Original ArticlesEpidemiology and Outcomes

Associations of Anemia and Renal Dysfunction with Outcomes among Patients Hospitalized for Acute Decompensated Heart Failure with Preserved or Reduced Ejection Fraction

Katsuya Kajimoto, Naoki Sato, Takehiko Keida, Yasushi Sakata and Teruo Takano
CJASN November 2014, 9 (11) 1912-1921; DOI: https://doi.org/10.2215/CJN.04400514

Abstract

Background and objectives The relationship among anemia, renal dysfunction, left ventricular ejection fraction, and outcomes of patients hospitalized for acute decompensated heart failure is unclear. The aim of this study was to evaluate the association between cardiorenal anemia syndrome and postdischarge outcomes in patients hospitalized for heart failure with a preserved or reduced ejection fraction.

Design, setting, participants, & measurements Of 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes Registry between April 1, 2007 and December 31, 2011, 4393 patients were evaluated to investigate the association among anemia, renal dysfunction, preserved or reduced ejection fraction, and the primary end point (mortality and readmission for heart failure since discharge). The patients were divided into four groups on the basis of eGFR and hemoglobin at discharge. The median follow-up period after discharge was 432 (range=253–659) days.

Results The primary end point was reached in 37.6% and 34.8% of the preserved and reduced ejection fraction groups, respectively. After adjustment for multiple comorbidities, there was no significant association of either renal dysfunction or anemia alone with the primary end point in patients with preserved ejection fraction, but the combination of renal dysfunction and anemia was associated with a significantly higher risk than that without either condition (hazard ratio, 1.54; 95% confidence interval, 1.12 to 2.12; P<0.01). In patients with reduced ejection fraction, adjusted analysis showed that a significantly higher risk of the primary end point was associated with renal dysfunction alone (hazard ratio, 1.65; 95% confidence interval, 1.21 to 2.25; P=0.002) and also, renal dysfunction plus anemia relative to the risk without either condition (hazard ratio, 2.19; 95% confidence interval, 1.62 to 2.96; P<0.001).

Conclusions The findings show that renal dysfunction combined with anemia is associated with an increased risk of adverse postdischarge outcomes in patients with preserved ejection fraction, whereas renal dysfunction is an independent predictor of the risk of adverse outcomes in patients with reduced ejection fraction, regardless of anemia.

Introduction

Renal impairment is a common risk factor for morality in patients with heart failure (HF) (1–4). It was recently reported that anemia is frequent in patients with chronic HF (5–8). HF may precipitate renal failure, because a decrease of cardiac output reduces renal perfusion, whereas renal failure may inhibit erythropoietin production and ultimately, induce anemia, leading to an increase of cardiac workload that completes a vicious circle (9–11). Thus, it has been reported that CKD, chronic HF, and anemia have an additive effect on mortality. It is the so-called cardiorenal anemia syndrome (12). However, the association of this syndrome with postdischarge outcomes of HF has not been fully investigated in patients with a preserved or reduced left ventricular ejection fraction (LVEF). Recently, it has been suggested that patients hospitalized for HF are recognized to be at substantially higher risk for mortality in the period early after discharge, although the majority of patients with HF is judged to be stable at discharge (13,14). Therefore, we evaluated the association of anemia and/or renal dysfunction at discharge with postdischarge outcomes in patients with HF discharged alive after hospitalization for acute decompensated HF with a preserved or reduced ejection fraction (EF).

Materials and Methods

Study Design and Data Collection

As a nationwide prospective observational multicenter cohort study, the Acute Decompensated Heart Failure Syndromes (ATTEND) Registry Study accumulates data on patients with acute decompensated HF admitted to 53 hospitals in Japan (Supplemental Material). The data included in this study were collected from April 1, 2007, to December 31, 2011. The study design and methods as well as the patient profile have been described previously (15). Briefly, the ATTEND Study aims to clarify the features of acute decompensated HF, including the demographic and clinical characteristics of the patients, current treatment, in-hospital mortality, and morbidity or mortality after discharge. Treatment is not specified, and therefore, management of acute HF is selected by the attending physician. The information obtained about the registered patients includes their demographic data, medical history, baseline characteristics, initial evaluation, treatment, procedures, hospital course, and disposition. This study was conducted in accordance with the principles of the Declaration of Helsinki. Institutional review board approval was obtained at each participating medical center before the study, and all patients gave written informed consent to enrollment. The end point classification committee (two experienced cardiologists who were not investigators) reviewed the data and if any problems were encountered, asked the primary physician to confirm the cause of death. The median follow-up period after discharge was 432 (range=253–659) days.

Patients and Definitions

The ATTEND Registry Study targets consecutive eligible patients with a discharge diagnosis of acute decompensated HF. Inpatients with acute decompensated HF who meet the modified Framingham criteria are eligible for inclusion in the registry if acute decompensated HF is the primary reason for admission to hospital (16). Patients ages<20 years old, those with acute coronary syndrome, and others considered unsuitable for the study by the attending physician are excluded. A preserved EF was defined as LVEF>40% or qualitative assessment of LVEF as normal to mildly impaired at admission, whereas a reduced EF was defined as LVEF≤40% or moderate to severe left ventricular systolic dysfunction on qualitative assessment at admission. Renal dysfunction was defined as an eGFR<60 ml/min per 1.73 m2 at discharge: eGFR=194×(serum creatinine−1.094)×(age−0.287)×0.739 (for women) (17). Anemia was defined according to the World Health Organization classification as a hemoglobin (Hb)<13.0 g/dl for men and <12.0 g/dl for women at discharge (5,18). The patients were divided into four groups on the basis of their eGFR and Hb values at discharge. Patients in group 1 had an eGFR≥60 ml/min per 1.73 m2 without anemia, whereas group 2 had an eGFR≥60 ml/min per 1.73 m2 with anemia, group 3 had an eGFR<60 ml/min per 1.73 m2 without anemia, and group 4 had an eGFR<60 ml/min per 1.73 m2 with anemia. Using these four groups, we investigated the association of renal dysfunction and/or anemia with the outcomes after discharge in patients with a preserved or reduced EF. The primary outcome was a combination of all-cause death and readmission for HF.

Statistical Analyses

Data are presented as the mean (SD), median with interquartile range, or proportion. One-way ANOVA or Kruskal–Wallis H test was used for an omnibus test among groups; t or Mann–Whitney U test was used for between-group comparison when appropriate. The chi-squared test was used to compare variables across nominal categorical variables. Univariate and multivariate analyses on the basis of the Cox proportional hazards model were performed to test the association of candidate variables with the primary outcome. The multivariate model included variables that were predictors of mortality or morbidity on univariate analysis as well as other factors known to influence the outcome after hospital discharge: age, sex, ischemic etiology, hypertension, diabetes, readmission for HF, New York Heart Association (NYHA) functional class, body mass index, systolic BP, brain natriuretic peptide, use of spironolactone, use of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, use of β-blocker, use of aspirin, and use of warfarin at discharge. The P value of linear trend test when group variables were a continuation level was also calculated in this model. The influences of profile, interaction, and multicollinearity in these models were examined by regression diagnostic analysis. Two-tailed P values <0.05 were considered to indicate statistical significance. An independent statistical data center (STATZ Institute, Inc., Tokyo, Japan) performed all analyses using SAS system version 9.3 software (SAS Institute, Cary, NC).

Results

Baseline Characteristics of the HF Patients at Discharge from Hospital

Among 4842 patients entered into the ATTEND Registry between April 1, 2007, and December 31, 2011, 4530 patients were discharged alive after presenting with acute decompensated HF. Of these 4530 patients, 4393 (97.0%) patients with data on Hb at discharge, eGFR at discharge, and LVEF and postdischarge follow-up information were included in this analysis. The median follow-up period after discharge was 432 (253–659) days. Of 4393 patients analyzed, 2393 (54.5%) patients had a reduced EF. In patients with a preserved EF, 72.8% had renal dysfunction, and 68.0% had anemia at discharge (Table 1). In patients with a reduced EF, 70.2% had renal dysfunction, and 54.3% had anemia at discharge, indicating that this cohort had a high prevalence of renal dysfunction or anemia in both EF groups (Table 2). The combined end point (all-cause death and readmission for HF) was reached by 37.6% of patients with a preserved EF and 34.8% of patients with a reduced EF.

View this table:
Table 1.

Baseline characteristics of patients with HF and preserved EF stratified by renal dysfunction and anemia

View this table:
Table 2.

Baseline characteristics of patients with HF and reduced EF stratified by renal dysfunction and anemia

Demographic Profiles of the Groups Stratified by Renal Dysfunction and Anemia at Discharge

The baseline clinical characteristics of the four groups obtained through stratification by renal dysfunction and anemia at hospital discharge are shown in Tables 1 and 2 for patients with preserved and reduced EFs, respectively. In patients with a preserved EF, there were no significant differences of sex, hypertensive or valvular etiology, stroke, and frequency of NYHA functional class III or IV at discharge among the four groups. The patients with anemia (groups 2 and 4) were significantly older, had a lower body mass index, were more likely to have ischemic HF, and were less likely to have atrial fibrillation at discharge compared with those without anemia (groups 1 and 3). For patients with a reduced EF, the patients with anemia (groups 2 and 4) had a significantly lower body mass index, were more likely to have an ischemic or idiopathic dilated etiology, and were less likely to have atrial fibrillation at discharge compared with patients who did not have anemia (groups 1 and 3). In both EF groups, the presence of both renal dysfunction and anemia was significantly associated with higher brain natriuretic peptide levels at discharge compared with the other three groups.

Outcomes of Patients Stratified by Renal Dysfunction and Anemia at Discharge

Figure 1A shows the unadjusted relationship between anemia and the combined end point of all-cause mortality and readmission for HF in patients with preserved EF with and without renal dysfunction at discharge. According to univariate analysis, patients with either anemia alone or both renal dysfunction and anemia had a higher rate of reaching the combined end point than patients with neither renal dysfunction nor anemia in the preserved EF group, whereas renal dysfunction alone did not increase this risk (Table 3). When multivariate analysis was done, adjustment for multiple comorbidities attenuated the association of anemia with the end point, although patients with both renal dysfunction and anemia still had a significantly higher risk (hazard ratio [HR], 1.54; 95% confidence interval [95% CI], 1.12 to 2.12; P<0.01) than patients with neither condition. Figure 1B shows the unadjusted relationship between anemia and the combined end point of all-cause mortality and readmission for HF in patients with reduced EF with and without renal dysfunction at discharge. The unadjusted HRs revealed a significantly higher risk of the combined end point in patients who had anemia, renal dysfunction, or both compared with patients who had neither condition (Table 4). Adjusted HRs showed a significantly higher risk for patients who had renal dysfunction (HR, 1.65; 95% CI, 1.21 to 2.25; P=0.002) and patients with both anemia and renal dysfunction (HR, 2.19; 95% CI, 1.62 to 2.96; P<0.001) relative to patients with neither condition. However, there was no significant association of anemia alone with the risk of reaching the end point in the reduced EF group. Furthermore, when we examined the interaction between renal dysfunction and preserved or reduced EF with respect to the combined end point, the association of renal dysfunction with the end point was significantly greater in patients with reduced EF than patients with preserved EF (P=0.01 for the interaction).

Figure 1.
Figure 1.

Kaplan–Meier estimates of the combined end point (mortality and readmission for HF) in four groups stratified by renal dysfunction and anemia at discharge. (A) Patients with HF and preserved EF. (B) Patients with HF and reduced EF. EF, ejection fraction; HF, heart failure.

View this table:
Table 3.

Unadjusted and adjusted risks of postdischarge mortality and readmission for HF in patients with preserved EF stratified by renal dysfunction and anemia

View this table:
Table 4.

Unadjusted and adjusted risks of postdischarge mortality and readmission for HF in patients with reduced EF stratified by renal dysfunction and anemia

Discussion

In patients with HF discharged alive after hospitalization for acute decompensated HF, this study revealed three main findings. First, anemia at discharge was a marker for a higher risk of the primary outcome (mortality and readmission for HF) rather than a direct risk factor in both EF groups. Second, renal dysfunction at discharge was an independent predictor of the primary outcome in patients with reduced EF, whereas it was not association with the primary outcome in patients with preserved EF. Third, the combination of anemia and renal dysfunction at discharge was an independent predictor of the primary outcome in both EF groups.

It was recently reported that patients with HF with anemia are more likely to have concomitant renal dysfunction and that a lower Hb is associated with higher mortality among patients with HF (19). In addition, some previous studies have found an independent effect of anemia on the outcome after adjustment for renal function (20,21). However, we found no adverse influence of anemia without renal dysfunction on the adjusted risk of postdischarge outcomes in both EF groups. There are several possible explanations for our findings. First, anemia decreases the oxygen-carrying capacity of the blood, which is mainly compensated for by an increase of the heart rate and stroke volume, resulting in an increase of cardiac output and maintenance of tissue oxygenation. This adaptive response may occur in patients without renal dysfunction from both EF groups (7,21). Second, previous studies evaluated the relation between Hb at admission (decompensated HF) and outcomes, whereas we evaluated the association of outcomes with the Hb at discharge (compensated HF). It has been reported that patients who have HF and anemia with hemodilution have a worse prognosis than patients who have HF and true anemia, suggesting that volume overload may make an important contribution to the poor outcome of patients who have HF and anemia (22). Also, it has been suggested that investigating Hb at discharge minimizes the influence of hemodilutional anemia (23). Accordingly, nonhemodilutional anemia without renal dysfunction may have little influence on the long-term prognosis of patients with HF. Third, it has been reported that the contribution of anemia to a higher risk of mortality is dependent on the degree of renal dysfunction (8,9,24), likely reflecting the dominant effect of renal dysfunction on clinical outcomes in the cardiorenal anemia syndrome. Thus, in both EF groups, anemia alone may not be a key factor in the exacerbation of chronic HF. Recently, the Reduction of Events with Darbepoetin Alfa in Heart Failure (RED-HF) Trial showed that the correction of anemia with the use of an erythropoiesis-stimulating agent was not associated with a reduced risk of death or hospitalization for HF in patients who have HF and anemia (25). However, approximately 30% of the patients enrolled in the RED-HF had anemia but not renal dysfunction (eGFR<60 ml/min per 1.73 m2), suggesting that these patients may not be associated with adverse outcomes. Therefore, in the setting of HF, additional prospective study is needed to clarify whether there are subgroups of patients with anemia who may benefit from erythropoiesis-stimulating agent treatment (26).

Renal dysfunction and anemia have an additive effect on the mortality of HF (9–11,23). However, it has been unclear whether renal dysfunction alone without anemia is associated with HF mortality, particularly when patients are stratified into groups with a preserved or reduced EF. Our results showed that renal dysfunction was associated with postdischarge outcomes in patients with a reduced EF rather than those with a preserved EF. The mechanism of this difference with respect to the association of renal dysfunction with the long-term prognosis is not entirely clear. However, it has been reported that both a decrease of the eGFR and a lower LVEF were significant independent predictors of a worse outcome of HF and that decreases of eGFR and EF have an additive effect on predicted mortality (27). Accordingly, in patients with HF with a preserved EF, it seems that renal dysfunction itself may not be a key factor in the exacerbation of chronic HF.

It was reported that the cardiorenal anemia syndrome is a risk factor for higher mortality in patients with chronic HF and a reduced EF (11,12,23). We found that the presence of both anemia and renal dysfunction at discharge was an independent predictor of outcomes in both the preserved and reduced EF groups. The mechanism of this association is not entirely clear, but the following factor can be suggested. Recently, it has been reported that inflammation and increased cytokine production occur with HF and can suppress erythrocytosis by the bone marrow, suggesting that HF causes anemia of chronic disease through cytokine-mediated bone marrow suppression (4). Additionally, when worsening renal function occurs in patients with HF, relative erythropoietin deficiency may ensue (4). Thus, in both EF groups, the combination of renal dysfunction and anemia in patients with HF may be associated with elevated inhibitory cytokine levels for morbidity and mortality (24). Furthermore, our findings showed that the higher risk associated with renal dysfunction and anemia in the reduced EF group is largely explained by the association of renal dysfunction alone, whereas together, they are predictive in the preserved EF group, because there was no significant association of either factor alone with the outcome in this group. Thus, there were major differences between the preserved EF and reduced EF groups with respect to the association of renal dysfunction and/or anemia with postdischarge outcomes, although the reasons remain unclear. Accordingly, additional investigation will be needed to clarify the mechanisms underlying the association of renal dysfunction and anemia with postdischarge outcomes in patients with HF and preserved or reduced EF.

There are several limitations that should be considered when interpreting the results of this study. First, eGFR and Hb were assessed at a single point in time (at discharge), and thus, we did not address the association of changes in renal function and anemia with risk (possibly related to therapy). Recently, it was suggested that the correction of anemia in patients with HF and renal dysfunction may prevent the progression of both conditions (23). Additionally, it was reported that changes in Hb over 12 months were inversely associated with risk of morbidity and mortality, independent of the effects of baseline anemia (28). Accordingly, prospective investigations will be needed to clarify the association between the changes in eGFR and Hb during follow-up and postdischarge outcomes in patients with HF. Second, our definitions of renal dysfunction and anemia were obtained from published studies rather than recategorization of raw data (2,17,18), because there is no specific Hb or eGFR value that is universally accepted as defining clinically relevant renal dysfunction or anemia in patients with HF. Because the prognosis may have been influenced by the definitions that we used (11), additional investigations will be needed to clarify the association between the severity of renal dysfunction or anemia and clinical outcomes in patients with HF. Third, we could not investigate the etiology of anemia in our subjects (iron deficiency, renal, etc.), although the causes of anemia in patients with HF are likely to be multiple and complex. Moreover, the presence of anemia at discharge may be associated with a removal of blood for tests during hospitalization. Fourth, although anemia was a marker for a higher risk of adverse events rather than a direct risk factor in both EF groups, the lack of significance may be a result of sample size.

In conclusion, our study showed that the presence of both renal dysfunction and anemia was predictive for postdischarge outcomes in patients with preserved EF, whereas renal dysfunction was an independent predictor of the outcome in patients with reduced EF, regardless of whether they had anemia. After hospitalization for acute decompensated HF, patients who had a preserved or reduced EF showed differences with respect to the association of renal dysfunction and/or anemia at discharge from hospital with the outcome after discharge. Therefore, a better understanding of the pathophysiology of HF associated with renal dysfunction and/or anemia at discharge is needed to develop targeted therapy that can improve postdischarge prognosis of patients hospitalized for HF.

Disclosures

None.

Acknowledgments

We thank the study investigators for their contributions. We also thank Katsunori Shimada (STATZ Institute, Inc., Tokyo, Japan) for his expert assistance with the statistical analyses.

The study was supported by the Japan Heart Foundation on the basis of a statement issued by the International Committee of Medical Journal Editors in September of 2004, which had no role in the conduct of the study. The funding for statistical support and administration in the study was accepted.

Before the launch of the Acute Decompensated Heart Failure Syndromes (ATTEND) Registry Study, information on the objectives of this study, its social significance, and an abstract were provided for clinical trail registration with the University Hospital Medical Information Network (UMIN; Clinical Trail Registration ID UMIN000000736)

Footnotes

  • Received May 5, 2014.
  • Accepted July 16, 2014.

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Associations of Anemia and Renal Dysfunction with Outcomes among Patients Hospitalized for Acute Decompensated Heart Failure with Preserved or Reduced Ejection Fraction
Katsuya Kajimoto, Naoki Sato, Takehiko Keida, Yasushi Sakata, Teruo Takano
CJASN Nov 2014, 9 (11) 1912-1921; DOI: 10.2215/CJN.04400514
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