IRON DEFICIENCY’S IMPACT ON NEW-ONSET CHRONIC HEART FAILURE OUTCOME: DANISH HEART FAILURE REGISTRY INSIGHTS

IRON DEFICIENCY’S IMPACT ON NEW-ONSET CHRONIC HEART FAILURE OUTCOME

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Introduction

Iron deficiency (ID) is a common condition affecting more than half of patients with chronic heart failure (HF). It is linked to reduced ability to exercise, lower quality of life, higher chances of hospitalization, and increased risk of death, regardless of whether the patient has anemia. Current guidelines recommend regular screening and treatment for ID. Still, there is ongoing debate about the best way to define it in HF patients. The European Society of Cardiology (ESC) suggests specific ferritin and transferrin saturation levels, but these criteria are not fully validated. Other studies propose alternative measures like serum iron levels, which may be more accurate. This study aims to examine how often ID occurs in patients with new-onset chronic HF, compare different ways of defining ID, and assess the impact of these definitions on HF outcomes like mortality and hospitalizations.  

Background

Iron deficiency (ID) is a common issue in patients with chronic heart failure (HF), affecting more than half of them. It is linked to poorer exercise capacity, reduced quality of life, a higher likelihood of hospitalization, and an increased risk of death, even in those without anemia [1,2]. Because of these adverse effects, current guidelines recommend regular screening and treatment for ID in HF patients [3]. However, an ongoing debate exists about the best way to define ID in this group [4].

The European Society of Cardiology (ESC) defines ID as a ferritin level below 100 ng/mL or a ferritin level between 100 and 299 ng/mL combined with a transferrin saturation (TSAT) below 20% [3]. However, this definition is based on clinical trial criteria. It has not been validated against the gold standard test, which is bone marrow iron staining. Other studies suggest alternative definitions, such as TSAT below 20% or serum iron levels of 13 μmol/L or lower, which may offer better accuracy for diagnosing ID [5].

Research comparing different definitions of ID in HF patients is limited, and most studies are small in scale. As a result, it remains unclear which criteria are most effective for predicting important outcomes like death or hospitalization [4,5]. Understanding the prevalence of ID and its relationship to these outcomes is crucial for improving patient care.

This study investigates the prevalence of ID in patients with new-onset chronic HF using various definitions, including the ESC guidelines and alternative criteria. It also examines how these definitions are associated with all-cause mortality, cardiovascular deaths, and first-time hospitalizations for worsening HF. The goal is to provide insights that could enhance the diagnosis and management of ID in HF patients.

 

 

THE STUDY METHOD

This study was designed as a nationwide cohort study using data from the Danish Heart Failure Registry (DHFR), which includes patients with new-onset heart failure (HF) since 2003. The study utilized several linked national databases to obtain comprehensive data, including the clinical laboratory information system, the Danish Civil Registration System, and the Danish National Patient Registry. Patients included in the study had available laboratory data on iron biomarkers between 60 days before and one year after their HF diagnosis. Only those with complete data were considered, and exclusions were made for patients with severe kidney issues, missing iron biomarker data, or those receiving specific treatments like erythropoietin or intravenous iron therapy.

Four different definitions of iron deficiency (ID) were applied in this study based on various iron biomarker levels. These included definitions based on ferritin levels, transferrin saturation (TSAT), and serum iron levels. The study followed patients from the date their ID status was determined until the end of 2019, tracking primary outcomes like all-cause mortality and secondary outcomes such as cardiovascular mortality and first hospitalization for HF. The data was analyzed using Cox proportional hazard models, adjusting for age, gender, comorbidities, and treatment history. The study also accounted for the probability of receiving ID testing by incorporating inverse probability weights into the models. Statistical methods included Kaplan–Meier curves and Aalen–Johansen cumulative incidence plots to evaluate the relationship between ID status and outcomes.

ANALYSIS

The researchers analyzed the data using advanced statistical methods to understand how different definitions of iron deficiency (ID) relate to important health outcomes in patients with heart failure (HF). They looked at factors like all-cause death, heart-related death, and hospitalizations for worsening heart failure. By using several definitions of ID based on iron levels in the blood, they could compare how well each definition predicted these outcomes. The analysis considered various patient factors, such as age, medical history, and treatments, to ensure the results were accurate. The study used models to estimate the risk of poor outcomes based on ID status and examined how different levels of iron deficiency affected patient survival and hospitalization rates over time.

RESULTS

Study Population and Baseline Characteristics:

• The study included 9,477 patients with new-onset heart failure (HF).
• The median follow-up period for all-cause mortality was 27 months, with no patients lost to follow-up.
• The median age of patients was 72 years, and 66.3% were male.
• The majority of patients were diagnosed with HF between 2015-2017.
• Patients with HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF) were more likely to have conditions like diabetes and hypertension.

Prevalence of Iron Deficiency (ID):

• The prevalence of ID varied from 35.8% to 64.3%, depending on the definition used.
• The highest prevalence of ID was found using serum iron ≤13 μmol/L.
• It was more common in patients with anemia, regardless of the applied ID criteria.

Impact of ID on Mortality:

• Of the 2,820 deaths during follow-up, 44.9% were due to cardiovascular causes.
• ID defined by ESC guidelines, TSAT < 20%, or serum iron ≤13 μmol/L was associated with higher all-cause and cardiovascular mortality in non-anemic patients.
• Only TSAT < 20% or serum iron ≤13 μmol/L was linked to increased mortality in anemic patients.

Risk of First Hospitalization for HF:

• ID defined by ESC guidelines, TSAT < 20%, or serum iron ≤13 μmol/L increased the risk of first hospitalization for HF, regardless of anemia status.
• Ferritin <100 ng/mL did not significantly affect the HF hospitalization risk.

Overall Findings:

• The study suggests that iron deficiency, mainly when defined by serum iron ≤13 μmol/L or TSAT < 20%, is associated with higher mortality and hospitalization risk in heart failure patients.

DISCUSSION

This study explored the prevalence and prognostic implications of iron deficiency (ID) in newly diagnosed chronic heart failure (HF) patients using the European Society of Cardiology (ESC) guidelines and other proposed definitions. The study revealed that the prevalence of ID ranged between 39.3% and 67.3%, depending on the criteria used. Importantly, low serum iron (≤13 μmol/L) and transferrin saturation (TSAT) below 20% were linked to higher risks of all-cause and cardiovascular mortality, as well as first hospitalization for HF, regardless of anemia status [1].

Interestingly, ID, as defined by ESC guidelines, was only associated with higher mortality in non-anemic patients. At the same time, TSAT < 20% and serum iron ≤13 μmol/L were linked to poor outcomes across all patients. These findings are consistent with previous studies, such as one by Masini et al., which found TSAT and serum iron to be stronger predictors of mortality than ESC-defined ID [2,3]. The study also emphasized that ferritin-based definitions, like the ESC guidelines, might underestimate actual ID due to ferritin’s susceptibility to inflammation and other non-iron-related conditions [4].

The research further pointed out the limitations of current ESC guidelines in identifying HF patients who might benefit from iron supplementation. Many patients with low serum iron or TSAT but normal ferritin levels were excluded from the ESC-defined ID group, potentially missing opportunities for treatment. This issue could also bias clinical trials on iron therapy, as some patients with actual ID might not be included [5]. These findings underscore the need for a more reliable diagnostic approach to identify ID in HF patients accurately [6].

Another notable observation was the higher prevalence of ID in patients with heart failure with preserved ejection fraction (HFpEF) compared to those with reduced ejection fraction (HFrEF). This could be attributed to the older age and higher comorbidity burden in HFpEF patients, including conditions like chronic kidney disease and atrial fibrillation that predispose them to ID [7]. The study also reinforced the importance of TSAT and serum iron as more reliable diagnostic and prognostic markers for ID in HF than ferritin [8].

The study concludes that redefining ID criteria in heart failure is crucial for improving patient care. Future research should focus on validating TSAT and serum iron as standard markers for ID and evaluating their potential for guiding iron supplementation therapy. Additionally, clinical trials should ensure broader inclusion criteria to capture all patients who could benefit from iron treatment [9,10].

 

STUDY LIMITATIONS

Observational Nature

• This observational study cannot establish cause-and-effect relationships between iron deficiency and heart failure outcomes.

Screening Practices

• Screening for iron deficiency became standard practice only after the 2016 ESC guidelines.
• Most patients in the study were diagnosed between 2015 and 2017, so earlier cases might not have been consistently screened for iron deficiency.

Selection Bias

• Patients included in the study were generally sicker than those excluded.
• This might mean the prevalence of iron deficiency reported here doesn’t represent all Danish patients with new-onset chronic heart failure.

Iron Status and Supplementation

• Changes in iron levels over time were not tracked in the study.
• The study didn’t consider whether patients received iron supplementation after being included, which could affect the results.

Guideline Limitations

• The ESC definition of iron deficiency was based on trials invulving patients with reduced ejection fraction (LVEF ≤ 45%) on stable medical therapy.
• The inclusion of patients with preserved and mildly reduced ejection fractions or those not yet on proper therapy may have impacted the effectiveness of the ESC definition in this study.

Confounding Factors

• Anemia often triggers testing for iron biomarkers, which can introduce bias related to the reason for the testing.
• Only a few patients (76) received intravenous iron during fullow-up, so its impact on the findings was minimal.

 

Conclusion

In conclusion, the study found that iron deficiency defined by low serum iron (≤13 μmol/L) or transferrin saturation (TSAT < 20%) was strongly linked to a higher risk of death from all causes and heart-related issues. The current ESC guidelines for iron deficiency were also linked to these risks but only in patients without anemia. However, they were associated with an increased risk of hospitalization for heart failure in all patients. These findings suggest that using serum iron or TSAT levels as markers may better predict outcomes than the current guidelines. More research is needed to see if treating iron deficiency based on these new definitions can improve patient outcomes.

 

References

1. Von Haehling S, Gremmler U, Krumm M, Mibach F, Schön N, Taggeselle J, et al. Prevalence and clinical impact of iron deficiency and anemia among outpatients with chronic heart failure: the PrEP Registry. Clin Res Cardiol. 2017;106:436-443. doi:10.1007/s00392-016-1073-y
2. 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:10.1186/s12872-018-0942-x
3. 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:10.1016/j.ahj.2013.01.017
4. 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 is associated with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol. 2019;108:203-211. doi:10.1007/s00392-018-1344-x
5. 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:10.1080/00015385.2017.1351239

1. 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. https://doi.org/10.1002/ejhf.473
2. Grote Beverborg N, IjT K, Meems LM, et al. Iron deficiency and heart failure: from diagnosis to treatment. Eur J Heart Fail. 2020;22:1342-1350. https://doi.org/10.1002/ejhf.1820
3. Anker SD, Comin CJ, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436-2448. https://doi.org/10.1056/NEJMoa0908355
4. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36:657-668. https://doi.org/10.1093/eurheartj/ehu385
5. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165:575-582. https://doi.org/10.1016/j.ahj.2013.01.017

 

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