DISCUSSION.
Anemia is an important comorbidity in patients with AHF, however, most studies on the influence of early and long-term mortality included patients admitted to different hospitalization units16,25. The EAHFE registry includes patients with AHF attended in HEDs, including patients admitted as well as those discharged after their first episode or managed in alternative hospitalization units (Observation Units or Short-stay Units), which are not usually represented in other studies. The ANEM-AHF study was also aimed at determining the influence of anemia as a prognostic factor of short- and long-term mortality in patients with AHF attended in HEDs and to determine the influence in relation to the rest of the variables which act as confounding factors, an aspect which, up to now, has not been reported in the literature. On the other hand, it also measured the potential increase in individual risk at different time points during follow-up.
The principal findings of the ANEM-AHF were: 1) the frequency of anemia in patients attended in HEDs is higher than what has been reported in the literature in hospitalized populations and significantly increases with age; 2) anemia is a prognostic factor of early (30 days after inclusion) and long-term (at one year) mortality, and this prognostic capacity is independent of the differences between the groups with and without anemia; 3) age, sex and comorbidity are confounding factors which produce a clinically relavant effect on the relation between anemia and mortality at 30 days and at one year, and the remaining parameters (baseline NYHA, previous treatment, clinical and analytical and electrocardiographic data of the acute episode, emergency treatment and hospital admission) have a lesser impact; and 4) the effect of anemia on mortality is much greater in the long term than in intermediate follow-ups.
The prevalence of anemia in our cohort was 56.9%, being higher than that of other studies which ranged from 30 to 50%, and increased with age9. This greater frequency is probably influenced by age since its coincides with the findings of the study by Formiga26 who analyzed the effect of anemia in 155 patients with AHF over 90 years of age and found a prevalence of 60%, which is very similar to that of our patients.
Patients with anemia differ from those without this comorbidity, being a common aspect in different studies9,16,23: these patients are older, have more comorbidities, a worse basal status, and are more often admitted for an acute episode. Anemia was more frequent among males than controls, contrary to what has been described in the literature in which women predominate among patients with anemia or there are no differences between sexes9,16. Taking into account the data of our large, country-wide study, we consider that these findings are representative of the real population with anemia and AHF.
Anemia is correlated with a higher early and long-term mortality. The relationship between Hb values and mortality was not linear. Patients with lower Hb values (7 g/dL) presented a lower mortality than those with intermediate values. This aspect differs from that seen in patients with chronic heart failure27 and favors the results of older studies which attempted to demonstrate that the relation between Hb values and mortality followed a J curve28. This result may have been due to these patients with such low Hb values having received treatment for anemia early on, whether by transfusion or with intravenous iron, conditioning the prognosis, especially in the short term.
The principal finding of our study is the relationsip between anemia and both short- (30 days) and long-term mortality (at one year), which remained independent of all the confounding factors composed of 56 variables including comorbidity, both basal functional status and dyspnea, chronic treatment of the patient, data of the acute episode, analytical results, treatment administered in the HED and hospital admission or stay in an observation unit. After controlling for these factors, patients with anemia presented an excess of mortality of 30% at 30 days and 30% at one year. The factors which had the greatest impact on this relation and produced a significant change in the HRs were age, sex and comorbidity. Previous studies have analyzed long-term mortality and other prognostic factors such as readmission within 30 days. Our results of mortality at one year are concordant with previous studies which have also observed that the presence of low Hb values is an independent marker of mortality at 3 years, although the survival curves separate from the beginning and become parallel after one year of follow-up16. This may have implications in the follow-up of patients with AHF once the acute phase has been overcome. On one hand, it would be important to establish the etiological diagnosis of anemia to administer treatments targeted at reestablishing Hb values, especially in patients with values for which transfusion is not indicated. Based on the findings of the Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study29,30, the use of is recommended in patients with iron deficiency who do or do not have anemia. Indeed, the clinical guidelines of the ESC22 recommend that this comorbidity should be monitored during the follow-up of these patients. In the analysis of the impact of anemia on mortality at different one month time periods between 30 days and one year, we observed that anemia is independently correlated with early mortality and mortality after 300 days of follow-up, at which time mortality exponentially increases, making close follow-up of these patients necessary in order to control the Hb values.
To our knowledge no study has analyzed the effect of anemia on short-term mortality or has measured the risk of individual mortality at the different time periods analyzed until the end of follow-up. In the case of mortality at 30 days, anemia is an independent marker of risk. This highlights the need for studies on the etiology of anemia at the time of diagnosis in order to implement the most adequate treatment, since anemia is a comorbidity, which, on many occasions, in easily treatable considering that the main causes are usually nutritional deficits, mainly of iron or situations of chronic inflammation which are often found in patients with HF.
LIMITATIONS.
This study has several limitations which should not condition the validity of the results. On one hand, patients with a previous diagnosis of anemia were not recruited and this was established based on the Hb value during care in the HED. On the other hand, it is a study on real-life management of patients with AHF, without intervention and in which the physicians attending the patients did not receive instructions regarding their management. Another limitation is that this was not the principal objective of the study, although it had a multipurpose design. The last limitation is that patient inclusion was based on clinical criteria and patients belonging to a single country, although the participating hospitals were from all around Spain.
Nonetheless, despite these limitations we believe that the results of the ANEM-AHF study including a large registry of patients with AHF attended in HEDs are perfectly valid and can be extrapolated to other similar populations.
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Table 1. Baseline characteristics of the study population and comparison of the characteristics of the patients based on whether they had anemia or not.