Introduction

Anemia is a common condition in patients with chronic heart failure (HF) regardless of the level of left ventricular ejection fraction (LVEF) and is an efficient predictor of readmission and mortality [1,2,3,4]. Although almost half of patients hospitalized with acute heart failure (AHF) are anemic [5], the impact of anemia on prognostic still remains unclear. Data from large registries and randomized controlled trials have shown controversial results implying anemia played a different role in associating with both long-term [6] and short-term [5, 7,8,9,10] with age, gender and renal function adjusted mortality. The pathogenesis of HF-associated anemia considered multifaceted, for instance, volume overload dilution, chronic kidney dysfunction (CKD), malnutrition, and drugs such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) might be the key confounders of mortality in patients with AHF [11]. However, very limited evidence from literature unveiled the relationship of anemia and long-term mortality with key confounders adjusted in this patient population. There are two studies showed that the presence of anemia on admission was associated with an increased risk of mortality [6, 12]; in contrast, a recent report indicated that the relationship between anemia and 1-year outcomes was not associated in multivariate analysis, despite a significant association in univariate analysis [13]. To understand the risk association of anemia and 1-year outcomes in patients with AHF, we evaluated the independent effect of anemia on the clinical outcomes in patients with AHF.

Methods

Study design and data collection

The Beijing Acute Heart Failure Registry (Beijing AHF Registry) study was an observational, patient-centered, prospective, multicenter registry study recruited in a total of 3335 patients with AHF admitted in 14 emergency departments (EDs) in Beijing from 1st January 2011 to 23rd September 2012. It was designed to clarify the profile of AHF patients in Beijing, including demographics and clinical characteristics, current treatments, morbidity or mortality in ED stay and during the follow-up [14]. This study was conducted under the principles of the Declaration of Helsinki. Ethic approval was obtained from Institutional Review Board Approval of Fuwai Hospital (2010, approval number: 218). Data were collected only after detailed information regarding the study was provided and a signed written informed consent has been obtained from each patient.

Patients and definitions

Patients presented any signs and symptoms of HF, as well as one of the following criteria, were defined as AHF: (i) symptomatic lung congestion confirmed via chest X-ray or (ii) objective findings consistent with left ventricular systolic dysfunction. This study analyzed patients enrolled in the Beijing AHF Registry with whose data on hemoglobin (Hb) at admission were available (Fig. 1). According to the World Health Organization (WHO) classification, anemia was defined as Hb < 13.0 g/dl for men and Hb < 12.0 g/dl for women. Among the anemia patients, mild anemia was defined as Hb ≥ 9.1 g/dl, moderate anemia was defined as 6.1 g/dl ≤ Hb < 9 g/dl, and severe anemia was defined as Hb < 6 g/dl [15]. The lower hematocrit was defined as hematocrit < 40% for men and hematocrit < 37% for women. The primary endpoint was all-cause mortality in 1 year, and the secondary endpoint was all-cause events including all-cause death and readmission in 1 year.

Fig. 1
figure 1

Flowchart of the study

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Statistical analysis

Data were reported as the median (with interquartile range, IQR) for continuous variables, or as numbers (percentages) for categorical variables. Mann–Whitney U test and Pearson chi-square (χ2) test for continuous and categorical variables were used respectively to estimate the differences between patients with or without anemia in the baseline. Kaplan–Meier curve and log-rank test were used to analyze the outcomes. Univariate and multivariate logistic regression models were used to analyze the correlation between anemia and age, gender, CKD, white blood cell (WBC) counts, hematocrit, albumin, loop diuretics use, beta-blockers use, ACEIs/ARBs use, spironolactone use in ED. Unadjusted and adjusted Cox proportional hazards regression models were used to estimate the impact of anemia and Hb on clinical outcomes in patients with AHF. Adjustment covariates in the multivariable model included age, female, body mass index (BMI), New York Heart Association (NYHA) functional class IV, cardiovascular ischemia, cardiomyopathy, diabetes mellitus, heart rate (HR), systolic blood pressure (SBP), serum creatinine (Scr), WBC count, hematocrit, diuretics use, beta-blockers use, and ACEIs/ARBs use in the ED. In addition, we performed multivariable Cox regression models for anemia relevant to AHF outcomes in various subgroups divided by age (stratified at 75 years), gender, BMI (stratified at 25 kg/m2), NYHA functional class (I–II vs. III–IV), cardiovascular ischemia, HR (stratified at 100 bpm) SBP (stratified at 120 mmHg), LVEF (stratified at 40%), Scr (stratified at 133 umol/l), diuretic use, beta-blockers and ACEIs/ARBs use in the EDs. All subgroup analyses were fully adjusted with the same covariates in the main multivariable models. Statistical analyses were performed using SAS software (version 9.3, Cary, NC). A 2-sided p value < 0.05 was considered to be statistically significant.

Results

Study population

Of 3335 patients who were originally enrolled in the registry, patients were serially excluded for unavailable Hb data at admission (n = 56). Thus, a total of 3279 patients were eligible for this study, 1490 (45.4%) patients were diagnosed with anemia based on the World Health Organization criteria (Table 1). Among the total cohort, 1137 (34.68%), 295 (9%) and 58 (1.77%) patients were diagnosed with mild, moderate and severe anemia, respectively. The median age of the study population was 71 (IQR 58–79) years old, with 46.9% female, and the median follow-up period was 372 (IQR 366–581) days.

Table 1 Clinical characteristics and management in acute heart failure patients with and without anemia
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Clinical characteristics

Baseline characteristics of AHF population are shown in Table 1. The median Hb of the non-anemic patients was 14.1 (13.3–15.1) g/dl, compared with 10.7 (9.1–11.6) g/dl for anemic patients. The anemic group was significantly older, more female patients, and comorbidities of previous ischemia, diabetes mellitus, hypertension and CKD. Compared with the non-anemic group, lower HR, higher SBP and LVEF, lower hematocrit and serum albumin, higher Scr and BNP/N-terminal pro-BNP (NT-proBNP) was observed in anemic patients. Patients who received intensive diuretics, vasodilators and inotropes intravenously instead of orally in the ED, had higher in-hospital mortality and less compliance after discharged.

Associations between clinical variables and anemia in AHF patients

In multivariate logistic analysis, characteristics including older age, female, CKD, hematocrit and albumin decreasing, loop diuretics applied and beta-blockers, ACEIs/ARBs, spironolactone unapplied in ED were independently associated with the occurrence of anemia in AHF patients. While, previous ischemia, lower WBC count was significantly associated with anemia in univariate logistic regression analysis (Table 2).

Table 2 Univariate and multivariate logistic regression analysis for anemia in patients with acute heart failure
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Associations between anemia and outcomes in AHF patients

The mortality and events including all-cause death and readmission in 1 year both showed significantly higher rates in the patients with anemia (mortality 38.4% vs. 27.2%; events 63.2% vs. 56.7%; p < 0.0001) (Fig. 2a and b). The severer anemia patients had poorer outcomes both of 1-year mortality and events rate. (Fig. 2c and d).

Fig. 2
figure 2

Kaplan–Meier curves of clinical outcomes. a All-cause mortality in 1 year of patients with and without anemia; b all-cause events in 1 year of patients with and without anemia; c all-cause mortality in 1 year of patients with mild, moderate and severe anemia; d all-cause events in 1 year of patients with mild, moderate and severe anemia. Significant differences in outcomes were displayed between patients with and without anemia. Significant differences in outcomes wee also displayed in patients with mild, moderate and severe anemia

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In Cox regression models, anemia was independently associated with mortality (adjusted hazard ratio [HR] 1.278; 95% confidence interval [CI] 1.114–1.465; p = 0.0005) and all-cause events (adjusted HR 1.136; 95% CI 1.025–1.259; p = 0.0154). Moreover, a higher level of hemoglobin (per 1 g/dl) was independently associated with decreasing the risk of all-cause mortality (adjusted HR 0.938; 95% CI 0.912–0.964; p < 0.0001) and all-cause events (adjusted HR 0.965; 95% CI 0.945–0.986; p = 0.0011). The severer anemia patients had higher risks of both 1-year all-cause mortality and events (Table 3).

Table 3 Unadjusted and adjusted Cox regression analysis for 1-year clinical outcomes in patients with acute heart failure
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Figure 3 showed the independent impact of baseline anemia on the risk of mortality rate was significant in the subgroup of patients who were younger than 75 years old, male gender, with BMI < 25 kg/m2 and BMI ≥ 25 kg/m2, with NYHA functional class I-II and NYHA functional class III-IV, with and without cardiovascular ischemia, with HR < 100 bpm and HR ≥ 100 bpm, with SBP < 120 mmHg and SBP ≥ 120 mmHg, with LVEF < 40% and LVEF ≥ 40$, with Scr < 133 umol/l, with diuretics use in ED, with and without beta-blockers use in ED and without ACEIs/ARBs use in ED.

Fig. 3
figure 3

Subgroup analyses for all-cause mortality. ACEI angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, BMI body mass index, HR hazard ratio, LVEF left ventricular ejection fraction, NYHA New York Heart Association, SBP systolic blood pressure, Scr serum creatinine

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Discussion

In this population-based sample of patients hospitalized with AHF, anemia was an independent risk factor for death and events. Approximately half of the AHF patients had anemia on admission. Compared with non-anemia, anemic patients were significantly older, more female, with more comorbidities, presented a lower HR, higher SBP and an elevated BNP/NT-proBNP level, and received less guideline-recommended HF therapies. Several characteristics of AHF patients including older age, male, CKD, hematocrit and albumin decreasing, loop diuretics applied and beta-blockers, ACEIs/ARBs, spironolactone unapplied in ED were independently associated with anemia on admission. Higher mortality and events (all-cause death or readmission rate) were found in patients with anemia, and correspondence with the severity of anemia. On admission anemia was independently associated with a 27.8% increased risk of mortality and 13.6% increased risk of events in 1 year in patients with AHF.

Previous studies showed that the prevalence of anemia was relatively high in AHF patients (33–59.6%) who were older, not overweight, with ischemia etiology, with preserved ejection fraction and elevated creatinine, with intensive diuretics use [5, 6, 16, 17]. The prevalence of anemia in our data (47.3%) and baseline characteristics of patients with anemia were similar to these previous reports. Although pathogeneses of anemia in AHF are still unclear, hemodilution, inflammation, malnutrition (iron deficiency) and erythropoietin levels might be the main reasons for anemia in patients with AHF, and erythropoietin levels were affected by kidney function, medication of ACEIs/ARBs and beta-blockers [18]. In our study, CKD as well as hematocrit and albumin decreasing, on loop diuretics in ED, malnutrition and volume overload were all independently associated with anemia in AHF patients. Contrary to previous report [18], medication of beta-blockers, ACEIs/ARBs and spironolactone was less likely to develop anemia in patients with AHF. This may because patients with guideline-recommended therapy were more compliance with doctors’ advice and less severe ill. More evidence should be investigated in the impact of guideline-recommended medications on anemia occurrence in patients with AHF. Interestingly, HF patients with iron deficiency who treated with intravenous iron showed an improvement in the quality of life, exercise tolerance, and NYHA [19, 20]. Moreover, in the CONFIRM-HF trial [21], intravenous iron therapy was associated with a remarkable reduction in rehospitalizations for worsening HF and with an insignificant reduction of mortality.

A study of 182 patients from Von Haehling [12] showed patients with moderate or severe anemia had a significantly increased 12-month mortality after adjusting for age, NYHA functional class, systolic and diastolic blood pressure, and creatinine, which indicated anemia was an independent predictor of death. This finding is similar to ours. Recent reports [6, 12, 13] indicated that the anemia was associated with increased 1-year mortality. While independent associations between anemia and 1-year clinical outcomes were also showed after covariate adjusted in our study. Furthermore, events were increasing correspondence to the severity of anemia. And independent associations of continuous hemoglobin levels with clinical outcomes were also displayed in our study. Similar results could be found in the previous report, there was an inverse relationship between the risk of death and hemoglobin level that seems “almost linear” [8]. The continuous hemoglobin levels may reflect the over load volume, malnutrition, and severity of illness in the certain degree. In addition, anemia was diagnosed with certain levels of hemoglobin. The points above could explain the linear relationship between hemoglobin and outcomes risks.

Consistent with a previous study [6], we also found that the presence of anemia on admission was associated with a significantly increased mortality in patients with age < 75 years than 75 years or older. Anemia appears to be more common in older patients with AHF, however, the interaction of anemia, age and clinical outcomes is still unclear. Similar to Duncan [22] found that anemia affected mortality in patients of both genders with chronic HF but this effect is weaker in women, the impact of baseline anemia on mortality was more significant in male patients.

Whether the impact of anemia differs by heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction is uncertain. The associations of anemia with 1-year mortality were both independently significant in patients with HFrEF and HFpEF, and the risk was higher in the HFpEF subgroup in our study. In an observational cohort, anemia was associated with patients with HFrEF instead of HFpEF after adjusted analysis [23]. While in another HFrEF cohort, there was no association of anemia at admission with all-cause mortality [17]. The incremental risks of death associated with anemia are more pronounced in AHF patients classified with HFpEF than HFrEF [24]. Previous report showed that anemic patients with HFpEF were less often treated with diuretics, and that anemia was only associated with diuretics in patients with HFrEF [24]. This raises the possibility that hemodilutional anemia prevalence may differ by HF type. In a small study involving 46 ambulatory HF patients identified with anemia, the examination of plasma volume by I-131 labeled albumin revealed 12% with HFpEF to be hemodilutional, compared to 41% with HFrEF [25]. In the PROTECT trial, involving 1969 patients hospitalized with HFrEF, hemoglobin levels were closely monitored by measurements on days 1–4 and day 7 of the hospitalization. Short term improvement in hemoglobin levels was attributed to diuresis and abatement of hemodilution, and associated with better mortality outcome [26]. The disparity in relative outcomes that we observed among anemic HFpEF and HFrEF patients may relate to differing anemia etiologies.

Low erythropoietin levels are associated with CKD and inhibition of angiotensin II [18]. That is, in the subgroups of AHF patients with Scr ≥ 133 umol/l and with ACEIs/ARBs medication were more likely to be anemic. While CKD and ACEIs/ARBs medication were two important independent prognostic factors for AHF, that anemia contributes little to mortality relative to these two confounders.

Study limitations

This is a retrospective study collecting the patient data from a registry. The dynamic changes of Hb level in follow up were not considered. Second, the pathogeny of anemia was unknown, especially data on iron deficiency were not collected. Because different types of anemia may have different prognostic impacts, this issue also remains to be investigated in future studies. Finally, this is an observational study with Chinese AHF patients, caution should be taken when generalizing the present findings to other populations.

Conclusions

Anemia is an independent risk factor for 1-year outcomes in patients with AHF. It is associated with age, cardiovascular ischemia and comorbidities, and increased the mortality and events in AHF, particularly in younger, male, less severe heart failure, and overweight individuals.