Treatment options for anemia in the elderly

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Review

Treatment options for anemia in the elderly Fabiana Busti, Giacomo Marchi, Acaynne Lira Zidanes, Annalisa Castagna, Domenico Girelli

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Department of Medicine, Section of Internal Medicine, University of Verona, EuroBloodNet Referral Center for Iron Metabolism Disorders, Azienda Ospedaliera Universitaria Integrata Verona, 37138 Verona, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords: Anemia Elderly Aging Iron deficiency Clonal hematopoiesis Hepcidin

Anemia in elderly (AE), though often mild, is quite common and independently associated with important clinical outcomes, including decreased quality of life, risk of falls and fractures, cognitive decline, increased length of hospital stay, and even mortality. AE is generally overlooked, and hence undertreated, especially when comorbidities distract the attention of physicians and caregivers. This also partially reflects difficulties in dissecting the cause(s) of AE, which is typically multifactorial, as well as our limited diagnostic approach often categorizing AE as apparently “unexplained”. Therapeutic approaches have been traditionally limited to transfusions, or supplementation with hematinics, including group B vitamins and iron. The latter has been largely underutilized, because of missing diagnosis of iron deficiency using inappropriate laboratory thresholds, as well as complex schedule and adverse effects associated with traditional preparations. After decades of stagnation, new oral and intravenous iron preparations look promising, particularly in the elderly. Moreover, a number of innovative anti-anemic drugs, like hepcidin modulators, Hypoxia Inducible Factor (HIF) stabilizers, and activin type II receptor agonists are entering the clinical arena and may substantially improve our therapeutic armamentarium to AE in the near future.

1. Anemia in the elderly: definition and prevalence of a multifactorial detrimental disorder Anemia is a common disorder in older people, representing a major public health problem [1] predicted to further increase in the coming years because of the aging of the global population [2]. There is some debate on which hemoglobin (Hb) threshold should be used to define anemia in the elderly (AE). In many studies, anemia has been defined according to the classical World Health Organization (WHO) criteria [3] as Hb < 13 g/dl in males and Hb < 12 g/dl in females. These criteria have been criticized for several reasons, particularly since the reference population in the original study did not include subjects aged > 65 years [4]. Different Hb thresholds have been proposed over the years. Since the Hb decline with age tends to be more pronounced in males, likely because of a progressive androgen deficiency, a Hb threshold < 12 g/dl has been suggested in both genders [5,6]. On the other hand, some researchers have proposed to rely on Hb concentrations relevant to clinical outcomes in the elderly, as emerged from many longitudinal studies (see below). On this basis, “optimal” lower Hb thresholds near 13.7–14 g/dl for men, and 12.6–13 g/dl for women have been associated with better survival [7,8]. However, using such “optimal” values for defining AE would lead to a substantial increase of

AE diagnosis, possibly causing excessive or unnecessary diagnostic procedures particularly in the “oldest old” (i.e., people aged > 80–85 years) [1]. At present, none of these alternative Hb thresholds for defining AE can be considered ideal, and many authors agree that the classical WHO criteria remain "the most acceptable compromise" [1]. The awareness of the enormous impact of AE has led the WHO to launch in 2017 an ambitious project to revise the Hb thresholds in different populations, including the elderly (http://www.who.int/ nutrition/events/2017-meeting-haemoglobin-concentrations-anaemia29novto1dec/en/). Prevalence of AE has wide variability in the literature [9–15]. This is partly related to the different defining Hb thresholds, but also to the heterogeneous health status of the elderly included in the studies. Large studies on community-dwelling elderly in the U.S. and Europe have reported prevalence rates ranging from 8 to 25% [16]. According to a systematic review including 34 studies using WHO criteria, the higher prevalence has been reported in nursing-home residents (47%), followed by hospitalized (40%), and community-living subjects (12%) [17]. Moreover, the prevalence increases with age, reaching nearly 50% in both hospitalized and non-hospitalized men older than 80 years [11]. On the other hand, some studies in relatively small cohorts of elderly without overt concurring diseases (the so-called “wellderly”) have

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Corresponding author. E-mail addresses: [email protected] (F. Busti), [email protected] (G. Marchi), [email protected] (A. Lira Zidanes), [email protected] (A. Castagna), [email protected] (D. Girelli). https://doi.org/10.1016/j.transci.2019.06.018

1473-0502/ © 2019 Published by Elsevier Ltd.

Please cite this article as: Fabiana Busti, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.06.018

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younger adults, and diuretic treatment should be considered in particular to avoid transfusion-associated circulatory overload (TACO) [40]. The emerging practice of transfusing on a single unit basis, e.g. if one unit adequately improves symptoms and clinical status no further unit should be given regardless of initial Hb values [41], appears particularly appropriate for elderly patients. In anemic asymptomatic patients, the use of transfusions is more controversial and should be kept at minimum because of inherent risks. In fact, although useful in providing an immediate increase in Hb, transfusions are potentially associated with a number of serious adverse effects [42], including anaphylactic reactions, transfusion-related acute lung injury (TRALI), circulatory overload, iron accumulation, infectious pathogens transmission, and perioperative complications [43]. Elderly are especially sensitive to many of these immediate and delayed complications, because of intrinsic frailty. Indeed, the so-called “restrictive strategy” (e.g., Hb thresholds set at 7–8 g/dl) is becoming increasingly popular among many hematologists and geriatricians. Numerous studies have investigated the role of such strategy in different setting [39,44]. Initially, the Transfusion Requirements in Critical Care (TRICC) trial [45], published 10 years ago but still representing one of the most powerful study, found that intensive care patients could tolerate a restrictive transfusion strategy (Hb range 7–9 g/dl) with no differences in 30-day mortality rates as compared to a “liberal” regimen (Hb range 10–12 g/dl). Several other studies and a systematic review have substantially confirmed this [46–51], highlighting a decreased blood utilization by 30–40% [41,48] without increase mortality and morbidity. However, there are insufficient data to inform the safety of transfusion policies in specific subgroups of high-risk patients, including acute cardiovascular or neurological disorders, and malignancies [48]. In general, available guidelines agree that transfusion is not beneficial when Hb is > 10 g/dl, while should be considered when the Hb is < 6–7 g/dl [38]. Between these values, each patient should be evaluated individually and the choice to transfuse should be based on the tolerance of anemia, rather than on a universal Hb threshold. In this respect, it should be especially considered the coexistence of cardiovascular diseases (CVD), which are particularly frequent in the elderly. Many studies suggest that the presence of CVD is an important predictor of unfavorable outcomes [52], and that more liberal transfusion regimens are preferable in CVD patients, especially in those with acute coronary syndromes (ACS) [53,54]. For example, a retrospective analysis of Center for Medicare Services (CMS) data on 79,000 elderly patients hospitalized with acute myocardial infarction (MI) in the U.S., found that blood transfusions, in patients with hematocrit (Ht) at admission < 30%, were associated with significantly lower mortality rates [53]. The MINT trial [54] evaluated the feasibility of restrictive (Hb < 8 g/dl) versus liberal (Hb > 10 g/dl) transfusion thresholds in ACS patients. The primary composite outcome (death, MI, or revascularization) occurred in 10.9% of the liberal transfusion cohort, as compared with 25.9% in the restrictive cohort (P = 0.054). Mortality rates were 1.8% and 13.0%, respectively (P = 0.032). Overall, these two studies suggest that a more liberal transfusion practice represents a prudent management of high-risk patients with ACS. On the other hand, post-hoc analysis of prospectively collected data from 24,112 ACS patients [47] did not demonstrate a benefit of transfusion even when Hb levels was < 8 g/dl (Ht 25%). A small pilot trial randomized 45 patients with acute MI and Ht level < 30% to a liberal regimen (receiving transfusions to maintain hematocrit > 30%) or a conservative regimen (aimed at maintaining Ht 24%–27%) [55,56]. In this study the primary clinical safety measurement (in-hospital death, recurrent MI or worsening CHF) occurred in 8 (38%) of the liberal cohort versus 3 (13%) in the conservative cohort (P = 0.046). Thus, the best transfusion strategy in patients with ACS remains controversial. Acute heart failure (AHF) is one of the leading causes of hospitalization in the elderly. Kao and colleagues [56] examined the large public discharge database on 596,456 patients admitted for AHF, most of them

shown that the Hb decline during aging tends to be minimal [18], highlighting that anemia not should be merely considered as a normal consequence of aging, even in the oldest old. In most cases, AE is mild to moderate, with Hb values generally > 10 g/dl [1]. Nevertheless, AE is associated to a significant impairment of physical and cognitive performance, including fatigue [19,20], decreased muscular strength with an increased risk of falls and fractures [19,20], dementia [21–23], depression [24] and impaired quality of life (QoL) [25], leading to the typical “frailty” of older people. Low Hb levels in elderly have been associated with increased risk of hospitalization [8,26,27] and death [7,8,25,26,28–32]. Of note, most of these associations remained statistically significant after adjusting for multiple possible confounding factors, suggesting a negative impact of anemia per se, independently of concurrent morbidities like chronic kidney disease (CKD), chronic heart failure (CHF), and inflammatory disorders. The increased risk of mortality was evident even when Hb levels were merely low-normal (i.e., Hb around 11–12 g/dl) [8]. So far, no study has been specifically designed to investigate the existence of a direct pathophysiological link between anemia and functional decline and/or mortality in the elderly. It is plausible to speculate that chronic hypoxia provoked by anemia might worsen the dysfunction of aged organs, including the heart or the brain. For this reason, AE should not be overlooked. The etiology of AE is traditionally ascribed to 3 broad categories, each roughly representing one third of cases [1,33–35]: 1) deficiencies of nutritional hematinics, mainly iron deficiency (ID), but sometimes also B-group vitamins (folic acid and vitamin B12); 2) anemia of inflammation, also known as anemia of chronic disease (ACD), a multifaceted group including CKD, CHF, inflammatory or infectious diseases, and tumors, in which anemia is known to be driven by hepcidin-induced functional iron deficiency (see below) as well as by cytokinedependent suppression of erythropoiesis; and 3) “unexplained” anemia (UAE), that is essentially a diagnosis of exclusion in subjects with hypoproliferative anemia of unknown origin. Some of these cases are likely related to early-stage hematological disorders like unilinear myelodysplastic syndromes (MDS) or clonal hematopoiesis of indeterminate potential (CHIP) [1,36,37], which often goes undiagnosed because of the need of invasive procedures (i.e. bone marrow aspiration for MDS) and/or complex and costly molecular studies (i.e. next-generation sequencing for CHIP). Indeed, a complete diagnostic workup in the elderly is more challenging than in younger subjects, due to comorbidities and medications. Noteworthy, a significant proportion of AE (30–50%) is presumed to have multiple causes [35]. “Complexity” is the key element to understand AE and the starting point for the diagnosis and the treatment. 2. Therapeutic options for AE Management and treatment of AE usually require a multidisciplinary approach. Whenever possible, the primary goal is to treat the underlying cause of anemia, that unfortunately is a viable option only for a minority of patients, particularly those with nutritional deficiencies. In the remaining categories, treatment is more challenging. Traditional approaches, such as blood transfusions and erythropoietic stimulating agents (ESAs), have consistent drawbacks that have led to an intensive search for novel drugs. Below, we briefly review the currently available options, as well as some novel approaches that could potentially revolutionize the field in the near future (Table 1). 2.1. Blood transfusions Blood transfusions represent the first-line treatment for patients with severe anemia, with signs or symptoms due to inadequate tissue oxygenation and/or hemodynamic instability (e.g., angina, otherwise unexplained shortness of breath, tachycardia or CHF, etc.) [38,39]. As a general rule, geriatric patients should be transfused more slowly than 2

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Table 1 The evolving scenario of anti-anemic drugs. Class 3

rd

generation IV iron preparations

Androgens Hepcidin antagonists

Hypoxia Inducible Factors (HIF) stabilizers

Activin receptor IIA ligand traps

Examples

Indication(s)

Mechanisms

Comments

Fe-Carboxymaltose Ferumoxytol Fe-isomaltoside Testosterone (gel 1%)

Iron deficiency

Iron repletion

Single-infusion of therapeutic dose (particularly useful in elderly). Reassuring safety profile

Androgen deficiency (T. < 275 ng/dl) CKD? ACD? UAE?

↑ erythropoiesis (also indirectly by ↓ hepcidin) Inhibition of hepcidin or interference with its function

RCT [112]

CKD? ACD? UAE?

↑ endogenous EPO by inhibiting HIF prolyl-Hydroxylase; ↑ iron utilization by modifying iron-related gene expression ↓ ineffective erythropoiesis by TGF-β superfamily inhibition

Spiegelmer lexapeptid NOX-H94 Anticalin PRS-080 Heparin derivatives Anti-BMP6 agents Roxadustat Vadadustat Daprodustat Molidustat Luspatercept Sotarcept

MDS UAE?

Promising, but only in pre-clinical models for the moment

Oral administration; possible better CV risk profile compared to ESAs; concerns about offtarget effects s.c. administration every 3-4 weeks

[11,34,35]. Similarly, ferritin, the most reliable marker of ID, is difficult to interpret in the elderly since its level per se raises with aging [64], not only because of inflammatory comorbidities. The classical cut-off value of ferritin < 15-20 ng/ml, which defines ID in young adults, has been claimed as too stringent in elderly patients. For this reason, some authors suggest that ferritin thresholds for IDA in people aged > 65 years should be reconsidered. A threshold of at least 45 ng/ml, if not 100 ng/ml, could be reasonable, mainly when specific comorbidities occur, such as advanced CKD or CHF [1,65]. The uncertain interpretation of the conventional ID biomarkers in the elderly makes ID an overlooked condition by the majority of clinicians [66]. Additional testing for transferrin saturation (TSAT), which reflects circulating iron available for erythropoiesis rather than tissue iron stores like ferritin [67], has been proven useful. In CHF, for example, ID is defined (and effectively treated with IV iron) when TSAT is < 20% with ferritin values up to 300 ng/ml [63,68]. In a proportion of patients suffering from ID, oral iron supplementation seems to be sufficient [69]. However, oral iron often requires prolonged administration (at least 3–6 months), that results in scanty adherence, especially in subjects taking multiple medications [70,71]. Moreover, oral iron is often poorly tolerated in elderly patients, particularly because of abdominal discomfort, as well as poorly absorbed, because of the relative high prevalence of malabsorptive conditions like chronic gastritis [72–74]. Iron malabsorption has also been attributed to increased hepcidin levels occurring in the pro-inflammatory state that characterizes some disorders typical of elderly, such as CHF [75–77], or that could be the consequence of the accumulation of endogenous damaged molecules and reactive oxygen species occurring in the aging processes (also known as “inflammaging”) [78,79]. In recent years, innovative oral iron formulations, like sucrosomial iron [80,81], have been proven effective in different settings with good GI tolerance. If their benefit will be confirmed, they could represent a valuable oral alternative in elderly patients. In subjects non-adherent, intolerant, or unresponsive to oral iron, the third-generation IV iron preparations (e.g., ferric carboxymaltose, ferumoxytol, and iron isomaltoside) appear attractive for treating ID in elderly [68]. Indeed, these formulations allow rapid correction of ID since the total therapeutic dose of iron can usually be administered in a single injection. This avoids the need for multiple hospital accesses, which can be particularly cumbersome for elderly patients with reduced mobility and their caregivers. Moreover, the safety profile of the new compounds is consistently reassuring, as compared to the traditional preparations [82]. Ferric carboxymaltose can lead to hypophosphatemia, with a peculiar mechanism related to fibroblast growth factor 23 modulation [83]. However, this is usually mild, transient, and asymptomatic [84], except in rare cases with predisposing conditions and requiring multiple infusions repeatedly [85]. Thus, it would be

being elderly. Anemia was present in 27.1% of patients, and 6.2% received a red blood cell transfusion. While anemia was associated with increased mortality (adjusted OR 1.12, 95% CI 1.07–1.17), transfusions magnified this effect and emerged as the strongest single predictor of mortality (OR 3.81, 95% CI 3.51–4.13). Data specifically addressing the outcomes of transfusions in elderly patients are relatively sparse. The FOCUS trial [57,58] included patients hospitalized for hip fractures with a mean age of 80 years. In this cohort, a restrictive transfusion strategy did not result in increased mortality, inability to walk on 60-day follow-up, or in-hospital complications, as compared with a liberal strategy. The Authors concluded that “it is reasonable to avoid transfusions in patients who have undergone surgery in the absence of symptoms of anemia or a decline in the Hb level below 8 g/dl, even in elderly patients with underlying CVD”. However, all the studies mentioned above should be kept with caution because of inherent limitations [39]. First, the severity of anemia and clinical reasons for which a transfusion was required were not always available and/or adjusted for. These and other unmeasured confounders could have affected the results of multivariable analyses. Second, and most relevant to this review, it is clear that the eligibility for trial participation was not centered on the elderly in most studies, except for the FOCUS trial. Further prospective randomized controlled trials (RCTs) are required to definitively clarify the role of transfusions in older people with anemia and different types of CVD. 2.2. Iron replacement therapy Iron deficiency (ID) is the most widespread nutritional deficiency disorder, also representing the most frequent single cause of anemia in the world [1,59]. In elderly, ID can be determined by multiple factors not rarely coexisting in the same patient, for example inadequate dietary intake, reduced efficiency of iron absorption (possibly aggravated by frequent use of proton pump inhibitors) [60], and occult or overt gastrointestinal blood loss (potentially favored by concomitant antithrombotic therapies) [61]. Subjects with multimorbidity or institutionalized are at highest risk of ID [62]. Tissue ID, which precedes the development of anemia can be debilitating per se, and can exacerbate any underlying chronic disease [1], particularly CHF [60,63] Accurate laboratory diagnosis of ID anemia (IDA) in the elderly is challenging because of the high prevalence of concomitant chronic diseases that complicate the interpretation of traditional biomarkers. Indeed, the red blood cells mean corpuscular volume (MCV) is often a starting index in the evaluation of a patient with anemia, being typically reduced in IDA. However, microcytosis in the elderly is present in < 30% in early stages and/or blunted by other concomitant nutritional deficiencies, such as those of folic acid or vitamin B12 3

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inhibitors are a class of novel small molecules able to stabilize the HIF-α subunits, thereby increasing HIF-dependent production of endogenous EPO [105,106]. Beyond control of EPO production, HIFs also coordinate the expression of genes involved in iron metabolism, leading to iron mobilization toward the bone marrow [107]. The use of HIF-PH inhibitors results in dose-related increases in Hb, while decreasing hepcidin, ferritin and TSAT levels. It has been postulated that the considerably lower but persistent increase of EPO levels induced by HIF-PH inhibitors, as compared with ESAs, may be associated with fewer adverse cardiovascular effects at comparable Hb levels. However, this attracting hypothesis has yet to be proven in long-term clinical trials. The oral route of administration represents an obvious advantage over traditional ESAs, especially in patients with non-dialysis-dependent CKD. Although manipulation of HIF-PH pathway may have several benefits, concerns regarding safety have been raised. For example, the long-term use of HIF-PH inhibitors may promote latent cancers in elderly, since HIF activation in tumor hypoxic environments could promote cell survival and growth. Furthermore, the off-target effects on other critical pathways under HIF control, like VEGF and angiogenesis, have also yet to be determined. Currently, HIF-PH inhibitors are essentially under development for anemia in patients with CKD. However, given the biology of the HIF pathway, it is plausible to assume that such drugs may have pleiotropic effects (e.g., anti-inflammatory, as HIF-1α induces the production of inflammatory cytokines). Targeting HIF may become a potential therapeutic strategy for anemic patients also with other chronic diseases.

prudent to check or monitor serum phosphate levels in elderly patients with overt malnutrition or neoplastic disorders [68]. The measurement of serum hepcidin levels would be likely helpful in choosing the optimal route of iron administration in ID elderly [61,86]. However, hepcidin assays are not routinely available and need international standardization before definitively entering the clinical practice [87,88]. 2.3. Erythropoiesis stimulating agents Erythropoiesis-stimulating agents (ESAs) are useful in treating anemia in patients affected by end-stage CKD [89,90], inflammatory/ chronic diseases before elective surgery [90], neoplastic disorders treated with chemotherapy with or without combined radiotherapy [91], and in those with MDS [92], in which the only alternative therapy may be periodic blood transfusions. Data on the use of ESAs in the elderly with other subtypes of anemia are limited. A single study has reported beneficial effects of Epoetin alpha in African-American women (aged ≥65 years) with apparently unexplained anemia [93]. In that study, ESAs significantly increased Hb levels and also QoL. Analogously with low-risk MDS, treatment with ESAs could be considered in elderly with anemia in the setting of documented CHIP, namely with clonal cytopenia of uncertain significance (CCUS) [94]) and concomitant low EPO levels [95,96]. However, this has not been tested in clinical trials, and safety concerns may arise for widespread use of ESAs in the elderly, a population intrinsically at increased risk of thromboembolic complications [97].

2.4.3. Activin type II receptor agonists Activin type II receptor agonists (Luspatercept, Sotarcept) are currently being investigated in anemic patients with MDS [108,109], that typically occur in the elderly. These recombinant fusion proteins act by inhibiting negative regulators of late-stage erythropoiesis, such as the growth differentiation factor 11 (GDF-11), activin B, and other transforming growth factor beta (TGF β) superfamily ligands. Luspatercept rapidly increased Hb and reticulocyte counts, as well as normalized the marrow myeloid:erythroid ratio in a mouse model of MDS [110]. In healthy postmenopausal women, Luspatercept induced a sustained increase in Hb levels [111]. In a phase II trial in anemic transfusion-dependent patients with lower risk MDS (generally ESA naïve), Luspatercept administered subcutaneously every three weeks caused a dose-dependent erythroid response and the independence from transfusion in more than half of the subjects [108]. More frequent and robust response rates were observed in MDS with ringed sideroblasts and SF3B1 mutations. Interestingly, although higher response rates occurred in patients with baseline serum erythropoietin less than 200 IU/l, Luspatercept was effective even in patients with higher erythropoietin concentrations, which are typically associated with poor ESA response. To date, the safety profile for Luspatercept appears quite favorable. However, further in-depth studies are needed.

2.4. Novel therapies 2.4.1. Hepcidin antagonists The recent enormous advances in understanding the mechanisms regulating erythropoiesis [67,95] have paved the way for the development of new anti-anemic drugs. One of the potentially major targets is represented by iron maldistribution. Such condition, mediated by high levels of hepcidin [87,98], typically characterizes the so-called anemia of inflammation or anemia of chronic disease (ACD) [99], that accounts for near one-third of AE. Hepcidin overexpression reduces iron availability for erythropoiesis through sequestration within macrophages, a condition also known as "functional" ID. The optimal treatment for ACD would be the cure of the underlying disorder, but this is often unfeasible. Thus, innovative approaches, i.e. hepcidin antagonists, are being developed (for extensive reviews, see [100–102]. Hepcidin antagonists act by two main mechanisms: inhibition of hepcidin production, or interference with hepcidin function. The first can be achieved by inhibiting positive regulators of hepcidin (e.g. BMP6 that can be neutralized by specific monoclonal antibody or by highaffinity ligands like certain heparin derivatives). The second can be accomplished by compounds able to directly bind and antagonize hepcidin (e.g. Spiegelmer lexapeptid NOX-H94, and anticalin PRS-080). Currently, hepcidin antagonists are mainly developed for anemia in CKD and cancer patients. Although promising, most of the available data derive from preclinical models. If benefits will be confirmed, hepcidin antagonists may play a role in the future treatment of anemia associated with overt inflammatory conditions. Moreover, they may also help in conditions increasingly recognized in association with “unexplained” AE, like CHIP [103] and inflammaging [78], both characterized by subclinical inflammation [15].

2.4.4. Androgens Androgen deficiency represents a factor likely contributing to apparently unexplained anemia in older men. Roy and colleagues recently performed a randomized placebo-controlled trial in which subjects with low testosterone levels and mild anemia received testosterone gel (1%) or placebo for 12 months [112]. Androgen supplementation successfully corrected anemia in 58% of patients, as compared to 22% of those receiving the placebo (P = 0.002). Beyond their known erythropoiesisstimulating activity, androgens are able to suppress hepcidin production [87], which may further facilitate red blood cell production through iron mobilization. These promising results in a relatively small cohort need confirmation by further studies.

2.4.2. Hypoxia inducible factor (HIF)–prolyl hydroxylase (PH) inhibitors Hypoxia-Inducible Factors (HIFs) are physiological regulators of the transcriptional responses to hypoxic conditions [104]. HIFs are heterodimers made up of an O2-regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. Under normal conditions, HIF-α subunits undergo hydroxylation of a proline residue by prolyl hydroxylase (PH), ultimately leading to degradation of the protein. PH

3. Concluding remarks AE represents a global health emergency, involving millions of older 4

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people worldwide. AE is generally multifactorial, but initial studies suggested that etiology remains unexplained in near one-third of cases. The awareness of physicians about this complex and common condition need to be enhanced. Indeed, while typically mild, AE negatively impacts on QoL and is an independent predictor of hospital admissions and reduced survival. Alongside traditional therapeutic approaches, such as blood transfusions and ESAs, in recent years novel agents have enriched the scenario of treatments for AE. Increasingly available new therapeutic options may allow effective treatment of AE in the near future, eventually testing whether or not the relationship between anemia and adverse outcomes in elderly is truly causal.

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