Prevalence and possible consequences of ID complicating HF have more recently been attracting increasing attention. Many (mostly secondary) analyses were published that addressed the prevalence of ID in HF cohorts often derived from other clinical studies [13, 15‐17]. In this context, Opasich et al. demonstrated, e.g., that the majority of patients with chronic HF and low haemoglobin levels had anaemia of chronic disease, and nearly, all had deficient iron supply for erythropoiesis and/or blunted endogenous erythropoietin production [15]. Among more than 500 ambulatory patients with stable HF, Jankowska et al. found an ID rate of 32 and 57% in anaemic and non-anaemic subjects, respectively [13]. Schou et al. using the same cut-off criteria as Jankowska et al. to define ID, found among Danish outpatients with characteristics similar to those of the PrEP-participants (25% female, NYHA III-IV, mean LVEF 32%) an ID prevalence of 45% and thus very comparable to our findings [17]. Our findings from the PrEP registry regarding ID prevalence are thus in accordance with published data from several clinical cohorts as well as from smaller outpatient cohorts. The PrEP results also correspond to a recent report from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF): [18]. Among outpatients with systolic HF, 30% presented with anaemia and 45% with ID. Remarkably, and also in line with our observations, exercise capacity decreased in parallel to decreasing haemoglobin levels (r = 0.24, p < 0.001) in SICA-HF. Furthermore, exercise capacity proved significantly lower in 19% of the patients who presented with both, anaemia and ID, compared with those with either ID or anaemia, respectively.

Even though the prevalence of restless legs syndrome or a history of depression was low, the proportion of ID among affected PrEP-participants was significantly higher than among patients without ID. This finding is in line with the previous observations by Allen et al., who found a 23.9% prevalence of this syndrome among 251 first-presenters with ID and anaemia and no treatment for restless legs syndrome [19]. A similar association was previously also suggested for depression [20]. In conjunction with the previous findings, our present results indicate the possibility of adverse neuro-psychiatric effects of ID as yet another intriguing facet of its complex systemic sequels. However, prospective research needs to ascertain these interrelations, since our observation of a higher prevalence of patient-reported restless leg syndrome or a history of depression in patients with ID does not establish causality, as it is subject to various kinds of bias. In particular, future studies need to employ appropriate validated tools to evaluate and quantify both conditions at the time of study enrolment rather than rely on patients’ history.

Common clinical practice treatment options of anaemia in patients with HF, which might be considered after exclusion of treatable/reversible causes (e.g., gastrointestinal bleeding), include application of erythropoietin and its derivatives, blood transfusions, or iron administration. However, the Reduction of Events in Heart Failure trial (RED-HF) using darbepoetin-alfa in anaemic patients with HF recently ended neutral, [21] and blood transfusions should be restricted to selected symptomatic patients with very low haemoglobin levels, predominantly those <8 g/dl, leaving repletion of iron stores as the only promising treatment option with anaemia and ID that may be applied routinely in clinical practice. Our findings of a high prevalence of ID not always coincide with anaemia among PrEP-participants and the independent association of ID with reduced exercise capacity in our cohort buttress applicability of the current guideline recommendation regarding repletion of ID also in the outpatient setting. They suggest that iron substitution should be considered in symptomatic outpatients with chronic stable HF with reduced ejection fraction and ID and anaemia, but also, if there is no concomitant anaemia [2].

Using the same definition of ID as employed in the PrEP registry, the Ferinject Assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) trial randomized patients with symptomatic HF and a LVEF ≤40% (or ≤45% and NYHA III) with ID and haemoglobin levels between 9.5 and 13.5 g/dl to intravenous ferric carboxymaltose or saline [22]. After 24 weeks, self-reported patient global assessment had improved significantly more often in patients receiving ferric carboximaltose (50% vs 28%, p < 0.001), and various secondary endpoints, including NYHA class and quality of life, had also improved [23]. Using a similar study design, the ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (CONFIRM-HF) study extended these findings in an outpatient population with ID and similar characteristics to an observation period of 52 weeks [24]. Importantly, hospital admissions for worsening HF, which constituted a pre-defined secondary endpoint, were significantly reduced in CONFIRM-HF. The Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Iron Deficiency and Chronic Heart Failure (EFFECT-HF) trial, even though open label, further extended these findings by showing that intravenous iron therapy with ferric carboxymaltose improves exercise capacity as assessed using spiroergometry [25]. A recent meta-analysis involving five trials, which evaluated intravenous iron therapy in iron-deficient patients with systolic heart failure, confirmed that this treatment improves clinical outcomes, exercise capacity, and quality of life, and to alleviate HF symptoms [26]. In line with these results, another meta-analysis showed that iron supplementation reduced the need for blood transfusions and increased haemoglobin levels in patients with chronic kidney disease or in the peri-partal period [27]. The recently published Oral Iron Repletion effects ON Oxygen UpTake in Heart Failure (IRONOUT) trial has underscored missing benefit of oral iron therapy, as no increase in exercise capacity and only a minimal increase in serum ferritin level were noted after 12 weeks of therapy [28].

Against this background, current guidelines for the management of HF advocate the repletion of ID with the inclusion criteria of FAIR-HF as defining features for patients eligible for treatment [2]. In addition, the guidelines state that blood biochemistry parameters should be regularly assessed to “detect reversible/treatable causes of HF (e.g., hypocalcaemia, thyroid dysfunction) and co-morbidities (e.g., iron deficiency)”. With regard to anaemia, the guidelines list “chronic HF, haemodilution, iron loss or poor utilization, renal failure, chronic disease, (and) malignancy” as potential reasons for anaemia development, and recommend to perform a “diagnostic work-up” and to “consider treatment” [2]. A recent French position paper states that iron supplementation should be considered “for all patients with chronic HF or hospitalized for acute decompensation of chronic HF with biological evidence of iron insufficiency” [29].

Findings of this study should be interpreted in the light of its limitations. First, the PrEP registry derived all study data from informations obtained during routine patient care. Patient phaenotyping was, therefore, not strictly standardized and performed according to local circumstances, which precluded, e.g., the use of uniform exercise testing or determination of just one natriuretic peptide. The diagnosis of co-morbidities as restless leg syndrome, depression, diabetes, or COPD was based on patients’ reports and not ascertained in the frame of the study. Moreover, cardiologists were asked to recruit patients consecutively, but did not complete a screening and enrolment log. Although they did not report any patients denying participation, patient selection may have been biased by factors unaccounted for in this study. Finally, PrEP-participants were recruited between 2010 and 2012, when in general, diagnosis and management of co-morbidities received less attention than recommended in the most recent version of the European Society of Cardiology HF guidelines. Awareness of anaemia and ID as common characteristics of the HF syndrome with adverse impact on prognosis may since have increased also amongst physicians responsible for HF outpatient care. However, the PrEP registry results, derived from the so far largest stable outpatient cohort of symptomatic HF patients, provide for the first time strong arguments to diagnose and treat these conditions also in stable outpatients attending cardiologist practices, and appear suited to call cardiologists into responsibility in this respect. PrEP results may thus significantly reinforce routine assessment of iron status and help to establish iron supplementation as a treatment option also in current ambulatory HF care.

The PReP registry, which involved a large cohort of patients with symptomatisc systolic HF enrolled in 42 German office-based cardiology practices, demonstrated high prevalence of both anaemia and ID (18.9% and 42.5%, respectively) in this population. Despite this high prevalence, anaemia was often unappreciated, and ID was previously unknown in all PrEP-participants. Clinical relevance, treatability, and independent association with reduced physical performance as demonstrated by the PrEP results call for routine diagnostic clarification of anaemia and ID-screening in ambulatory healthcare settings to further improve current outpatient HF care.