Anemia in heart failure: still an unsolved enigma

Background Anemia affects one-third of heart failure patients and is associated with increased morbidity and mortality. Despite being one of the commonest comorbidities associated with heart failure, there is a significant knowledge gap about management of anemia in the setting of heart failure due to conflicting evidence from recent trials. Main body The etiology of anemia in heart failure is multifactorial, with absolute and functional iron deficiency, decreased erythropoietin levels and erythropoietin resistance, inflammatory state and heart failure medications being the important causative factors. Anemia adversely affects the already compromised hemodynamics in heart failure, besides being commonly associated with more comorbidities and more severe disease. Though low hemoglobin levels are associated with poor outcomes, the correction of anemia has not been consistently associated with improved outcomes. Parenteral iron improves the functional capacity in iron deficient heart failure patients, the effects are independent of hemoglobin levels, and also the evidence on hard clinical outcomes is yet to be ascertained. Conclusion Despite all the research, anemia in heart failure remains an enigma. Perhaps, anemia is a marker of severe disease, rather than the cause of poor outcome in these patients. In this review, we discuss the current understanding of anemia in heart failure, its management and the newer therapies being studied.


Background
Heart failure (HF) is a clinical syndrome characterized by inability of heart to perform circulatory function efficiently due to structural and/or functional abnormalities. It continues to be an important global health issue with an estimated worldwide prevalence of more than 37.7 million [1]. With an epidemic of coronary artery disease, diabetes mellitus and other life style diseases, it is estimated that globally the number of HF patients would increase by 25% by the year 2030 [2]. Despite best of medical and device therapies, the mortality rate of HF patients is 50% at 5 years of diagnosis [3], which is more than that of breast, prostate and colon cancer [4].
One-third of HF patients are anemic and almost 50% have iron deficiency (ID) [5]. Both anemia and ID are associated with worst clinical outcomes in patients with HF. Whether these are the mediators of poor outcome or are just the bad prognostic markers, the debate is far from over. While treatment of ID has shown to produce symptomatic improvement in these patients, correction of anemia has failed to show any significant positive outcomes. In this article, we aim to review the existing data on management of anemia and ID in HF patients and discuss the future therapies under development.
HF severity [6,7]. The anemic patients with HF are found to be older and have more comorbidities like diabetes mellitus, chronic kidney disease (CKD) and have worse functional capacity with poorer quality of life. They tend to have lower blood pressure, more edema, higher requirement of diuretics [8][9][10][11][12][13][14].

Anemia in HF: etiology
Anemia in HF is multifactorial. Fifty percent of patients with HF have ID; either they have depleted iron stores (low ferritin (less than 100 ug/dL) and low transferrin saturation (equal to or less than 20%) or they have functional iron deficiency in the form of normal iron stores (ferritin (100-300 ug/dL) and low transferrin saturation (equal to or less than 20%) [8,9]. Transferrin saturation is obtained by dividing the serum iron by total iron binding capacity. The nutrient deficiency may occur either due to decreased intake or due to decreased absorption of iron in the gut. However, the deficiency of other nutrients like folic acid and vitamin B12 are less well described as contributing factors. HF is a complex inflammatory state which is associated with upgradation of inflammatory markers like interleukin-1, interleukin-6 and tumor necrosis factor and is usually associated with multiple comorbidities like CKD [13,14]. The appropriate erythropoietin (EPO) response to anemia may be blunted due to kidney dysfunction. In addition, the cytokines produce a state of resistance to EPO. Though the upgradation of sympathetic and renin angiotensin system increases the production of EPO in kidneys, the drugs used in heart failure commonly blunts this response. Also the use of antithrombotics in patients with HF for various indications may lead to occult gastrointestinal blood loss leading to ID. Figure 1 summarizes the potential mechanisms of anemia in HF.

Anemia in HF: pathophysiology
Anemia in HF decreases the delivery of oxygen to the tissues and aggravates the symptoms of dyspnea and fatigue with worsening quality of life. In a patient without HF, anemia produces a hyperdynamic state and compensates with increased heart rate and stroke volume. These reserves are limited in patients with HF, and hence, anemia can decompensate such hemodynamics. It may lead to adverse left ventricular modeling and demand supply mismatch. In a large meta-analysis, the crude mortality risk associated with anemia in HF was an odd ratio of 1.96 (95% confidence interval 1.74-2.21), and the adjusted hazard ratio was 1.46 (95% confidence interval 1.26-1.69) [15]. There has been data which shows that treatment of HF resolved anemia and brought the mortality risk to baseline; however, the treatment of anemia in HF has not been associated with consistent positive outcomes. On the other hand, correction of ID (overt and occult) in HF is associated with better quality of life and symptomatic improvement and is hence recommended to be evaluated for and treated, irrespective of Hb levels. However, the effect of treatment of ID in HF on hard outcomes is yet to be seen. Hence, the debate, whether the anemia is a marker of HF severity or it leads to adverse outcomes, is far from over.

Anemia in HF: treatment
1. Transfusion: In severe symptomatic anemia, a liberal transfusion strategy (trigger threshold of Hb 7-8 gm/ dL) is recommended in patients with heart disease [16,17]. Despite having some temporary benefits, the transfusion therapy can lead to volume overload and ischemic events in HF patients [18,19], apart from other adverse events like hemolytic reactions, acute lung injury and infections. 2. Erythropoietin-Stimulating Agents (ESAs): Exogenous erythropoietin was studied in patients with HF in Reduction Of Events by Darbepoetin Alpha in Heart Failure (RED-HF) trial, where more than 2000 HF patients with ejection fraction equal to or less than 40% and anemia were randomized to receive Darbepoetin Alpha or placebo [20]. There was no difference in primary outcome (death or HF hospitalization) in two groups; however, there was significantly increased number of ischemic strokes and thromboembolic events in the ESA group. The reason for the observed outcome was heterogeneity of anemia in HF patients and a large proportion of HF patients already have high EPO levels, with resistance of bone marrow to its action [21]. Hence, EPO is not recommended to treat anemia in HF [22][23][24]. Even in patients with CKD, higher Hb targets with EPO are associated with worse cardiovascular outcomes. 3. Iron Therapy: Parenteral iron therapy, in patients with HF with reduced ejection fraction and iron deficiency, irrespective of Hb levels, has shown to improve New York Heart Association functional class, quality of life and exercise capacity [25][26][27][28]. The effect of parenteral iron therapy on hard outcomes is yet to be ascertained. Most of the studies have taken a ferritin cutoff of equal to or less than 100 ug/dL or ferritin of 100-300 ug/dL and transferring saturation of equal to or less than 20%. Recent studies have found that transferrin saturation, rather than ferritin  tiple genes including EPO [40]. One of the HIF stabilizers, roxadustat (FG-4592), has shown to increase EPO and Hb levels and decrease the hepcidin in CKD patients [41].

Anemia in HF: current guidelines
The current guidelines recognize that anemia is an important prognostic marker in HF patients and lay stress on evaluating the etiology of same, though most of the times no specific cause is found [17,[22][23][24]. A special emphasis is laid on correction of iron deficiency in HF with parenteral iron, irrespective of the Hb levels, to improve the functional status.

Conclusion
Despite all the research, anemia in HF remains an enigma. Affecting almost one-third of HF patients, anemia is associated with bad outcomes. However, the treatment of anemia and rise in Hb levels have not been consistently linked to better prognosis. Though parenteral iron improves the functional capacity in iron deficient HF patients, the effects are independent of Hb levels; and also the evidence on hard clinical outcomes is yet to be ascertained.