likely to be anaemic, have more advanced stage of chronic kidney disease and have more comorbidities, such as ischaemic heart disease, previous ischaemic stroke, peripheral artery disease, chronic liver disease and chronic obstructive pulmonary disease (tables 1–2). A total of 64 patients received intravenous iron therapy during the follow-up period, the majority of whom were patients with AF and HF. Baseline characteristics stratified according to the different definitions of ID are presented in online supplemental tables 2–5.
Baseline characteristics
Laboratory finding
Prevalence of iron deficiency
Figure 1 illustrates the prevalence of ID according to different definitions in patients having AF, with and without HF. The overall prevalence of ID in the study population, based on available iron biomarkers, ranged from 36.2% to 61.7% in patients with AF with HF and from 38.6% to 62.7% in patients with AF without HF. Overall, 53.5% of patients were classified as anaemic (table 2). When comparing patients with and without anaemia, those with anaemia had a higher prevalence of ID, regardless of the applied definition for ID, in both groups (figure 1)
Prevalence of iron deficiency according to different definitions. Prevalence of iron deficiency defined by ESC guidelines (ferritin
The relationship between ID, as defined by the ESC guidelines, ferritin figures 2 and 3. Among patients with AF and HF, 24% and 13.6% of those with ID defined by serum iron ≤13 µmol/L and TSAT 13 µmol/L and TSAT >20%, while for patients with AF without HF, this was 19.6%. Approximately 14%–22% of the total population had serum iron ≤13 µmol/L and TSAT >20%, while 3%–5% had TSAT 13 µmol/L (figures 2–3). In the subgroup of patients with serum iron ≤13 µmol/L and TSAT >20%, 60.5% were found to have low transferrin levels, which may explain the observed discrepancy (online supplemental figure 2).
Relationship between different criteria for iron deficiency in patients with atrial fibrillation and heart failure. Venn diagram showing the relationship between iron deficiency defined by ESC guidelines (ferritin
Relationship between different criteria for iron deficiency in patients with atrial fibrillation without heart failure. Venn diagram showing the relationship between iron deficiency defined by ESC guidelines (ferritin
Association between outcomes and different definition of iron deficiency
During the follow-up period, a total of 3680 (33.9%) patients died. Among these, 1696 deaths (46%) were due to cardiovascular causes. No significant interactions were observed in the adjusted models between the four definitions of ID and anaemia status across all outcomes in both groups (online supplemental tables 6 and 7). In the adjusted Cox regression analysis, in patients with AF and HF, ID defined by TSAT HR 1.25, 95% CI 1.14 to 1.37 and HR 1.44, 95% CI 1.31 to 1.58, respectively) and cardiovascular mortality (HR 1.31, 95% CI 1.14 to 1.49 and HR 1.42, 95% CI 1.24 to 1.63, respectively), as well as all-cause hospitalisation (HR 1.19, 95% CI 1.12 to 1.27 and HR 1.17, 95% CI 1.10 to 1.25, respectively) compared with patients without ID defined by TSAT >20% and serum iron >13 µmol/L, respectively (figure 4). In patients with AF without HF, an association between ID defined by TSAT HR 1.39, 95% CI 1.18 to 1.64 and HR 1.67, 95% CI 1.41 to 1.97, respectively) and cardiovascular mortality (HR 1.54, 95% CI 1.18 to 2.00 and HR 1.46, 95% CI 1.13 to 1.89, respectively) were also observed. No significant association was observed between ID defined by the ESC guidelines or ferritin figure 4). However, both definitions were associated with an increased risk of all-cause hospitalisation in patients with AF and HF (HR 1.15, 95% CI 1.08 to 1.23 and HR 1.16, 95% CI 1.09 to 1.23, respectively). Cumulative incidence curves for all-cause mortality according to the different ID definition are shown in figures 5 and 6. Corresponding curves showing cumulative incidence of cardiovascular mortality and all-cause hospitalisation can be found in online supplemental figures 3–6.
HRs for the association between ID using different definitions and all-cause and cardiovascular mortality, as well as all-cause hospitalisation. Forest plot presenting HRs for all-cause and cardiovascular mortality, as well as all-cause hospitalisation associated with ID in patients with atrial fibrillation, with and without heart failure. ID is defined according to ESC guidelines (ferritin
Cumulative incidence curve for all-cause mortality according to different definitions of ID in patients with atrial fibrillation and heart failure. Cumulative incidence of all-cause mortality according to ID defined by: ESC guidelines (ferritin
Cumulative incidence curve for all-cause mortality according to different definitions of ID in patients with atrial fibrillation without heart failure. Cumulative incidence of all-cause mortality according to ID defined by: ESC guidelines (ferritin
Supplementary analyses
In the supplementary analyses of the AF subpopulation with HF and available iron indices within the first 12 months after AF diagnosis, ID defined by TSAT online supplemental figure 7). In the corresponding AF subpopulation without HF, only ID defined as serum iron ≤13 μmol/L were associated with higher all-cause mortality. However, all four definitions were associated with increased risk of all-cause hospitalisation in patients with AF and HF. For patients with AF without HF, this was only observed for ID defined by TSAT
Discussion
In our study population, ID, defined as TSAT
Patients with AF are more susceptible to anaemia and ID due to the increased risk of clinical and subclinical bleeding associated with anticoagulation therapy for stroke prophylaxis.2 While existing literature on the prognostic role of ID, irrespective of anaemia, in the context of AF is scarce, a recent comprehensive retrospective study focusing on hospitalised patients with AF revealed that prevalence of a coded diagnosis of ID with anaemia in patients with AF was 2.5% and was not associated with increased all-cause mortality.24 A critical limitation for this study is the use of ICD codes for ID with anaemia, which may have a low sensitivity in capturing all patients with ID and anaemia. Another retrospective study on ID in 101 patients with AF and without HF defined ID as in the ESC guidelines for HF. This study found that 47.6% of individuals with AF had ID, irrespective of anaemia status.10 However, this prevalence is lower than what we observed in our study, where we found an ID prevalence of 62% among the total included patients using a similar definition (ESC guidelines). Even though we included significantly more patients in our study, a possible explanation for the higher prevalence observed could be the inclusion of highly selective patients with AF, who might be sicker and, therefore, most likely do not reflect the general prevalence in the broader AF patient population.
A study that applied iron staining to bone marrow in patients with HF with left ventricular ejection fraction (LVEF) ≤45% found that the ID defined by ESC guidelines had lower sensitivity and specificity compared with TSAT ≤19.8% and serum iron ≤13 µmol/L in detecting ID in the bone marrow. Moreover, TSAT ≤19.8% and serum iron ≤13 µmol/L were associated with a higher risk of all-cause mortality.25 This is further supported by two retrospective studies that conducted a similar investigation as our study, solely in patients with chronic HF.6 26 These studies showed that TSAT 6 The lower sensitivity and specificity of the ESC guidelines for detecting ID in the bone marrow may be due to the inclusion of ferritin. Ferritin is an acute-phase protein that can increase during states of cell damage, inflammation and infection.1 AF and HF are associated with a state of low-grade systemic inflammation,11 which may result in elevated ferritin levels, even when true ID occurs within the bone marrow. This can theoretically mask the actual ID status.27
Currently, there is no indication to treat ID in patients with AF independently of anaemia.28 Given the demonstrated benefits of intravenous iron therapy in patients with HF,29 the ongoing IRON-AF randomised controlled trial is designed to evaluate the efficacy of intravenous iron treatment in patients with AF with ID.30 However, there are currently no consensus or validated diagnostic criteria using blood biomarkers to diagnose ID in patients with AF. The ongoing IRON-AF trial is using the same criteria for ID as those used for patients with HF. These criteria have not been validated in patients with HF either but are solely based on criteria used in intravenous iron trials.7 Meta-analyses of clinical trials on intravenous repletion in patients with HF, using these criteria for diagnosing ID, have shown a reduction in the composite end point of hospitalisation for HF or cardiovascular death, primarily driven by a reduction in HF hospitalisations.29 In our study, among patient with AF without HF with ID defined by serum iron ≤13 µmol/L or TSAT
Strength and limitation
A major strength of this study was the large sample size and long follow-up. However, several limitations exist in this study. First, its observational nature prevents the drawing of causal conclusions. Second, inclusion was limited to patients with AF who underwent ID testing. Screening for ID in patients with AF is not recommended routinely as it is for patients with HF, resulting in selection bias and thus affecting the observed prevalence of ID and the study findings. To determine a more accurately prevalence, the study needs to be conducted in an unselected cohort of patients with AF. Third, the decision to test ID is often prompted by the presence of anaemia, raising the possibility of confounding by indication. Fourth, important parameters related to cardiac function and HF severity such as LVEF, New York Heart Association functional class, left atrial diameter and B-type natriuretic peptide levels were not available in the registries used. As a result, we could not include or adjust for these parameters in our multivariable Cox regression analysis. Lastly, our analysis did not account for the use of iron supplement (both intravenous and oral) during follow-up, which could potentially introduce residual confounding. However, as only 64 patients received intravenous iron during follow-up, it is unlikely to significantly influence the main findings. Additionally, we were unable to account for the use of oral iron supplements, as they can be purchased without prescription in Denmark.
Conclusion
ID defined by TSAT
Data availability statement
No data are available. The data are not available to the public. The data are accessed by the authors through Statistic Danish after approval by the Danish Data Protection Agency.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by the Danish Data Protection Agency. According to Danish regulations, register-based retrospective studies do not require ethical approval.
