Open Access Original

Article DOI: 10.7759/cureus.47778

Intravenous Iron Technique Evaluation in

Chronic Heart Failure With Iron Deficiency
Received 08/24/2023
Anemia
Review began 09/26/2023
Review ended 10/23/2023 Rohit Gosavi 1 , Nitin B. Jadhav 1 , Abhijeet Nashte 1
Published 10/27/2023

© Copyright 2023 1. Department of Medicine, Krishna Vishwa Vidyapeeth, Karad, IND

Gosavi et al. This is an open access article
distributed under the terms of the Creative Corresponding author: Rohit Gosavi, [email protected]
Commons Attribution License CC-BY 4.0.,
which permits unrestricted use, distribution,
and reproduction in any medium, provided
the original author and source are credited.
Abstract
Objective: This study aimed to investigate and assess whether IV iron improves symptoms of chronic heart
failure (CHF) in patients with iron deficiency anemia (IDA).

Method: A total of 66 subjects with heart failure (HF) seeking therapy in the Department of Medicine's
Inpatient Department (IPD) and Outpatient Department (OPD) were included. The data were collected
during an outpatient or inpatient visit, documented in a predesigned and pretested proforma and then
evaluated. All subjects received history-taking, examinations and regular laboratory tests after being
informed and signing an agreement. On admission, the following data was collected: name, age, gender and
comorbidities. The examination of subjects included a general examination and a systematic examination.
Hematological parameters including hemoglobin (Haemometer, Top Tech Bio Medicals Mumbai), serum iron
(Roche Cobas c501, USA), total iron binding capacity (TIBC, Beckman Coulter AU480, India), transferrin
saturation percentage (TSAT% = (serum iron/TIBC) × 100), left ventricular ejection fraction (LVEF, 2D
echocardiography, Nivan Healthcare Solutions, India) and ferritin (Abbott Architect Ferritin Assay, Delhi)
are also important. Other blood tests like liver and renal function tests include an electrocardiogram (12-
lead ECG) and two-dimensional echocardiography on admission and follow-up.

Results: In our study, 66 patients in total received IV iron as a treatment option to improve the symptoms of
CHF with IDA; the New York Heart Association (NYHA) classification showed significant improvement (p-
value <0.001). Before the intervention, 57.58% of patients had NYHA class II and 42.4% of patients had
NYHA class III. After treatment, 33.33% of patients showed NYHA class II and 19.70% of patients showed
NYHA class III. After iron therapy treatment, out of 29 cases of NYHA class III, nine (31.03%) cases
converted to NYHA class I, seven (24.14%) cases converted to NYHA class II, and 13 (44.83%) cases belonged
to the same NYHA class. Out of 37 cases of NYHA class II, 22 (59.45%) cases converted to NYHA class I, and
15 (40.54%) cases belong to the same NYHA class.

Conclusion: Thus, we come to the conclusion that the NYHA classification has exhibited notable
enhancement subsequent to the administration of parenteral iron therapy. Sufficient evidence exists to
substantiate the advantageous effects of intravenous iron therapy in the treatment of iron deficiency
anemia. The administration of iron therapy has been observed to yield favorable outcomes in the mitigation
of symptoms among individuals afflicted with cardiac insufficiency.

Categories: Internal Medicine

Keywords: coronary heart disease, hemoglobin levels, true anemia, inflammatory cytokines, heart failure,
erythropoiesis-stimulating agents, iron deficiency, chronic heart failure

Introduction
Many studies have shown that despite receiving excellent conventional treatment, many patients with
chronic heart failure (CHF) remain asymptomatic, exercise intolerant and have high rates of hospitalization
and mortality [1,2]. It has been shown by studies that iron deficiency anemia (IDA) is most commonly seen
in patients with CHF along with unfavorable effects [1,2]. In the past, the presence of iron deficiency anemia
was the sole clinical indicator of iron deficiency (ID). Almost one-third of patients with CHF without anemia
can have IDA, despite the fact that iron deficiency anemia is often found in anemic CHF patients [1,2]. Up to
half of all episodes of anemia are thought to be caused by IDA, making it the most common kind of anemia
worldwide [1,2]. Studies in the past have also concluded that IDA with heart failure (HF) can lead to poor
cardiac function, myocardial contractility and renal function which can lead to morbidity and mortality in
the patients. It is found that patients who have had cardiac disease in the past (with increasing age and
chronic cardiac disease) can present with signs and symptoms of cardiac failure in the absence of clinically
apparent iron deficiency anemia. Hence, studies have also shown that, in early iron deficiency conditions,
anemia is not detected, so for that reason, the initiation of intravenous iron therapy should be started,
which can result in symptomatic improvement and even improve cardiac function in heart failure patients
[2].

How to cite this article

Gosavi R, Jadhav N B, Nashte A (October 27, 2023) Intravenous Iron Technique Evaluation in Chronic Heart Failure With Iron Deficiency Anemia.
Cureus 15(10): e47778. DOI 10.7759/cureus.47778
 More recently, studies found that administration of intravenous iron in patients with heart failure and
absolute or functional iron deficiency with or without anemia improves symptoms and exercise capacity [3].
Furthermore, studies also concluded that if anemia and IDA are indeed mediators of poor outcomes in
patients with HF, then correcting these comorbidities would be necessary, and thus, novel therapeutic
agents are required to improve outcomes. Several small studies show that the use of erythropoiesis-
stimulating agents (ESAs) to increase hemoglobin in patients with HF with reduced ejection fraction is
associated with beneficial effects on clinical outcomes [4,5]. Additionally, researchers have also concluded
that hemoglobin levels are reduced to below-optimal levels when iron deficiency occurs [6,7].

Studies also revealed that the prevalence of anemia in patients with HF (defined as hemoglobin <13 g/dl in
men and <12 g/dl in women) [8] is ≈30% in stable patients and ≈50% in hospitalized patients. Regardless of
whether patients have heart failure with preserved ejection fraction (HF(p)EF) or heart failure with
decreased ejection fraction (HF(r)EF), the prevalence of anemia is higher in patients under the age of 85,
surpassing 20% [9-11]. Studies have shown that compared to non-anemic patients with HF, anemic patients
are older and more likely to be female with diabetes, chronic kidney disease (CKD), severe HF with worsened
functional status, decreased exercise capacity, worsened health-related quality of life (QOL), edema, lower
blood pressure, the greater requirement of diuretics and higher neurohumoral and pro-inflammatory
cytokine activation [12-14]. However, many studies showed that anemic patients have a better left
ventricular ejection fraction (LVEF). Hemoglobin is inversely related to LVEF [15,16], an increase in
hemoglobin over time is associated with a decrease in LVEF [17]. This was contradictory to our research
basis.

Hence, studies have also concluded that the measurement of hemoglobin serves as an accurate indicator of
true anemia in the majority of anemia patients with HF [18]. Another similar study examined 148 patients
with stable heart failure (HF) and found that a specific cause of anemia was identified in only 43% of the
participants. Only 5% of patients had ID, whereas the rest (57%) had chronic disease anemia due to pro-
inflammatory cytokine activation, insufficient erythropoietin synthesis, or poor iron utilization. Therefore,
chronic disease anemia and an active pro-inflammatory state may be the most common underlying causes of
anemia in HF [19]. Recently many studies have linked an increase in inflammatory cytokines like
interleukin-1 and (interleukin) IL-6 to an increased risk of coronary heart disease in humans and a
worsening of cardiac remodeling in mice [20,21], which is caused by mutation or deficiency of genes that
regulate hematopoiesis.

So far, according to many studies, we have a limited number of studies that have shown the use of ID as a
standalone prognostic factor in CHF. The comparative impact of ID alone on prognostic outcomes in
patients with CHF, stratified by the presence or absence of anemia, has not yet been investigated [22]. So, the
goal of our study was to find out how often ID happens, what causes it, and how important it is as a predictor
in people with systolic CHF who get care as outpatients, even if they have anemia.

Materials And Methods

Our study adopted a hospital-based, prospective, observational and descriptive (cross-sectional) approach,
focusing on patients diagnosed with both chronic heart failure (CHF) and iron deficiency anemia (IDA). The
study encompassed a total of 66 patients as participants, and the research spanned a duration of 18 months,
from December 1, 2017, to May 31, 2019. The study was carried out at Krishna Hospital and Medical
Research Centre, involving patients from both general inpatient wards and the Intensive Care Unit (ICU)
specializing in Medicine and Cardiology.

Patients meeting the inclusion criteria were those with ambulatory CHF, classified as New York Heart
Association (NYHA) class I, II, or III, with hemoglobin levels ranging from 7 g/dl to 11 g/dl, and patients with
systolic HF. Patients aged under 18 years were also included. Conversely, patients with conditions other than
iron deficiency anemia, those having rheumatic valvular heart disease or congenital heart disease, patients
with impaired liver and renal function, and individuals exhibiting hypersensitivity reactions to intravenous
iron were excluded from the study. The sample size can be calculated as sample size=n=4 / 2, where
p=79%=0.79, q=1-p=0.21, considering ‗e‘ absolute errors of 10% n=4×0.79×0.21/0.1×0.1 n=0.66, n=66.

A total of 66 subjects diagnosed with HF seeking treatment in the Department of Medicine Inpatient
Department (IPD) and Outpatient Department (OPD) were included and investigated for the presence of IDA.
The data was collected during an outpatient or inpatient department visit, recorded in a predesigned and
pretested proforma and analyzed. After receiving informed and written consent, all subjects underwent
history-taking, examination and routine laboratory investigations. On admission, the following data was
collected from each subject: name, age, gender and comorbidities. The examination of subjects also included
a general examination and a systemic examination, along with the recording of vitals. Hematological
parameters include hemoglobin (Haemometer, Top Tech Bio Medicals Mumbai), serum iron (Roche Cobas
c501, USA), total iron binding capacity (TIBC, Beckman Coulter AU480, India), transferrin saturation
percentage (TSAT% = (serum iron/TIBC) × 100), left ventricular ejection fraction (LVEF, 2D
echocardiography, Nivan Healthcare Solutions, India) and ferritin (Abbott Architect Ferritin Assay, Delhi).
Other blood investigations include liver function tests and renal function tests. Other investigations include
two-dimensional echocardiography on admission and follow-up and a 12-lead ECG.

2023 Gosavi et al. Cureus 15(10): e47778. DOI 10.7759/cureus.47778 2 of 8

 Statistical analysis
The obtained data were coded, analyzed and tabulated (Statistical Package for Social Science (SPSS version
16) trial version). Basic descriptive statistical analysis of the quantitative variables was performed in the
form of frequencies, means, percentages, standard deviations and the chi-square test. The variables are
shown as the number of cases with a percentage mean and standard deviation (±SD). The p-values <0.05
were considered as statistically significant.

Ethical consideration
Before conducting the study, ethical permission was obtained from the ethical committee of Krishna Vishwa
Vidyapeeth. The study was assigned an institutional review board number IEC/KVV/2017/22.

Results
Demographic characteristics of study participants
A total of 66 patients were included in the present prospective observational study. Out of 66 patients, 33
(50%) were males and 33 (50%) were females. A total of four (6.06%) patients were in the age group of less
than 30 years; of them, one (3.03%) was male and three (9.09%) were female. A total of 21 (31.82%) were in
the age group between 31 and 60 years; of them, 10 (30.30%) patients were males and 11 (33.33%) were
females. A total of 41 (62.12%) patients were in the age group of more than 60 years; of them, 22 (66.67%)
were males and 19 (57.58%) were females. The youngest patient is 23 years old, and the oldest patient is 87
years old, with an average age of 63.36 years and a standard deviation of 13 years. About 62.12% of patients
have an age greater than 60 years (p<0.056), DF=2 and X2=1.267 (Table 1).

Female Male
Age in years Total %
n % n %

≤30 03 9.09% 01 3.03% 4 6.06%

31-60 11 33.33% 10 30.30% 21 31.82%

>60 19 57.58% 22 66.67% 41 62.12%

Total 33 100% 33 100% 66 100%

TABLE 1: Demographic characteristics of study participants

Demographic profile and distribution of age with risk factors

The study consisted of 66 participants, with four individuals below the age of 30. Among the participants,
one male patient (1%) had a medical history of ischemic heart disease (IHD), while one male and one female
patient had a history of tobacco chewing. Additionally, one female patient (1%) had a medical history of
hypothyroidism. The remaining participants did not have any significant past medical history. In the age
group of 30-60 years, a history of hypertension was present in two (3%) males and three (4.1%) females.
History of ischemic heart disease was present in four (6.4%) males and one (1%) female patient. History of
type 2 diabetes was present in one (1%) male and three (4.1%) females, tobacco and smoking history was
present in five (7.12%) males and eight (12.2%) females and one patient had no past history. In the age group
more than 60 years, a history of hypertension was present in which four (6.4%) are males and nine (13.4%)
are females; a history of IHD was present in eight (12.2%) males and six (9.3%) females. History of type 2
diabetes mellitus was present in two (3%) males and four (6.4%) females, chronic obstructive pulmonary
disease (COPD) was present in two (3%) males and one (1%) female patient, history of tobacco chewing and
smoking was present in eight (12.2%) males and four (6.4%) females and five patient had no past history.

2023 Gosavi et al. Cureus 15(10): e47778. DOI 10.7759/cureus.47778 3 of 8

 < 30 years 30-60 years >60 years
Risk factors
Male Female Male Female Male Female

Ischemic heart disease (IHD) 0 0 2 (3%) 3 (4.1%) 4 (6.4%) 9 (13.4%)

Hypertension 1 (1%) 0 4 (6.4%) 1 (1%) 8 (12.2%) 6 (9.3%)

Type 2 DM (Diabetes mellitus) 0 0 1 (1%) 3 (4.1%) 2 (3%) 4 (6.4%)

COPD (chronic obstructive pulmonary disease) 0 0 0 0 2 (3%) 1 (1%)

Tobacco 1 (1%) 1 (1%) 5 (7.12%) 8 (12.2%) 8 (12.2%) 4 (6.4%)

Other 0 1 (1%) 0 0 0 0

No past history 0 1 (1%) 1 (1%) 0 3 (4.1%) 2 (3%)

TABLE 2: Risk factor

Study parameters in patients at the time of admission

Various parameters of heart disease patients were studied at the time of admission. Observed hemoglobin
was 8.09 ± 2.17 mg/dl, iron was 34.27 ± 15.03 μg/dl, total iron binding capacity (TIBC) was 294.59 ± 82.44
μg/dl, transferrin saturation percentage (TSAT%) was 11.83 ± 6.50, ferritin was 17.94 ± 5.41 ng/dl and LVEF
was 42.39% ± 11.78% (Table 3).

Parameters Mean SD (±)

Hb (hemoglobin) 8.09 2.17

Iron 34.27 15.03

TIBC (total iron binding capacity) 294.59 82.44

TSAT% 11.83 6.50

Ferritin 17.94 5.41

LVEF (left ventricular ejection fraction) 42.39% 11.78%

TABLE 3: Parameter (at the time of admission)

TSAT%: transferrin saturation percentage, SD: Standard deviation.

Changes in study parameters before and after treatment

Two parameters were studied before and after treatment, hemoglobin and LVEF. For comparison of
improvement in LVEF and hemoglobin, before and after treatment paired t-test was used. Observed
hemoglobin before and after treatment was 8.09 ± 2.17 and 10.29 ± 1.05, respectively, observed
improvement in hemoglobin was significant (8.09 versus 10.29, p<0.0001) and the percentage change was
27.19%. Observed LVEF before and after treatment was 42.39 ± 11.78% and 47.21 ± 9.99%,
respectively, observed improvement in LVEF was significant (42.39% versus 47.21%, p=0.012) and
percentage change was 11.37% (Table 4).

2023 Gosavi et al. Cureus 15(10): e47778. DOI 10.7759/cureus.47778 4 of 8

 Before After
Parameters p-value Percentage change in values after treatment
Mean SD Mean SD

Hemoglobin 8.09 2.17 10.29 1.05 <0.0001 27.19%

LVEF 42.39% 11.78% 47.21% 9.99% 0.012 11.37%

TABLE 4: Change in parameter after treatment

LVEF: left ventricular ejection fraction.

NYHA class before and after treatment

In the present study, after treatment NYHA classification showed significant improvement (p-value <0.001).
Before the intervention, 57.58% of patients had NYHA class II and 42.4% of patients had NYHA class III.
After treatment, 33.33% of patients showed NYHA class II and 19.70% of patients showed NYHA class III.
After Iron therapy treatment, out of 29 cases of NYHA class III, nine (31.03%) cases converted to NYHA class
I, seven (24.14%) cases converted to NYHA class II and 13 (44.83%) cases belong to the same NYHA class.
Out of 37 cases of NYHA class II, 22 (59.45%) cases converted to NYHA class I and 15 (40.54%) cases
belong to the same NYHA class (Table 5).

NYHA class (after treatment)

NYHA class (before treatment)
No symptoms I II III

I 15 (22.72%) 14 (21.21%) 1 (1%) 0 (0%) 0 (0%)

II 28 (42.42%) 15 (22.72%) 13 (19.69%) 0 (0%) 0 (0%)

III 23 (34.84%) 2 (3.03%) 9 (13.63%) 12 (18.18%) 0 (0%)

Total 66 (100%) 31 (46.96%) 23 (34.48%) 12 (18.18%) 0 (0%)

TABLE 5: NYHA class (before and after treatment)

NYHA: New York Heart Association.

Discussion
Our research team conducted a study that yielded favorable results in improving the New York Heart
Association (NYHA) class when intravenous iron was administered for a duration of 24 weeks. The observed
benefit was evident at the four-week mark and persisted for the duration of the whole study. The observed
enhancements in hemoglobin levels and left ventricular ejection percent were found to be uniform across all
predetermined groups, thereby validating these results. The various studies that can be compared are
illustrated in Table 6 [23-30].

2023 Gosavi et al. Cureus 15(10): e47778. DOI 10.7759/cureus.47778 5 of 8

 p-value for
Mean age Hb before Hb after LVEF Before LVEF after p-value for
Study name Males Comorbidity change in
(years) treatment treatment treatment treatment change in Hb
LVEF

Okonko et al.
60% 64 IHD (79%) 12.2 12.6 30% 32% <0.87 0.66
(2008) [23]

Bolger et al.
75% 68.3 IHD (65%) 11.2 12.6 26% 33% <0.002 =0.001
(2006) [24]

Silverberg et al.
79% 70.1 HTN (71%) 10.16 12.10 27.7% 35.4% <0.05 <0.002
(2000) [25]

Ponikowski et al.
68% 60.2 HTN (60%) 12.37 14.20 37.1% 39.2% <0.001 <0.005
(2015) [26]

Rangel et al. Dyslipidemia

69% 63.2 13.7 14.3 26.7% 35% <0.001 <0.001
(2014) [27] (76%)

Toblli et al. (2007)

64% 65.2 IHD (62%) 12.5 14.9 30.1% 32.4% <0.004 <0.001
[28]

van Veldhuisen et
75% 64 IHD (57%) 11.4 12.8 36.9% 40.1% <0.001 <0.004
al. (2011)[29]

Anker et al. (2009)

52.3% 67.8 IHD (79.9%) 11.9 14.6 31.9% 36.2% <0.002 <0.04
[30]

IHD
Present study 50% 63.36 8.09 10.29 42.39% 47.21% <0.0001 =0.002
(30.30%)

TABLE 6: Comparison of various studies with our study

HTN: hypertension, LVEF: left ventricular ejection fraction, IHD: ischemic heart disease, Hb: hemoglobin.

In this regard, among all study populations, two parameters were studied before and after treatment:
hemoglobin and LVEF. Observed hemoglobin was 8.09 ± 2.17 mg/dl, iron was 34.27 ± 15.03 μg/dl, TIBC was
294.59 ± 82.44 g/dl, TSAT% was 11.83 ± 6.50, ferritin was 17.94 ± 5.41 ng/dl and LVEF was 42.39% ± 11.78%.
NYHA class I was found in 15 (22.72%), class II in 28 (42.42%) and class III in 23 (34.84%). In our study
before treatment, the most commonly observed symptom was easy fatigability (66%), followed by
breathlessness and exertion (24 cases, 36.36%), and preceding that, 14 (21.21%) cases had palpitation and
14 (21.21%) cases had pedal edema. It has been well demonstrated that anemia is a powerful factor for
predicting adverse outcomes in these patients, so anemia is concomitant with other risk factors. In our
study, the most commonly observed past history was IHD (20 cases, 30.30%), followed by hypertension (19
cases, 28.79%), type 2 diabetes mellitus (10 cases, 15.15%), chronic obstructive pulmonary disease (three
cases, 4.54%) and others such as tobacco chewing or smoking (27 cases, 39.92%), which may have synergistic
effects to deteriorate the outcome of disease. Hence, a correct diagnosis can easily be arrived at using
parameters such as serum ferritin and transferrin saturation.

The study limitations include a relatively small sample size of 66 subjects, potentially limiting the
generalizability of the findings to a broader population. The study was conducted in a single medical
department, which might limit the diversity of patient profiles and the generalizability of results to other
healthcare settings. The long-term impact of iron therapy and potential relapses in NYHA classification over
extended periods were not explored. The study lacks a control group for comparison, making it challenging
to determine if the observed improvements in NYHA classification are solely due to iron therapy or could be
influenced by other factors. The assessment of NYHA classification might be influenced by the participants'
and medical staff's expectations or perceptions, introducing a potential bias in the reported results.

Conclusions
Overall, our study underscores the importance of addressing iron deficiency anemia in individuals with
systolic chronic heart failure. Iron therapy exhibited a significant positive impact on the patient's functional
status, as evidenced by the improvement in NYHA classification. These findings provide valuable insights
into the potential benefits of incorporating iron therapy into the management of CHF patients receiving
outpatient care. Further research and clinical trials are warranted to confirm and expand upon these
encouraging results.

2023 Gosavi et al. Cureus 15(10): e47778. DOI 10.7759/cureus.47778 6 of 8

 Additional Information
Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Krishna Vishwa
Vidyapeeth issued approval IEC/KVV/2017/22. Animal subjects: All authors have confirmed that this study
did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform
disclosure form, all authors declare the following: Payment/services info: All authors have declared that no
financial support was received from any organization for the submitted work. Financial relationships: All
authors have declared that they have no financial relationships at present or within the previous three years
with any organizations that might have an interest in the submitted work. Other relationships: All authors
have declared that there are no other relationships or activities that could appear to have influenced the
submitted work.

References
1. Ezekowitz JA, McAlister FA, Armstrong PW: Anemia is common in heart failure and is associated with poor
outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation. 2003,
107:223-5. 10.1161/01.cir.0000052622.51963.fc
2. McMurray JJ, Adamopoulos S, Anker SD, et al.: ESC Guidelines for the diagnosis and treatment of acute and
chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart
Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure
Association (HFA) of the ESC. Eur Heart J. 2012, 33:1787-847. 10.1093/eurheartj/ehs104
3. Yancy CW, Jessup M, Bozkurt B, et al.: 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA
guideline for the management of heart failure: a report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
Circulation. 2017, 136:e137-61. 10.1161/CIR.0000000000000509
4. Anand IS: Anemia and chronic heart failure: implications and treatment options . J Am Coll Cardiol. 2008,
52:501-11. 10.1016/j.jacc.2008.04.044
5. Kotecha D, Ngo K, Walters JA, Manzano L, Palazzuoli A, Flather MD: Erythropoietin as a treatment of
anemia in heart failure: systematic review of randomized trials. Am Heart J. 2011, 161:822-31.e2.
10.1016/j.ahj.2011.02.013
6. Silverberg DS, Wexler D, Iaina A, Schwartz D: The interaction between heart failure and other heart
diseases, renal failure, and anemia. Semin Nephrol. 2006, 26:296-306. 10.1016/j.semnephrol.2006.05.006
7. World Health Organization: The prevalence of anaemia in women : a tabulation of available information,
2nd ed. (1992). Accessed: August 10, 2023: https://apps.who.int/iris/handle/10665/58994.
8. McMurray JJ, Parfrey PS, Adamson JW, et al.: Kidney disease: improving global outcomes (KDIGO) anemia
work group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012,
2:279-335.
9. Tang YD, Katz SD: The prevalence of anemia in chronic heart failure and its impact on the clinical
outcomes. Heart Fail Rev. 2008, 13:387-92. 10.1007/s10741-008-9089-7
10. O'Meara E, Clayton T, McEntegart MB, et al.: Clinical correlates and consequences of anemia in a broad
spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of
Reduction in Mortality and Morbidity (CHARM) Program. Circulation. 2006, 113:986-94.
10.1161/CIRCULATIONAHA.105.582577
11. Tang WH, Tong W, Jain A, Francis GS, Harris CM, Young JB: Evaluation and long-term prognosis of new-
onset, transient, and persistent anemia in ambulatory patients with chronic heart failure. J Am Coll Cardiol.
2008, 51:569-76. 10.1016/j.jacc.2007.07.094
12. Tehrani F, Dhesi P, Daneshvar D, Phan A, Rafique A, Siegel RJ, Cercek B: Erythropoiesis stimulating agents
in heart failure patients with anemia: a meta-analysis. Cardiovasc Drugs Ther. 2009, 23:511-8.
10.1007/s10557-009-6203-6
13. Swedberg K, Young JB, Anand IS, et al.: Treatment of anemia with darbepoetin alfa in systolic heart failure .
N Engl J Med. 2013, 368:1210-9. 10.1056/NEJMoa1214865
14. Goodnough LT, Schrier SL: Evaluation and management of anemia in the elderly . Am J Hematol. 2014,
89:88-96. 10.1002/ajh.23598
15. Anand IS, Kuskowski MA, Rector TS, et al.: Anemia and change in hemoglobin over time related to mortality
and morbidity in patients with chronic heart failure: results from Val-HeFT. Circulation. 2005, 112:1121-7.
10.1161/CIRCULATIONAHA.104.512988
16. Opasich C, Cazzola M, Scelsi L, et al.: Blunted erythropoietin production and defective iron supply for
erythropoiesis as major causes of anaemia in patients with chronic heart failure. Eur Heart J. 2005, 26:2232-
7. 10.1093/eurheartj/ehi388
17. McMahon LP, Mason K, Skinner SL, Burge CM, Grigg LE, Becker GJ: Effects of haemoglobin normalization on
quality of life and cardiovascular parameters in end-stage renal failure. Nephrol Dial Transplant. 2000,
15:1425-30. 10.1093/ndt/15.9.1425
18. van der Meer P, Lipsic E, Westenbrink BD, et al.: Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-
lysyl-proline partially explain the occurrence of anemia in heart failure. Circulation. 2005, 112:1743-7.
10.1161/CIRCULATIONAHA.105.549121
19. Anand IS, Veall N, Kalra GS, et al.: Treatment of heart failure with diuretics: body compartments, renal
function and plasma hormones. Eur Heart J. 1989, 10:445-50. 10.1093/oxfordjournals.eurheartj.a059508
20. Weiss G: Iron metabolism in the anemia of chronic disease . Biochim Biophys Acta. 2009, 1790:682-93.
10.1016/j.bbagen.2008.08.006
21. Jaiswal S, Natarajan P, Silver AJ, et al.: Clonal hematopoiesis and risk of atherosclerotic cardiovascular
disease. N Engl J Med. 2017, 377:111-21. 10.1056/NEJMoa1701719
22. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL: Prevalence of iron deficiency in the United

2023 Gosavi et al. Cureus 15(10): e47778. DOI 10.7759/cureus.47778 7 of 8

 States. JAMA. 1997, 277:973-6. 10.1001/jama.1997.03540360041028
23. Okonko DO, Grzeslo A, Witkowski T, et al.: Effect of intravenous iron sucrose on exercise tolerance in
anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a
randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008, 51:103-12.
10.1016/j.jacc.2007.09.036
24. Bolger AP, Bartlett FR, Penston HS, O'Leary J, Pollock N, Kaprielian R, Chapman CM: Intravenous iron
alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol. 2006, 48:1225-7.
10.1016/j.jacc.2006.07.015
25. Silverberg DS, Wexler D, Blum M, et al.: The use of subcutaneous erythropoietin and intravenous iron for
the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal
function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000,
35:1737-44. 10.1016/s0735-1097(00)00613-6
26. 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, 36:657-68. 10.1093/eurheartj/ehu385
27. Rangel I, Gonçalves A, de Sousa C, et al.: Iron deficiency status irrespective of anemia: a predictor of
unfavorable outcome in chronic heart failure patients. Cardiology. 2014, 128:320-6. 10.1159/000358377
28. Toblli JE, Lombraña A, Duarte P, Di Gennaro F: Intravenous iron reduces NT-pro-brain natriuretic peptide
in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol. 2007, 50:1657-65.
10.1016/j.jacc.2007.07.029
29. van Veldhuisen DJ, Anker SD, Ponikowski P, Macdougall IC: Anemia and iron deficiency in heart failure:
mechanisms and therapeutic approaches. Nat Rev Cardiol. 2011, 8:485-93. 10.1038/nrcardio.2011.77
30. Anker SD, Comin Colet J, Filippatos G, et al.: Ferric carboxymaltose in patients with heart failure and iron
deficiency. N Engl J Med. 2009, 361:2436-48. 10.1056/NEJMoa0908355

2023 Gosavi et al. Cureus 15(10): e47778. DOI 10.7759/cureus.47778 8 of 8