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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 10  |  Issue : 1  |  Page : 30-36

Characterization of Iron deficiency in patients with chronic heart failure: A prospective, multicentric, observational study from India


1 Associate Professor and Head of Department of Cardiology, S.S. Hospital, IMS BHU, Varanasi, Uttar Pradesh, India
2 Consultant Cardiologist, Department of Cardiology, Dr. Phadke's Hospital, Mahakali Caves Road, Andheri -East, Mumbai, India
3 Consultant Cardiologist, Department of Cardiology, Gandhi Nagar Hospital, CCL, Ranchi, Jharkhand, India
4 Consultant Cardiologist, Department of Cardiology, Sunder Lal Jain Hospital, Ashok Vihar, Phase 3, New Delhi, India
5 Sr. Consultant Cardiologist, Director, Interventional Cardiology, Apollo Hospitals, Bhubaneswar, India
6 Consultant Cardiologist, Department of Cardiology, Jupiter Hospital Thane, Shreeji Arcade, Mahanagr Palika Marg, Nitin Company Bus Stop, Thane (West), India
7 Consultant Cardiologist, Department of Cardiology, Sri Balaji Institute of Medical Sciences, Raipur, Chhattisgarh, India
8 Consultant Cardiologist, Department of Cardiology, Sidhu Hospital, G.T.Road, Doraha, Ludhiana, India
9 Consultant Cardiologist, Department of Cardiology, Balurghat District Hospital, West Bengal, India
10 Consultant Cardiologist, Department of Cardiology, Sooriya Hospital, No:1, Arunachalam Road, Velayutham Colony, Saligramam, Near AVM Studio, Chennai, Tamil Nadu, India

Date of Submission01-Oct-2019
Date of Decision13-Nov-2019
Date of Acceptance22-Jan-2020
Date of Web Publication20-Apr-2020

Correspondence Address:
Dr. Dharmendra Jain
Associate Professor and Head of Department of Cardiology, SSH, IMS, BHU, Varanasi - 221 005, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JICC.JICC_43_19

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  Abstract 


Objective: The objective of the study is to assess the characteristics of iron deficiency (ID) in Indian patients with chronic heart failure (CHF). Materials and Methods: This was a prospective observational study involving in patients visiting the outpatient department and admitted to hospitals with a clinical diagnosis of CHF falling within the New York Heart Association (NYHA) classification (I–IV). ID was diagnosed based on hemoglobin (Hb), serum ferritin levels, serum iron, total iron-binding capacity, and transferrin saturation (TSAT) percentage. Absolute ID was diagnosed as ferritin level <100 μg/L. Functional ID was diagnosed as normal serum ferritin (serum ferritin, 100–299 μg/L) in combination with TSAT (>20%). Anemia was defined as Hb <13 g/dL for men and <12 g/dL for women, based on the definition by the World Health Organization. Results: A total of 584 patients (men, 311 [53.25%]; women, 259 [44.35%]) with a mean age of 56.68 ± 14.53 years were evaluated. Absolute ID was noted in 314 (53.8%) patients. Female patients had a higher prevalence of absolute ID than male patients (51.3% vs. 46.5%; P < 0.0001). Patients with ID tended to be younger and predominantly belonged to NYHA Class II. The prevalence of anemia was higher in patients with ID than those without ID [167 (57.6%) vs. 123 (42.4%); P=0.0602]. The functional ID was present in 34 (6.34%) of patients, with a higher prevalence in female patients. Conclusion: More than half of the study population had ID. Female sex, younger age, and NYHA Class II of heart failure were some of the parameters that were associated with the presence of ID.

Keywords: Chronic heart failure, iron deficiency, multicentric, observational study


How to cite this article:
Jain D, Desai BN, Rathi RK, Shekhar C, Sahoo PK, Burkule N, Mohanty SS, Sharma SK, Sidhu GK, Halder UK, Jayarajah M. Characterization of Iron deficiency in patients with chronic heart failure: A prospective, multicentric, observational study from India. J Indian coll cardiol 2020;10:30-6

How to cite this URL:
Jain D, Desai BN, Rathi RK, Shekhar C, Sahoo PK, Burkule N, Mohanty SS, Sharma SK, Sidhu GK, Halder UK, Jayarajah M. Characterization of Iron deficiency in patients with chronic heart failure: A prospective, multicentric, observational study from India. J Indian coll cardiol [serial online] 2020 [cited 2020 Aug 14];10:30-6. Available from: http://www.joicc.org/text.asp?2020/10/1/30/282975




  Introduction Top


Heart failure (HF) is a major public health concern affecting approximately 26 million people globally and poses an immense health and economic burden.[1],[2] In the United States alone, the prevalence of HF has increased from about 5.7 million in 2009–2012 to about 6.5 million in 2011–2014 among individuals aged ≥20 years.[3] Based on the latest statistics, the percentage of people diagnosed with HF is projected to increase by 46% by 2030, resulting in HF affecting more than 8 million people ≥18 years of age by 2030.[4] The burden of HF in Europe is substantial and likely to grow. At present, 15 million people with HF live in Europe, and the prevalence of HF continues to rise.[2],[5] HF as a primary diagnosis is the leading cause of hospitalization, resulting in more than 1 million admissions and representing 1%–2% of all hospitalizations annually in both the United States and Europe.[2],[6]

The risk of HF increases with advancing age. In North America and Europe, few patients with HF are 50 years of age or younger[7],[8] and more than 80% are 65 years of age or older.[1] The incidence of HF approaches 21/1000 population after 65 years of age.[9] The number of patients with HF is predicted to increase in countries with large aging populations.[10] However, HF is not a disease of the elderly in sub-Saharan Africa, where half of the patients hospitalized with the disease are 55 years of age or younger; this is in contrast to data from the United States and Europe.[11] Further, there has been an increase in the number of patients with HF in developing countries in Latin America and Asia. The prevalence estimates for HF across Asia range from 1.26% to 6.7%. Rheumatic heart disease is a major contributor to HF in certain parts of South Asia, such as India; however, recently, trends toward an ischemic cause for HF have been observed in Asia, especially in China and Japan.[12] Patients with HF in the Asia Pacific region also tend to be younger than their Western counterparts.[13]

Unlike in the Western world, the epidemiology of HF in developing countries such as India is still a critical issue where no large studies have been conducted to explore the burden of HF. In India, the estimated prevalence of HF is about 1% of the total population (8–10 million), and the estimated mortality attributable to HF is about 0.1–0.16 million individuals per year.[14] Furthermore, HF affects the younger population in India, unlike in Western countries, where HF is predominantly a disease of the elderly.[15]

Patients with chronic HF (CHF) are prone to develop iron deficiency (ID).[16] Iron is a metabolically active micronutrient with unique biochemical features. One of its crucial properties is its ability to shuttle between two oxidative states (ferric and ferrous iron), which makes it an efficient cofactor for several enzymes and catalysts in numerous biochemical reactions. Further, iron plays a crucial role in oxygen transport (as a component of hemoglobin), oxygen storage (as a component of myoglobin), and oxidative metabolism in the skeletal and heart muscles (as a component of oxidative enzymes and respiratory chain proteins). Iron is also involved in the synthesis and degradation of lipids, carbohydrates, deoxyribonucleic acid, and ribonucleic acid.[16]

The presence of ID has multifaceted clinical consequences, and it has shown potential involvement in CHF.[17],[18],[19] CHF is associated with both absolute and functional ID, at least in part because of reduced iron absorption and the presence of a generalized inflammatory state.[20] A first-of-its-kind study by Varma et al. demonstrated ID anemia to be an important risk factor for and a strong predictor of cardiac death as compared with other anemia or nonanemic patients.[21] In a recent pooled analysis of 1500 Caucasian patients with CHF, ID was common in patients with CHF and was more predictive of disease severity compared with anemia.[22] Similarly, in another recent study, patients with acute HF demonstrated profound ID, characterized by depleted body iron stores and unmet cellular iron requirements in target tissues. In contrast, patients with preserved iron status had a remarkably good outcome, with virtually no deaths reported during the 12-month follow-up.[23]

Very few studies have evaluated the association between ID and CHF in Asian patients.[24],[25] Yeo et al. conducted a study to understand the prevalence, clinical correlates, functional significance, and prognosis of ID in patients with HF in a multi-ethnic Southeast Asian population. The findings of this study suggested a pathophysiological role of ID in HF and supported the hypothesis that ID is an important therapeutic target in Asian patients with HF.[25] Currently, there are a few studies from India that estimate the association between ID and HF. A recent study by Sharma et al. highlighted a remarkably high prevalence of ID in patients with HF in south Rajasthan, India, with or without anemia.[26] Recently, a few interventional studies have also demonstrated favorable effects of iron supplementation on functional status and quality of life in ID patients with HF, regardless of the presence of anemia.[27]

Since iron supplementation improves prognosis in patients with HF, ID may prove to be an attractive therapeutic target – this hypothesis has recently been proven in clinical studies.[28] However, data on the association of ID and HF are scarce, and it is uncertain whether HF itself or underlying comorbidities contribute to ID. Further, there are no data from India on the prevalence of ID associated with CHF. Therefore, the current study is an attempt to assess the association between ID and clinical characteristics of patients with CHF.


  Materials and Methods Top


This was a prospective, observational, noninterventional, multicentric study to assess the association between ID in Indian patients with CHF falling within the New York Heart Association (NYHA) Class I–IV and reduced ejection fraction. The criterion for inclusion in the study was patients of either gender (male or female patients) aged >18 years clinically diagnosed with CHF as per NYHA Class I–IV.[29] Patients who had undergone routine laboratory measurements of iron parameters and had signed the informed consent form were included in the study.

Patients who did not sign the informed consent form, as well as patients without any condition indicating that they or their data were not suitable for recruitment, were excluded from the study.

Approximately 10 sequential patients were contributed by each of the 100 sites that were geographically representative of India and routinely collected iron parameters (as per the European Society of Cardiology HF [ESC-HF] guidelines).[30],[31] Investigators explained study procedures to patients who were clinically diagnosed with CHF. The investigator or designated personnel collected all relevant information from patients' and medical/laboratory records.

The data collected from patients comprised of demographic data, gender, date of birth, age, social status, dietary nutrition (vegetarian/nonvegetarian), time since HF, HF etiology, and number of comorbid factors (including atrial fibrillation and chronic obstructive pulmonary disease). Further, medical history including HF therapy and class of drugs, physical examination, concomitant medication records, laboratory data on complete blood count, hemoglobin (Hb), serum ferritin levels, total iron-binding capacity, transferrin saturation (TSAT) percentage, and blood chemistry (albumin, sodium, phosphorus, potassium, calcium, urea/blood urea nitrogen, creatinine, liver enzymes, bilirubin, and estimated glomerular filtration rate) were recorded. All the other laboratory data were available as per the standard of practice of hospitals. Data from each patient were recorded from a single time point, and patients were not entered more than once in the study.

The primary endpoint was the percentage of patients with absolute ID (defined as serum ferritin <100 μg/L) with anemia (Hb <12 g/dL in women and Hb <13 g/dL in men). Another primary endpoint included the percentage of patients with functional ID (defined as normal serum ferritin [100–300 μg/L] and low TSAT [<20%]) with anemia (Hb <12 g/dL in women and Hb <13 g/dL in men). The secondary endpoint was the percentage of patients with HF with or without anemia by Hb categories for women (≥12, 10–<12, 8–10, and <8 g/dL) and men (≥13, 10–<13, 8–10, and < 8 g/dL), NYHA Class (I–IV), age group (<50, 50–65, >65–80, >80 years), and Chronic Kidney Disease (CKD) Stage (1–5).

ID was defined as ferritin level <100 μg/L, or serum ferritin 100–299 μg/L in combination with TSAT <20% (as per the ESC guidelines). The absolute ID was diagnosed as ferritin level <100 μg/L. The functional ID was diagnosed as normal serum ferritin (serum ferritin 100–299 μg/L) in combination with TSAT <20%.[32] Anemia was defined as Hb <13 g/dL for men and <12 g/dL for women, based on the definition by the World Health Organization.[33]

The approach to the statistical analysis was descriptive and analytic in nature. The population was categorized into the following treatment groups: ID (none, absolute, or functional), anemia, NYHA functional class, age, sex, and comorbid factors. Categorical data were summarized by the number and percentage of patients in each category. Continuous data were summarized by mean, standard deviation, median, lower and upper quartiles, and minimum and maximum values. Exact two-sided 95% confidence intervals were presented, where appropriate, using Wilson's method. In this study, data analysis was conducted in terms of the frequency and percentage of patients with absolute ID, absolute ID with anemia, functional ID, and functional ID with anemia. Due to the noninterventional observational nature of this program, exploratory analyses were conducted to investigate the relationships between baseline characteristics and ID rates and to generate hypotheses for potential future investigation. Data summaries were generated while the study was ongoing to summarize patient characteristics and generate data for publication, as appropriate.


  Results Top


Baseline characteristics

Baseline characteristics of all patients are shown in [Table 1]. A total of 584 patients (men, 311 [53.3%]; women, 259 [44.3%]) were included in the study. Information on the gender of 14 patients is missing. The mean age of the study participants was 56.68 ± 14.53 years. Hypertension was the most common comorbidity in patients with HF, followed by dyslipidemia and diabetes mellitus. Majority of the patients (75.5%) were prescribed statins, followed by β-blockers in 70.2% of patients.
Table 1: Characteristics of study population

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Prevalence of iron deficiency

Absolute ID (defined as serum ferritin <100 ng/L) was present in 314 (53.8%) of the patients. Patients with ID were slightly younger than patients without ID (54.76 ± 14.18 vs. 59.13 ± 14.96; P = 0.0039). Female patients had a slightly higher prevalence of ID than male patients (51.3% vs. 46.5%; P < 0.0001). There was no significant association between the presence of ID and dietary status or other comorbidities [Table 2].
Table 2: CHF patients with or without ID

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Mean Hb levels were similar in patients with and without ID. More number of patients with absolute ID were diagnosed with anemia (defined as Hb level <12 g/dL in women and <13 g/dL in men) compared with patients without ID [167(57.6%) vs. 123(42.4%); P=0.0602]. However, ID status was found to be independent of anemia.

Patients with absolute ID and/or anemia were stratified according to NYHA class, and more number of patients with ID belonged to NYHA class II [Table 2]. Stratification of ID and/or anemia according to the NYHA class is shown in [Figure 1]. The NYHA class or severity of disease was not independent of the ID status but was independent of anemia.
Figure 1: Stratification of iron deficiency and/or anemia according to the New York Heart Association class

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Furthermore, patients with absolute ID were also categorized by CKD stage (1–5), and more number of patients with Stage 2 CKD had ID [115 (69.7%) vs. 50 (30.3%); P <0.0001] [Table 2].

Functional ID (defined as serum ferritin 100–299 μg/L and TSAT <20%) was present in 37 (6.34%) of patients, with a higher prevalence in female patients. Functional ID with anemia was observed in 18 patients, out of whom 15 were women.

[Table 3] shows percentage of patients with HF, with or without anemia by Hb categories for women (≥12, 10 to <12, 8–10, and <8 g/dL) and men (≥13, 10 to <13, 8–10, and <8 g/dL), NYHA class (I–IV), age group (<50, ≥50-≤65, >65-≤80 and >80 years), and CKD stage (1–5).
Table 3: Patients with HF with or without anaemia by Hb categories for women and men, NYHA class (I–IV), age group, and CKD stage (1–5)

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  Discussion Top


The prevalence of iron deficiency

In recent studies, ID has been demonstrated to be an emerging concern in patients with CHF and a strong predictor of a disordered iron status.[22] Further, clinical studies have demonstrated the effects of ID on the functional status, quality of life, and exercise capacity in patients with HF.[20] In a large population-based cohort study of community-dwelling patients with CHF, anemia was found to be a common and an independent prognostic factor for mortality.[19] A study by Yeo et al.[25] conducted in a multi-ethnic Asian population suggested that HF patients of Indian ethnicity have the highest rates of ID. The findings from our study highlight a significantly high prevalence of ID in Indian patients with CHF, affecting more than half of the HF population. Patients with ID in our study tended to be younger, were mostly women, and belonged to NYHA Class II. Furthermore, the prevalence of anemia was more common in patients with ID compared with patients without ID.

Mechanism of iron deficiency in chronic heart failure

The mechanisms of ID are multifaceted. ID plays a critical role in the anemia of CHF, and it can contribute to erythropoietin (EPO) resistance, as the bone marrow does not respond to EPO unless adequate iron stores are present. A critical point is despite seemingly adequate iron stores assessed by serum iron and ferritin, up to 73% of patients with anemia, normal kidney function, and advanced CHF had ID – as assessed by bone marrow aspiration in a study by Nanas et al.[18] The reason for the high serum ferritin level could be inflammatory mediators that accompany the CHF syndrome.[18] Chronic inflammatory state in HF may affect iron absorption and availability of iron, resulting in functional ID.[22] Further, patients with HF are at risk of iron loss secondary to gastritis or ulceration caused by concomitant pharmacotherapy, and from proteinuria arising from chronic renal disease.[34] In addition, the administration of antiplatelet drugs or anticoagulation agents increases susceptibility to bleeding, with consequent blood loss leading to anemia.[35]

Predictors of iron deficiency

Recent studies have found that different clinical characteristics, such as advanced NYHA class, female sex, lower mean corpuscular volume, and anemia, are associated with ID in patients with HF.[32] Our findings showed that women had a higher prevalence of absolute ID than men, which is in line with the findings of Klip et al.,[22] who also showed that women were more likely to have ID than men. The NYHA class or severity of disease was not independent of the ID status in our study. However, there was no association between NYHA class and anemia.

Literature suggests a cardiorenal interaction in the pathophysiology of CHF, and anemia and ID form an integral part of this pathophysiology of cardiorenal syndrome. Iron repletion is also an established treatment strategy in anemic patients with CKD. In our study, majority of the patients with ID demonstrated Stage 2 CKD, which suggests a possible correlation between ID and cardiorenal syndrome.[36]

Iron therapy

Some recent global studies, such as the 6-month FAIR-HF study, have demonstrated improvement in the functional capacity, symptoms, and quality of life in patients with CHF and ID (with or without anemia) following ferric carboxymaltose treatment.[27] Further, long-term data were provided by the CONFIRM-HF trial, in which symptomatic, ID patients with HF showed a sustained improvement in functional capacity, symptoms, and quality of life, as well as reduced risk of hospitalization due to worsening ID, over 1 year of iron therapy.[37] The ESC guidelines pointed out that ferric carboxymaltose therapy may be considered for these patients, although its effect in patients remains unknown.[31]

Therefore, the evaluation of ID in patients with CHF and its management seems to be an important approach in reducing the morbidity and mortality among these patients. This also seems to be highly appropriate among the Indian population who are prone to ID. However, such trials are lacking in Indian patients to understand the prevalence and effects of ID in CHF in the Indian scenario. Our study throws light on the current situation across India, suggesting the importance of this aspect (ID in patients with CHF) and considering ID to be an important therapeutic target in Indian patients with CHF.

Limitations of the study

This study has several limitations. First, the sample size was small, and there was no control group; therefore, it is difficult to predict whether ID is more prevalent in patients with CHF than in the general population in India. A larger study with a larger study cohort that includes age- and sex-matched controls is required to perform a comparative study and understand the effects of ID in a more comprehensive manner. Second, only data from single measurements in time were evaluated; therefore, the effects of temporal changes of iron status in patients with CHF were not demonstrated, with the consequent need for more studies with serial measurements of iron indices over time. Third, the effect of iron therapy in patients with CHF was not studied. Last, this study was not designed to elucidate the underlying detrimental mechanisms of ID in patients with CHF.


  Conclusion Top


ID was detected in more than half of the study population with CHF suggesting a high prevalence. ID was associated with female sex, younger age, and NYHA Class II of HF. Our study highlights a high prevalence of ID in patients with CHF in India. These findings suggest the need for more routine testing of iron parameters in patients with CHF in Indian settings. Routine diagnosis and management of ID in patients with HF, regardless of anemia status, and prompt intervention using iron therapy may prove to be an effective strategy. In addition, there is a need for performing larger randomized controlled trials in India to not only assess the association between ID and CHF but also the effects of iron supplementation in reducing the morbidity and mortality in such patients.

Acknowledgments

We would like to thank Lupin Ltd., for financial support for this project. We thank BioQuest Solutions Pvt., Ltd. for data management, analysis, and providing editorial services.

Financial support and sponsorship

We thank Lupin Ltd., for financial support for this project.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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