Prevalence of Anemia and Associated Factors in Patients with Heart Failure with Reduced Ejection Fraction Attending a Tertiary Cardiac Clinic in Ethiopia: A Cross-Sectional Study

1. Introduction

Heart failure (HF) is a major global public health problem, affecting more than 64 million people worldwide and contributing substantially to morbidity, mortality, and healthcare utilization[1]. Heart failure with reduced ejection fraction (HFrEF) accounts for approximately half of all HF cases and continues to be associated with poor clinical outcomes despite advances in guideline-directed medical therapy [1,15]. In sub-Saharan Africa, HF remains a leading cause of cardiovascular hospitalization, with non-ischemic etiologies, particularly rheumatic heart disease and cardiomyopathies, predominating, although the burden of ischemic heart disease is increasing [2,3].

Anemia is one of the most common comorbidities among patients with HFrEF, with reported prevalence ranging from 10% to 50%, depending on the study population, clinical setting, and diagnostic criteria used. [4,7,12,22] Numerous studies have demonstrated that anemia is associated with reduced exercise capacity, impaired health-related quality of life, increased rates of hospitalization, and higher mortality among patients with HF [8,10,11,18]. The adverse effects of anemia are thought to result from reduced oxygen delivery, increased cardiac workload, neurohormonal activation, chronic inflammation, and progressive ventricular remodeling [6,7].

The pathogenesis of anemia in HF is multifactorial [6,7].In addition to nutritional deficiencies such as iron, vitamin B12, and folate deficiency, impaired erythropoietin production, chronic kidney disease, systemic inflammation, hemodilution, and the effects of certain HF medications may contribute to the development of anemia [6,7].

Previous observational studies have identified several demographic and clinical characteristics associated with anemia in HF, including impaired renal function, advanced HF severity, and poorer patient-reported health status [12,19,24,26]. However, these findings have been inconsistent across populations, and evidence from sub-Saharan Africa remains scarce [2,29].

In Ethiopia, anemia is common in the general population [4,5]; however, little is known about its burden among patients with HFrEF or the clinical factors associated with its occurrence. Given the differences in the epidemiology of HF, patient demographics, nutritional status, and healthcare resources compared with high-income settings, locally generated evidence is essential to guide clinical practice and future research [3].

Therefore, this study aimed to determine the prevalence of anemia and identify demographic, clinical, and laboratory factors associated with anemia among patients with HFrEF attending the cardiac follow-up clinic of Tikur Anbessa Specialized Hospital, Ethiopia.

2. Methods

2.1. Study Design and Setting

A hospital-based cross-sectional study was conducted among adult patients with heart failure with reduced ejection fraction (HFrEF) attending the cardiac follow-up clinic of Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia, between June 1 and October 30, 2020.

Patients were evaluated during routine outpatient follow-up visits, and clinical, laboratory, and echocardiographic data were collected prospectively using a structured data collection tool.

Tikur Anbessa Specialized Hospital is the largest tertiary referral and teaching hospital in Ethiopia and provides specialized cardiovascular care for patients referred from different regions of the country.

2.2. Study Population

The study population consisted of adult patients with established HFrEF who attended routine follow-up at the cardiac clinic during the study period.

Patients were eligible for inclusion if they were aged ≥18 years and had a diagnosis of HFrEF confirmed by transthoracic echocardiography with a left ventricular ejection fraction (LVEF) ≤40%.

Patients were excluded if they declined participation, had incomplete clinical or laboratory data, did not undergo echocardiographic evaluation, or had an LVEF >40%.

Patients with acute decompensated heart failure requiring hospitalization at the time of enrollment were not specifically included unless they were attending follow-up.

2.3. Sample Size Determination and Sampling Technique

The sample size was calculated using the single population proportion formula. Assuming an expected anemia prevalence of 10% based on the Val-HeFT study [27], a 95% confidence level, and a 5% margin of error, the minimum required sample size was calculated as 138 participants. Consecutive sampling was used until the required sample size was achieved.

2.4. Variables

2.4.1. Dependent Variable

• The dependent variable was anemia status. Anemia was treated as a binary outcome variable, categorized as anemia present (Yes) or absent (No) according to the World Health Organization hemoglobin criteria.

2.4.2. Independent Variables

Independent variables considered in the analysis included sociodemographic characteristics, clinical characteristics, laboratory parameters, echocardiographic findings, and medication history.

• Sociodemographic variables included age and sex.
• Clinical variables included diabetes mellitus, heart failure etiology, NYHA functional class, and previous hospitalization due to heart failure.
• Laboratory variables included serum creatinine, estimated glomerular filtration rate (eGFR), mean corpuscular volume (MCV), and
• KCCQ-12 score.
• Echocardiographic variable included left ventricular ejection fraction (LVEF).
• Medication history included current ACE inhibitor or angiotensin receptor blocker (ACEI/ARB) use.

2.5. Data Collection and Measurements

Data were collected using a structured data collection tool through patient interviews and review of medical records.

Collected variables included sociodemographic characteristics, heart failure-related clinical characteristics, medication history, laboratory findings, echocardiographic parameters, and previous hospitalization history.

Laboratory investigations included complete blood count and renal function tests. Hemoglobin concentration was measured using standard laboratory procedures. Hemoglobin, hematocrit, and red blood cell indices including mean corpuscular volume (MCV) were obtained from the complete blood count. Serum creatinine was measured, and estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation.

Echocardiographic parameters including LVEF were obtained from transthoracic echocardiography reports.

2.6. Operational Definition

Heart failure with reduced ejection fraction (HFrEF):

HFrEF was defined as clinical evidence of heart failure with a left ventricular ejection fraction (LVEF) ≤40% on echocardiographic assessment[15].

Anemia:

Anemia was defined according to World Health Organization criteria as hemoglobin concentration <13 g/dL in males and <12 g/dL in females [4].

Diabetes mellitus:

Diabetes mellitus was considered present if the patient had a previous diagnosis of diabetes supported by available clinical records, glycated hemoglobin (HbA1c) ≥6.5%, or fasting blood glucose ≥126 mg/dL.

Heart failure etiology:

The underlying cause of heart failure was categorized based on clinical evaluation and available investigations [3].The major categories included ischemic heart disease, dilated cardiomyopathy, chronic rheumatic valvular heart disease, and other causes.

Patients with congenital heart disease, degenerative valvular disease, and tachycardia-induced cardiomyopathy were grouped as “other causes.”

Renal function:

Renal function was assessed using estimated glomerular filtration rate (eGFR) calculated using the CKD-EPI equation. Serum creatinine was measured using standard laboratory methods.

NYHA functional class:

Functional status was classified according to the New York Heart Association (NYHA) classification system (Class I–IV) based on symptoms and limitation of physical activity [15].

Health-related quality of life:

Health status was assessed using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) [9] The questionnaire score was calculated according to the standardized scoring algorithm and transformed to a scale from 0 to 100, with higher scores indicating better health status [9].

Previous hospitalization:

Previous hospitalization was defined as at least one prior hospital admission due to heart failure-related symptoms or decompensation before enrollment.

ACE inhibitor/angiotensin receptor blocker use:

ACE inhibitor or ARB use was defined as current prescription and use of either medication class at the time of study enrollment.

Statistical analysis

Data were analyzed using appropriate descriptive and inferential statistical methods. Continuous variables were assessed for distribution and are presented as mean ± standard deviation (SD) or median with interquartile range (IQR), as appropriate. Categorical variables are presented as frequencies and percentages. Baseline characteristics were compared between patients with and without anemia using the independent sample t-test or Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables, as appropriate.

Univariable binary logistic regression analysis was performed to identify factors associated with anemia among patients with HFrEF. Given the limited number of outcome events, variables with clinical relevance and those showing an association with anemia in univariable analysis were considered for inclusion in the multivariable logistic regression model. A parsimonious multivariable logistic regression model was constructed to minimize the risk of overfitting given the limited number of anemia events.

Results from logistic regression analyses are presented as crude odds ratios (CORs) and adjusted odds ratios (AORs) with corresponding 95% confidence intervals (CIs). Continuous variables, including age, serum creatinine, estimated glomerular filtration rate (eGFR), mean corpuscular volume (MCV), and KCCQ-12 score, were analyzed as continuous variables to preserve statistical information and avoid arbitrary categorization. Serum creatinine was included instead of eGFR in the final model to avoid collinearity between correlated renal function measures. Continuous variables were retained as continuous measures in regression analyses unless clinically justified otherwise.

Statistical significance was defined as a two-sided p-value <0.05. All analyses were performed using IBM SPSS Statistics version 20.0.

2.7. Ethical Considerations

Ethical approval was obtained from the Institutional Review Board of Tikur Anbessa Specialized Hospital, College of Health Sciences, Addis Ababa University.

Written informed consent was obtained from all participants before enrollment. Confidentiality of participant information was maintained throughout the study by using unique identification codes instead of personal identifiers.

The study was conducted in accordance with the principles of the Declaration of Helsinki.

Ethics Approval Code: AAU/CHS/IRB/2020/042

Ethics Approval Date: April 12, 2020

Quality Assurance

Data quality was managed by training the data collectors, and by crosschecking weekly. KCCQ-12 questionnaires were first prepared in English and then translated to Amharic.Independent supervisors monitored data quality throughout the study Pretest was done two weeks before the actual data collection at Tikur Anbessa Hospital Cardiac OPD with 5% of sample size to check its clarity, time required for completion and appropriateness, and the necessary correction was done accordingly.

3. Results

3.1. Study Population and Prevalence of Anemia

A total of 138 consecutive patients with heart failure with reduced ejection fraction (HFrEF) attending the cardiac clinic between June 1 and October 2020 were included in the analysis[31].

The mean age of participants was 47.5 years, and 75 (54.3%) participants were male. The mean left ventricular ejection fraction was 31.6%.

Anemia was present in 27 patients (19.6%) according to WHO criteria [4], while 111 patients (80.4%) had no anemia.

Among patients with anemia, the mean hemoglobin concentration was 10.9 g/dL, compared with 14.8 g/dL among patients without anemia.

3.2. Baseline Characteristics According to Anemia Status

Baseline characteristics are presented in Table 1.

Compared with patients without anemia, those with anemia had:

• significantly lower KCCQ-12 scores (33.7 vs 40.5, p=0.003),
• higher serum creatinine levels (1.6 vs 0.9 mg/dL, p=0.024),
• lower mean corpuscular volume (83.1 vs 88.9 fL, p=0.008),
• and a higher proportion of previous hospitalization (44.4% vs 12.6%, p<0.001).

There were no statistically significant differences between groups regarding:

• age,
• ejection fraction,
• diabetes mellitus,
• heart failure etiology,
• NYHA functional class,
• or ACE inhibitor/ARB use.

3.3. Univariable Logistic Regression Analysis

Factors associated with anemia in univariable logistic regression analysis are shown in Table 2.

Previous hospitalization was strongly associated with anemia, with patients having prior admission demonstrating higher odds of anemia compared with those without previous admission (COR 5.54; 95% CI 2.16–14.24; p<0.001).

Lower KCCQ-12 score was also associated with increased odds of anemia (COR 0.91 per one-point increase; 95% CI 0.85–0.96; p<0.001).

Higher serum creatinine was associated with increased odds of anemia (COR 5.31; 95% CI 1.73–16.31; p=0.004), while higher eGFR was associated with reduced odds of anemia (COR 0.98 per mL/min/1.73m² increase; 95% CI 0.97–0.999; p=0.037).

Lower MCV was also associated with anemia (COR 0.90 per fL increase; 95% CI 0.84–0.96; p=0.001).

3.4. Multivariable Logistic Regression Analysis

Variables considered clinically relevant and those associated with anemia in univariable analysis with P value<0.20 were included in the multivariable logistic regression model.

As shown in Table 3, male sex, serum creatinine level, and KCCQ-12 score remained independently associated with anemia after adjustment.

Male sex was independently associated with higher odds of anemia(AOR 5.34; 95% CI 1.33–21.50; p=0.018).

Increasing serum creatinine was independently associated with higher odds of anemia (AOR 3.76 per 1 mg/dL increase; 95% CI 1.11–12.72; p=0.033).

Conversely, higher KCCQ-12 scores were associated with lower odds of anemia (AOR 0.91 per one-point increase; 95% CI 0.84–0.98; p=0.008).

Age and previous hospitalization were not statistically significant after adjustment.

4. Discussion

In this study, we evaluated the prevalence of anemia and factors associated with anemia among patients with heart failure with reduced ejection fraction (HFrEF) attending a tertiary cardiac clinic in Ethiopia. Anemia was identified in 19.6% of patients. Compared with patients without anemia, those with anemia had lower health-related quality of life scores, higher serum creatinine levels, lower mean corpuscular volume, and a higher frequency of previous hospitalization. In multivariable logistic regression analysis, male sex, higher serum creatinine, and lower Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) scores were independently associated with anemia. These findings highlight the multifactorial nature of anemia in HFrEF and emphasize the importance of considering both clinical and patient-reported health parameters in the assessment of these patients.

The prevalence of anemia in our study was 19.6% among patients with HFrEF. This finding is within the range reported in previous studies, although the prevalence of anemia among patients with heart failure varies considerably depending on the population studied, anemia definition, disease severity, and clinical setting [7,12,22,24]. Differences between studies may be explained by variations in patient characteristics, including the proportion of patients with advanced heart failure, renal dysfunction, nutritional status, and underlying comorbidities [6,7]. The relatively lower prevalence observed in our cohort compared with some international reports like Swedish HF registry[12], ASIAN-HF registry [22], and CHARM program [24] may partly reflect the inclusion of predominantly ambulatory patients attending a tertiary clinic rather than patients hospitalized with acute decompensated heart failure, where anemia prevalence is generally higher[10,26,28]. Differences may also reflect variation in underlying HF etiologies, demographic characteristics, and healthcare access across settings [2,3].

Renal dysfunction is a recognized contributor to anemia in patients with heart failure [6,7,11]. In our study, higher serum creatinine levels were independently associated with anemia after adjustment for other clinical factors. This finding supports the important interaction between cardiac and renal dysfunction in the development of anemia among patients with HFrEF[18,25]. Several mechanisms may contribute to this relationship, including reduced erythropoietin production due to impaired renal function, chronic inflammation, impaired iron homoeostasis, and neurohormonal activation associated with heart failure [6,7]. Although lower eGFR was associated with anemia in univariable analysis, it did not remain statistically significant in the adjusted model, suggesting that the relationship between renal function and anemia may be influenced by other markers of disease burden and patient characteristics.

An important finding of our study was the independent association between anemia and poorer health-related quality of life as assessed by the KCCQ-12 score [9]. Patients with anemia had significantly lower KCCQ-12 scores compared with those without anemia, and this association remained significant after adjustment for other clinical factors. Anemia may contribute to increased symptom burden in patients with HFrEF through reduced oxygen-carrying capacity, impaired exercise tolerance, and worsening fatigue, which may negatively influence patients’ perception of their functional status and well-being [8]. Conversely, poorer health status may also reflect more advanced heart failure and a greater burden of comorbid conditions that predispose to anemia. [11,13] Given the cross-sectional nature of our study, the direction of this relationship cannot be established; however, the findings suggest that anemia status may serve as an additional marker of disease burden and overall clinical status.

In our study, male sex was independently associated with higher odds of anemia among patients with HFrEF. Although sex differences in anemia among heart failure populations have been reported [22], the mechanisms underlying this association remain uncertain. Possible explanations may include differences in the distribution of heart failure etiologies, comorbidity burden, renal function, inflammatory status, nutritional factors, and patterns of healthcare utilization between men and women [22]. However, this finding should be interpreted cautiously because of the relatively small number of anemia events and the wide confidence interval around the estimated effect. Further studies with larger sample sizes are needed to clarify the role of sex-related factors in the development of anemia among patients with HFrEF.

The findings of this study have several potential clinical implications. Anemia was relatively common among patients with HFrEF and was associated with markers of impaired renal function and poorer health-related quality of life. Therefore, routine assessment of hemoglobin levels should be incorporated into the comprehensive evaluation of patients with HFrEF, particularly among those with evidence of renal impairment or increased symptom burden [15]. Identification of anemia should prompt evaluation for potentially reversible causes, including nutritional deficiencies, iron deficiency, renal disease, and other contributing conditions [6,7,15]. Although correction of anemia was not evaluated in this study, recognizing and appropriately investigating anemia may represent an important component of optimizing supportive care in patients with HFrEF.(15)

Strengths and Limitations

Strengths of this study include the use of standardized clinical assessment, inclusion of patient-reported health status using the validated KCCQ-12 instrument [9], and adjustment for multiple clinically relevant factors in multivariable analysis.

This study has several limitations. First, the cross-sectional design limits the ability to determine temporal relationships between anemia and associated factors such as renal dysfunction and health-related quality of life. Second, this was a single-center study conducted in a tertiary cardiac clinic, which may limit the generalizability of the findings to other healthcare settings and populations. Third, although a parsimonious multivariable model was used, the relatively small number of patients with anemia may have limited statistical power and resulted in imprecise estimates for some associations. Fourth, detailed evaluation of the underlying causes of anemia was not possible because iron studies, vitamin B12, folate levels, inflammatory markers, and other investigations required for detailed anemia phenotyping were not available. Finally, because longitudinal follow-up data were not collected, the prognostic impact of anemia on mortality, hospitalization, and clinical outcomes could not be assessed.

5. Conclusions

Anemia was present in approximately one-fifth of patients with heart failure with reduced ejection fraction attending a tertiary cardiac clinic in Ethiopia. In this study, anemia was independently associated with male sex, higher serum creatinine levels, and poorer health-related quality of life as measured by the KCCQ-12. These findings highlight the importance of routine screening for anemia and evaluation of potentially reversible contributing factors as part of comprehensive HFrEF management. Further prospective studies are needed to better understand the underlying mechanisms of anemia and its impact on clinical outcomes among patients with HFrEF in sub-Saharan Africa.

Ethics Approval and Consent to Participate: Ethical approval for this study was obtained from the Institutional Review Board of Tikur Anbessa Specialized Hospital, College of Health Sciences, Addis Ababa University. Written informed consent was obtained from all participants before enrollment in the study. All procedures involving human participants were conducted in accordance with the ethical standards of the Institutional Review Board and the principles of the Declaration of Helsinki.

Ethics Approval Code: AAU/CHS/IRB/2020/042

Ethics Approval Date: April 12, 2020

Consent for Publication: Not applicable.

Availability of Data and Materials: The de-identified dataset supporting the findings of this study has been deposited in Zenodo and is publicly available through the following DOI: https://doi.org/10.5281/zenodo.21710102.

Reporting Guidelines: This manuscript was prepared in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for cross-sectional studies. A completed STROBE checklist is available as supplementary material.

Competing Interests: The authors declare that they have no competing interests.