Iron Deficiency as a Modifiable Risk Factor in Heart Failure: Evidence and Recommendations.

Targeting Iron Deficiency in Heart Failure: Existing Evidence and Future Expectations.

Intravenous iron supplementation, particularly ferric carboxymaltose (FCM), has emerged as an effective therapeutic strategy for correcting iron deficiency (ID) in patients with heart failure with reduced ejection fraction (HFrEF). However, the enhancement related to the quality of life (QoL) and functional capacity remains unclear, specifically in the Vietnam population. This study assesses the enhancement of QoL and functional capacity in intravenous FCM therapy in heart failure patients with ID. We conducted a cross-sectional analysis study in patients with chronic HFrEF. Eligible patients diagnosed with ID were treated with FCM. Endpoint was the improvement in QoL, assessed by the European Quality of Life 5 Dimensions 5 Level Version questionnaire, and functional capacity, measured by the change in the 6-minute walk test and New York Heart Association Functional Classification. A total of 132 patients with chronic HFrEF, with 35.60% of patients with ID. The study population had a mean age of 65.7 ± 9.4 years, males accounted for 56.8%. Female, New York Heart Association ≥3 and poor QoL significantly associated with ID. Notably, 12 weeks after intervention, patients with poor QoL decreased from 48.9% to 34.0% (P < .001). Functional capacity, assessed by the 6-minute walk test, improved with the median distance increasing from 239.90 (198.80–291.70) m at baseline to 262.60 (219.50–309.70) m (P < .01). Nausea was reported by a small minority at 4.25%. Our study highlights the significant burden of ID in patients with HFrEF, emphasizing its strong association with symptom severity, functional impairment, and reduced QoL. Intravenous FCM therapy demonstrated significant improvements in iron parameters, functional capacity, and QoL, with a favorable safety profile.

Iron deficiency (ID) is a common comorbidity in heart failure (HF), affecting 55% of chronic and up to 80% of acute HF patients, regardless of ejection fraction (EF). An ID is associated with reduced quality of life, impaired exercise capacity (VO2 peak), higher hospitalization rate and lower survival rate. It is also an independent predictor of HF outcomes. This consensus statement critically reviews the diagnostic criteria for ID in HF and provides recommendations for their use. The efficacy and safety of intravenous iron supplements, including ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), are analyzed highlighting the indications and potential adverse effects. Key clinical trials and guideline recommendations are summarized. In summary, the document addresses the diagnostics, treatment and monitoring of ID in HF.

Anemia and iron deficiency are highly prevalent and prognostically important comorbidities among patients with heart failure. Iron deficiency, in both the absolute and functional forms, affects up to 50-60% of patients with heart failure, even in the absence of anemia, and contributes to worsening symptoms, impaired exercise capacity, and increased morbidity and mortality. Iron plays central roles in oxygen transport, myocardial energetics, and skeletal muscle function. Mechanistically, inflammation, impaired iron absorption, hepcidin overproduction, and reduced erythropoiesis contribute to the complex pathophysiology of iron deficiency in heart failure. The diagnostic criteria for anemia are generally serum ferritin &lt; 100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation &lt; 20%. Although oral iron supplementation has shown limited efficacy in clinical trials, intravenous iron therapy -particularly ferric carboxymaltose and ferric derisomaltose therapy- has demonstrated benefits in improving symptom burden and quality of life and reducing hospitalization 0for heart failure in patients with reduced or mildly reduced ejection fraction. However, large trials such as the HEART-FID and FAIRHF2 failed to show significant reductions in cardiovascular events, highlighting the need for further research. Moreover, key challenges remain, including identifying responders, optimizing iron dosing and monitoring strategies, and evaluating the long-term effects of iron repletion on clinical outcomes. This review summarizes the current evidence and emphasizes the need for more refined diagnostic criteria, individualized treatment approaches, and robust long-term data to guide iron therapy in cases of heart failure.

Correction of Iron Deficiency in Hospitalized Heart Failure Patients Does Not Improve Patient Outcomes

IntroductionOver half of patients with heart failure (HF) also have iron deficiency (ID), and this is associated with decreased functional capacity, reduced quality of life and a poorer prognosis. Treatment...

A satellite symposium at the 2014 European Society of Cardiology (ESC) congress discussed the importance of iron deficiency (ID) in heart failure (HF). ID is the main cause of anaemia and is observed in almost 50 % of HF patients in Europe and up to 80 % of patients in Asia. ID is an independent factor associated with reduced exercise capacity, reduced quality of life (QoL) and poor outcomes in HF. The importance of ID in HF is reflected in the fact that the current ESC Guidelines for HF recognise ID as a co-morbidity in HF for the first time, and recommend routine diagnosis and monitoring for ID based on iron parameters. Intravenous (i.v) administration of ferric carboxymaltose (FCM) was considered as a possible treatment option according to the findings of the Ferric Carboxymaltose Assessment in Patients With IRon Deficiency and Chronic Heart Failure (FAIR-HF) clinical study, which showed that treatment with FCM in HF patients with ID improves symptoms, exercise capacity and QoL. These findings were confirmed by the recent Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (CONFIRM-HF) study, which demonstrated that, in symptomatic patients with chronic HF and ID treatment with i.v. FCM over one year resulted in sustainable improvements in exercise capacity, symptoms and QoL, and was associated with a reduced risk of hospitalisations due to worsening HF.

Background Iron deficiency (ID) is the most common extracardiac comorbidity in heart failure (HF) and associated with worse outcomes. While a uniform definition of ID in HF remains lacking, several biomarkers for ID, including ferritin and transferrin saturation (TSAT), are used in both clinical trials and clinical practice. However, which biomarker is a superior prognostic predictor for ID in HF remains unsettled. In addition, real-world clinical data on ID screening and intravenous (IV) iron treatment is largely missing. Purpose To determine which biomarker is a superior prognostic predictor for the composite endpoint of HF rehospitalisation (HHF) and all-cause mortality in a real-world cohort of patients with HF and coexisting ID, and to investigate frequency and predictors of ID screening and IV iron treatment. Methods In this retrospective cohort study, all patients aged 18-85 years hospitalised at a tertiary university hospital with new onset HF with reduced ejection fraction (HFrEF) in 2016-2020 were consecutively included from medical records by ICD-10 code I50.0-I50.9 and followed until 31 December 2021. Patient characteristics, comorbidities, medications, laboratory results and data on follow-up, including if ID was tested for, IV iron administration, HHF and all-cause mortality was collected. First available iron status after admission for index hospitalisation was used. Predictors for ID screening and IV iron use were identified with univariate logistic regression. The association between ID markers and the composite endpoint was analysed with Cox regression adjusted for age, sex, baseline anemia, estimated glomerular filtration rate (eGFR) &amp;lt;30 mL/min/1.73 m2 and N-terminal pro-B type natriuretic peptide (NT-proBNP) below median value with median ferritin and TSAT values set as references respectively. Results In all, 753 patients were included (66.5 ± 12.7 years, 508 (67.5%) men, ejection fraction 29.5 ± 6.9% and mean NT-proBNP 6241 ± 7183 ng/L). Of these, 484 (64.3%) were screened for ID and 235 (48.6%) fulfilled criteria for ID. Of these, 94 (40.0%) received IV iron. Of screened patients, 28.6% had ID with anemia and 20.8% ID without anemia (Table 1). Factors associated with screening for ID were follow-up at hospital, anemia, eGFR &amp;lt;30 mL/min/1.73 m2 and ischemic heart disease, and for IV iron additionally chronic kidney disease and peripheral artery disease. Median ferritin was 140 µg/L and TSAT 0.2. Both ferritin and TSAT displayed an inversely linear association with outcomes, while TSAT &amp;lt;0.2 showed a stronger association with increased risk of HHF and all-cause mortality compared to median values (Figure 1-2). Conclusions In a real-world clinical setting, TSAT was a superior prognostic biomarker for worse outcomes compared to ferritin in patients hospitalised for acute HF. While both ID screening and IV iron use remained greatly underutilised in clinical practice, identification of a reliable biomarker for ID is critical.

In spite of recent progress made in the management of heart failure as outlined in current guidelines, patients often remain symptomatic, and the event rate, even on optimal therapy and with devices, is still high. Besides pump failure itself, co-morbidities contribute importantly to the disease burden in heart failure patients. Besides renal failure and diabetes, many patients with heart failure have an iron deficiency, probably due to chronic inflammation associated with the disease process. Accordingly, the first manuscript, by Piotr Ponikowski from the Clinical Military Hospital in Wroclaw, Poland, is an ESC FAST TRACK manuscript entitled ‘Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency’ accompanied by a critical Editorial by Harry Crijns from the University Hospital Maastricht in the Netherlands. The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in 304 iron-deficient patients with heart failure and a reduced left ventricular ejection fraction and elevated natriuretic peptides enrolled in CONFIRM-HF and randomized to i.v. ferric carboxymaltose or placebo. The primary endpoint was the change in 6 min walk test distance from baseline at 4 months. Secondary endpoints included changes in New York Heart Association (NYHA) class, Patient Global Assessment, health-related quality of life, fatigue score, and hospitalization for worsening heart failure. Ferric carboxymaltose prolonged the 6 min walk distance beyond 1 year. Furthermore, ferric carboxymaltose improved NYHA class, Patient Global Assessment, quality of life, and fatigue score, and reduced hospitalizations for heart failure, while deaths and adverse events were comparable between groups. The authors conclude that treatment of symptomatic, iron-deficient heart failure patients with ferric carboxymaltose over 1 year results in a sustained improvement in functional capacity, symptoms, andqualityof life, aswell in a reduction of hospitalization for heart failure. It remains unknown, however, whether iron substitution beyond symptomatic benefit also provides protection from premature death in these patients. A large randomized trial certainly is an unmet need in this patient population. In addition to co-morbidities, baseline heart rate has been recognized as a risk factor in heart failure, while its modulation over time has not been studied. The second manuscript, by Scott Solomon et al. from the Brigham and Women’s Hospital in Boston USA, accompanied by a thought-provoking Editorial by Michel Komajda from the CHU Pitie-Salpetriere, Paris, France, is entitled ‘Prognostic importance of temporal changes in resting heart rate in heart failure patients: an analysis of the CHARM programme’. The authors explored the relationship between changes in heart rate from a preceding visit, time-updated heart rate (i.e. most-recent available heart rate value), and outcomes in 7599 patients with chronic heart failure recruited in the CHARM programme. Of note, an increase in heart rate from a preceding visit was associated with higher all-cause mortality and the composite of cardiovascular death or hospitalization for heart failure, while lowering of heart rate was associated with reduced risk. The authors showed for the first time that heart rate at follow-up, as well as a change or time-updated heart rate, predicts outcome in chronic heart failure. They further suggest that frequent outpatient monitoring of heart rate, and identification of changes over time, possibly with remote technologies, may identify patients at increased risk of re-hospitalization or death. With the help of modern devices, remote monitoring is already possible and may eventually find its way into the everyday management of patients with heart failure. Inflammation is associated not only with atherosclerosis but also with heart failure. On the other hand, myocardial inflammation can severely impair left ventricular function, for instance in myocarditis. It is of note that chemokines and cytokines may not only be damaging, but may also be protective. The third manuscript, by Konrad Hoetzenecker from the Medical University of Vienna in Austria, accompanied by an enlightening Editorial by Heinz-Peter Schultheiss from the Charite University in Berlin, Germany, reports on ‘Mononuclear cell secretome protects from experimental autoimmune myocarditis’. The authors investigated in the supernatants of serum-free cultured mononuclear cells a mix of immunomodulating factors (i.e. the so-called secretome), which is able to attenuate inflammatory responses in myocardial ischaemia. In this study, the authors aimed to characterize the influence of the mononuclear secretome on myocardial inflammation in an experimental model of a-myosin heavy chain autoimmune myocarditis. A single high-dose injection of the mononuclear secretome at day 14 attenuated myocardial inflammation. Mechanistically, the mononuclear secretome induced caspase-8-dependent apoptosis in autoreactive CD4+ T cells. Thus, the authors conclude that the mononuclear secretome is able to

Background: Data on the burden of Iron deficiency (ID) in Heart failure (HF) patients in India are sparse and there is very little information available about the prevalence of iron deficiency in heart failure with mid-range (HFmrEF) and preserved ejection fraction (HFpEF) in comparison to heart failure with reduced ejection-fraction (HFrEF).&#x0D; Aims and Objective: This study was carried out with aim to evaluate iron profile in HF patients and to know the prevalence of ID in HFpEF, HFmrEF and HFrEF in our region.&#x0D; Materials and Methods: Patients with clinically diagnosed HF were enrolled in the study. This was a single tertiary care centre, prospective, observational study carried out from December 2017 to November 2018. Patients were classified into HFrEF, HFmrEF and HFpEF on echocardiography. Serum ferritin (micrograms per liter), serum iron (micrograms per liter), total iron binding capacity (micrograms per liter), transferrin (milligrams per deciliter), and transferrin saturation were measured to assess iron status. Absolute ID was defined as serum ferritin &lt; 100 mg/L and functional ID was defined as normal serum ferritin (100–300 mg/L) with low TSAT (&lt;20%).&#x0D; Results: A total of 120 patients of HF (66.7% males and 33.3% females) were studied. Out of 120 patients, 78 (65%) patients of HF had ID. Absolute ID was in 38.3% and functional ID was seen in 26.7% patients. 62.5% of males had ID, whereas, 70% of females had ID in HF. Patients with ID had higher NYHA Class, 35.9% compared to 23.8% patients without ID. ID was high in all subsets of HF. ID was found in 61.11% in HFrEF, 67.44% in HFmrEF and 69.57% in HFpEF. P-0.71. 14.1% patients had ID, but no anemia (p- 0.02). In anemic patients, ID was more (85.2%) than non anemic patients (69%).&#x0D; Conclusion: In our study, prevalence of ID was higher in patients of HF than that reported from western literature. HFpEF had higher prevalence of ID followed by HFmrEF and HFrEF, respectively. Literature is scanty about HFmrEF, our study has given an insight of ID in this subset of HF. ID can occur even without anemia and females are more prone to have ID in HF. Our study highlights the importance of diagnosis and treatment of ID in all subsets of HF, in order to improve quality of life, morbidity and mortality in patients of HF.&#x0D; Keywords: Iron deficiency, Heart Failure, Anemia, HFrEF, HFmrEF, HFpEF

Abstract: Iron deficiency (ID) is an ominous non-cardiovascular co-morbidity highly prevalent in patients with heart failure (HF). The presence of ID in patients with HF, regardless of concomitant anaemia, translates into exaggerated HF symptoms, impaired exercise capacity, poor quality of life, frequent recurrent HF hospitalizations, high mortality and increased healthcare costs. ID is diagnosed in patients with HF when serum ferritin is #lt; 100 ng/mL (ng/mL = μg/L), or when serum ferritin is between 100 and 299 ng/mL combined with a transferrin saturation (TSAT) of #lt; 20% (TSAT = (iron/TIBC) × 100%). According to the ESC guidelines on HF (2016, 2021), all patients with HF are recommended to be screened for ID using serum ferritin and TSAT, regardless of left ventricular ejection fraction (LVEF), haemoglobin level and kidney function. The results of the FAIR-HF, CONFIRM-HF, and AFFIRM-AHF trials along with meta-analyses have established the basis for the ESC recommendation that intravenous iron supplementation with ferric carboxymaltose (FCM) should be considered in symptomatic patients with LVEF #lt;45% and ID (defined as above) in order to alleviate HF symptoms, improve exercise capacity and quality of life. The major results of the AFFIRM-AHF trial have led the foundations for the recommendation that intravenous iron supplementation with FCM should be considered in symptomatic HF patients recently hospitalized for HF and with LVEF #lt; 50% and ID (defined as above) in order to reduce the risk of HF hospitalization. Therapy with FCM has been demonstrated to be effective and safe. Cost-effectiveness analysis has confirmed that intravenous iron supplementation with FCM in iron deficient patients after an episode of acute HF is dominant in the UK, USA, and Switzerland, and is highly cost-effective in Italy. Ongoing clinical trials are expected to provide further evidence on the effect of this therapy on long-term cardiovascular mortality in iron deficient patients with HF (FAIR-HF2, IRONMAN, HEART-FID) and on exercise capacity and quality of life in iron deficient patients with HF with preserved ejection fraction (FAIR-HFpEF).

Usefulness of Iron Deficiency Correction in Management of Patients With Heart Failure [from the Registry Analysis of Iron Deficiency-Heart Failure (RAID-HF) Registry]

To discuss the pathophysiology of iron metabolism in chronic heart failure (CHF) and the current knowledge of the efficacy of intravenous (IV) iron therapy in patients with CHF and identify points of controversy as well as highlight areas for future research. Iron deficiency is a recognized complication of many chronic conditions. Numerous studies have reported that iron deficiency is highly prevalent in patients with CHF and is associated with exercise intolerance, reduced quality of life, and increased risk of hospitalization and mortality. Several small studies have demonstrated IV iron to be associated with improvements in symptoms, exercise capacity, quality of life, renal function, New York Heart Association (NYHA) functional class and left ventricular ejection fraction (LVEF), and reduction in NT-pro-brain natriuretic peptide (NT-proBNP) in patients with CHF and iron deficiency. Two larger-scale trials confirming these results (FAIR-HF and CONFIRM-HF) have led to guideline recommendations that IV iron therapy should be considered in patients with CHF with reduced ejection fraction and iron deficiency (serum ferritin <100μg/L, or ferritin between 100 and 299μg/L with transferrin saturation <20%) to provide symptomatic relief and improve exercise capacity and quality of life. Intravenous iron therapy improves symptoms, exercise capacity, and quality of life, at least in the short-to-intermediate time. However, there are still currently no standardized criteria used to define iron deficiency and the underlying mechanism of iron deficiency in CHF remains incompletely understood. Further work is required to improve the ability to identify iron deficiency in patients with CHF and evaluate the effect of iron repletion on hard endpoints including hospitalization and mortality.

Heart failure is an important community health problem. Prevalence and incidence of heart failure have continued to rise over the years. Despite recent advances in heart failure therapy, prognosis is still poor, rehospitalization rate is very high, and quality of life is worse. Co-morbidities in heart failure have negative impact on clinical course of the disease, further impair prognosis, and add difficulties to treatment of clinical picture. Therefore, successful management of co-morbidities is strongly recommended in addition to conventional therapy for heart failure. One of the most common co-morbidities in heart failure is presence of iron deficiency and anemia. Current evidence suggests that iron deficiency and anemia are more prevalent in patients with heart failure and reduced ejection fraction, as well as those with heart failure and preserved ejection fraction. Moreover, iron deficiency and anemia are referred to as independent predictors for poor prognosis in heart failure. There is strong relationship between iron deficiency or anemia and severity of clinical status of heart failure. Over the last two decades, many clinical investigations have been conducted on clinical effectiveness of treatment of iron deficiency or anemia with oral iron, intravenous iron, and erythropoietin therapies. Studies with oral iron and erythropoietin therapies did not provide any clinical benefit and, in fact, these therapies have been shown to be associated with increase in adverse clinical outcomes. However, clinical trials in patients with iron deficiency in the presence or absence of anemia have demonstrated considerable clinical benefits of intravenous iron therapy, and based on these positive outcomes, iron deficiency has become target of therapy in management of heart failure. The present report assesses current approaches to iron deficiency and anemia in heart failure in light of recent evidence.

Frank iron deficiency has been associated with a wide range of cardiac and pulmonary abnormalities including non-ischaemic cardiomyopathy. Iron deficiency anaemia and isolated iron deficiency are well-defined adverse prognostic factors in non-ischaemic cardiac failure. Furthermore, iron-deficient patients in chronic heart failure with a serum ferritin of <100μg/l or <300μg/l with reduced transferrin saturation of <20%, who were given intravenous iron showed improved clinical outcomes. Iron deficiency with or without anaemia affects over a quarter of the world's population, but the impact of iron deficiency in heart failure and the effective management of iron deficiency in heart failure in Lower and Middle Income Countries (LMICs) is not well described. Heart failure in African cohorts occurs at a younger age than in North America and Europe and is more likely to be due to hypertension. Recent studies suggest that iron deficiency anaemia, which is very common in heart failure patients in Africa, and iron deficiency are independently associated with a poor prognosis in heart failure. Preliminary data suggest that iron deficiency in patients with heart failure can be treated with oral iron, with significant beneficial effects on haematological and physiological variables. Cost may prohibit the use of intravenous iron on a large scale in LMICs and optimal regimes to treat iron deficiency in heart failure patients with oral iron therapy remain to be defined.