9-Year Trend in the Management of Acute Heart Failure in Japan: A Report From the National Consortium of Acute Heart Failure Registries.

Background Acute heart failure ( AHF ) is a heterogeneous condition, and its characteristics and management patterns differ by region. Furthermore, limited evidence is available on AHF outside of Western countries. A project by the National Consortium of Acute Heart Failure Registries was designed to evaluate the trends over time in patient backgrounds, in-hospital management patterns, and long-term outcomes of patients with AHF over 9 years in Japan. Methods and Results Between 2007 and 2015, registry data for patients with AHF were collected from 3 large-scale quality AHF registries ( ATTEND / WET - HF / REALITY - AHF ). Predefined end points were trends over time in age, sex, and clinical outcomes, including short- and long-term mortality and readmission for heart failure. The final data set consisted of 9075 patients with AHF . No significant differences in patient backgrounds and laboratory findings (eg, anemia or renal function) were observed, with the exception of patient age; mean age became substantially higher over 9 years (71.6-77.0 years; P for trend, <0.001). On the contrary, length of hospital stay became shorter (mean, 26-16 days). These changes were not associated with in-hospital mortality (4.7-7.5%) or 30-day heart failure readmission rate (4.8-5.4%), as well as 1-year mortality and heart failure readmission rate (20.1-23.3% and 23.6-26.2%, respectively). Conclusions Length of hospital stay in patients with AHF shortened over the 9-year period despite the increasing age of the patients. However, short- and long-term outcomes do not seem to be affected; continuous efforts to monitor clinical outcomes in patients with AHF are needed.

Trends and predictors of non-cardiovascular death in patients hospitalized for acute heart failure.

BACKGROUND: Little information is available on non-cardiovascular (CV) death in acute heart failure (AHF) patients. The present study determined the incidence, time course, and factors associated with long-term non-CV death in AHF patients in a real-world setting. METHODS: The ATTEND registry, a nationwide, prospective observational multicenter cohort study, included 4842 consecutive patients hospitalized for AHF. The primary endpoint of the present study was non-CV death. RESULTS: Median follow-up duration from admission was 513 (range, 385-778) days. Over the study period, 1183 patients died; 356 deaths (30.1%) were non-CV related. The proportion of non-CV deaths increased in the later follow-up phase (0-180days, 26.7%; 181-360days, 38.4%; >360days, 36.6%, p<0.001). After adjustment for all variables at baseline, age (hazard ratio [HR] 1.6 per decade, p<0.001) and non-cardiac comorbidities including chronic obstructive pulmonary disease (HR 1.58, p=0.003), history of stroke (HR 1.44, p=0.011), renal insufficiency (HR 1.07, per 10ml/min/1.73m2 decrease in estimated glomerular filtration, p=0.015), and hemoglobin (HR 1.15 per 1.0g/dl decrease, p<0.001) were strongly associated with non-CV death. Other predictors included ischemic etiology (HR 1.33, p=0.023), prior hospitalization for heart failure (HR 1.34, p=0.017), C-reactive protein (HR 1.04, p<0.001), and statin use (HR 0.70, p=0.016). CONCLUSIONS: The incidence of non-CV death was high in patients with AHF, accounting for 30% of long-term mortality. Furthermore, the proportion of non-CV death increased in the later follow-up phase. Better understanding of non-CV death and more comprehensive treatment of non-CV comorbidities are vital to further improving prognosis in AHF patients.

C-reactive protein level on admission and time to and cause of death in patients hospitalized for acute heart failure.

Aims: We analysed the association between C-reactive protein (CRP) levels measured on admission and timing and cause of death among patients hospitalized for acute heart failure (AHF). Methods and Results: The ATTEND study prospectively registered 4777 hospitalized AHF patients with data on CRP levels on admission. Mortality risks were assessed by univariable and multivariable Cox proportional and non-proportional hazards models. The overall median CRP level was 5.8 mg/L (intertertile range: 2.9-11.8 mg/L). There were significant increases in all-cause, cardiac, and non-cardiac mortalities from the lowest to highest CRP tertiles throughout the follow-up periods. Within 120 days after admission, CRP levels in the highest tertile (>11.8 mg/L) were independently associated with higher all-cause (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.69-2.88; P < 0.001), cardiac (HR, 1.88; 95% CI, 1.37-2.58; P < 0.001), and non-cardiac (HR, 3.21; 95% CI, 1.94-5.32; P < 0.001) deaths, while levels in the second tertile (2.9-11.8 mg/L) were not associated with poorer survival, compared with levels in the first tertile (<2.9 mg/L). However, in terms of cardiac death, the hazard ratios for patients in the third tertile decreased markedly with time and only CRP levels in second tertile were independently associated with poorer cardiac survival after the follow-up period of 120 days (HR, 1.44; 95% CI, 1.09-1.89; P = 0.011). Conclusions: Markedly elevated CRP levels at admission in patients with AHF may be associated with higher short-term cardiac and non-cardiac mortalities. In addition, modestly elevated CRP levels may be associated with higher mortality, especially cardiac mortality, after 120 days of long-term follow-up.

Relationship of renal insufficiency and clinical features or comorbidities with clinical outcome in patients hospitalised for acute heart failure syndromes.

BACKGROUND: Renal insufficiency is a well-known predictor of adverse events in patients with acute heart failure syndromes (AHFS). However, it remains unclear whether there are subgroups of AHFS patients in whom renal insufficiency is related to a higher risk of adverse events because of the heterogeneity of this patient population. Therefore, we investigated the relationship between renal insufficiency, clinical features or comorbidities, and the risk of adverse events in patients with AHFS. METHODS AND RESULTS: Of 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4628 patients (95.6%) were evaluated in the present study in order to assess the relationship of renal insufficiency and clinical features or comorbidities with all-cause mortality after admission. Renal insufficiency was defined as an estimated creatinine clearance of ⩽40 mL/min (calculated by the Cockcroft-Gault formula) at admission. The median follow-up period after admission was 524 (391-789) days. The all-cause mortality rate after admission was significantly higher in patients with renal insufficiency (36.7%) than in patients without renal insufficiency (14.4%). Stratified analysis was performed in order to explore the heterogeneity of the influence of renal insufficiency on all-cause mortality. This analysis revealed that an ischaemic aetiology and a history of diabetes, atrial fibrillation, serum sodium, and anaemia at admission had significant influences on the relationship between renal insufficiency and all-cause mortality. CONCLUSIONS: The present study demonstrated that the relationship between renal insufficiency and all-cause mortality of AHFS patients varies markedly with clinical features or comorbidities and the mode of presentation due to the heterogeneity of this patient population.

Incidence and predictors of in-hospital non-cardiac death in patients with acute heart failure.

BACKGROUND: Patients with acute heart failure (AHF) commonly have multiple co-morbidities, and some of these patients die in the hospital from causes other than aggravated heart failure. However, limited information is available on the mode of death in patients with AHF. Therefore, the present study was performed to determine the incidence and predictors of in-hospital non-cardiac death in patients with AHF, using the Acute Decompensated Heart Failure Syndromes (ATTEND) registry Methods: The ATTEND registry included 4842 consecutive patients with AHF admitted between April 2007-September 2011. The primary endpoint of the present study was in-hospital non-cardiac death. A stepwise regression model was used to identify the predictors of in-hospital non-cardiac death. RESULTS: The incidence of all-cause in-hospital mortality was 6.4% ( n=312), and the incidence was 1.9% ( n=93) and 4.5% ( n=219) for non-cardiac and cardiac causes, respectively. Old age was associated with in-hospital non-cardiac death, with a 42% increase in the risk per decade (odds 1.42, p=0.004). Additionally, co-morbidities including chronic obstructive pulmonary disease (odds 1.98, p=0.034) and anaemia (odds 1.17 (per 1.0 g/dl decrease), p=0.006) were strongly associated with in-hospital non-cardiac death. Moreover, other predictors included low serum sodium levels (odds 1.05 (per 1.0 mEq/l decrease), p=0.045), high C-reactive protein levels (odds 1.07, p<0.001) and no statin use (odds 0.40, p=0.024). CONCLUSIONS: The incidence of in-hospital non-cardiac death was markedly high in patients with AHF, accounting for 30% of all in-hospital deaths in the ATTEND registry. Thus, the prevention and management of non-cardiac complications are vital to prevent acute-phase mortality in patients with AHF, especially those with predictors of in-hospital non-cardiac death.

Serum sodium concentration, blood urea nitrogen, and outcomes in patients hospitalized for acute decompensated heart failure.

BACKGROUND: This study investigated the association of a low serum sodium and elevated blood urea nitrogen (BUN) with outcomes in acute decompensated heart failure (HF) patients. METHODS: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4438 patients discharged after hospitalization for acute decompensated HF were investigated to assess the association of a low serum sodium and/or elevated BUN at discharge with all-cause mortality. The patients were divided into four groups based on serum sodium (>136 or ≤136mEq/l) and BUN (<25 or ≥25mg/dl) at discharge. The median follow-up period after discharge was 517 (381-776) days. RESULTS: According to multivariate analysis, a low serum sodium (≤136mEq/l) or an elevated BUN (≥25mg/dl) was significantly associated with a higher risk of all-cause death compared with patients who had neither (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.22 to 1.94; P<0.001 and HR, 1.44; 95% CI, 1.19 to 1.73; P<0.001, respectively). Patients with both low serum sodium and elevated BUN had a higher risk of all-cause death relative to patients with neither (HR, 2.64; 95% CI, 2.17 to 3.20; P<0.001) and also relative to patients with either low serum sodium alone or elevated BUN alone (HR, 1.72; 95% CI, 1.36 to 2.18; P<0.001 and HR, 1.84; 95% CI, 1.53 to 2.21; P<0.001, respectively). CONCLUSION: These findings demonstrated that a low serum sodium and an elevated BUN may be additive risk factors for postdischarge mortality in acute decompensated HF patients.

Functional mitral regurgitation at discharge and outcomes in patients hospitalized for acute decompensated heart failure with a preserved or reduced ejection fraction.

AIMS: The relationship between functional mitral regurgitation (FMR), left ventricular ejection fraction (EF), and outcomes is unclear in acute decompensated heart failure (HF) patients. The aim of this study was to evaluate the relationship between FMR and post-discharge outcomes in HF patients with a preserved or reduced EF. METHODS AND RESULTS: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 3357 patients were evaluated to assess the association among FMR (none, mild, or moderate/severe) at discharge, a preserved or reduced EF, and the primary endpoint (all-cause mortality and readmission for HF). The median follow-up period after discharge was 530 (387-800) days. According to multivariate analysis, patients with either mild FMR or moderate/severe FMR from the preserved EF group had a significantly higher risk of reaching the endpoint than patients without FMR [hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.14-1.72; P = 0.001 and HR 1.40; 95% CI 1.09-1.81; P = 0.009, respectively]. In the reduced EF group, patients with moderate or severe FMR had a significantly higher risk relative to patients without FMR (HR 1.41; 95% CI 1.07-1.86; P = 0.015), but there was no significant association of mild FMR with the risk of reaching the endpoint (HR 1.09; 95% CI 0.84-1.42; P = 0.510). CONCLUSION: Our findings demonstrate that even mild FMR is associated with an increased risk of adverse outcomes in HF patients with a preserved EF, while moderate or severe FMR (but not mild FMR) is associated with adverse outcomes in HF patients with a reduced EF.

Heterogeneity of the prognostic significance of B-type natriuretic peptide levels on admission in patients hospitalized for acute heart failure syndromes.

BACKGROUND: We hypothesized that variation in baseline characteristics of patients with acute heart failure syndromes (AHFS) affects the prognostic significance of B-type natriuretic peptide (BNP) levels because of heterogeneity of this patient population. We evaluated the association of elevated BNP levels on admission with an increased risk of adverse clinical outcomes in subgroups of patients hospitalized for AHFS. METHODS: This study included patients from the acute decompensated heart failure syndromes (ATTEND) study, a multicenter prospective cohort of 4501 AHFS patients with BNP data on admission. RESULTS: The geometric mean BNP level was 654.9pg/mL (95% confidence interval: 636.1-674.2), and the optimal cut-off value for all-cause death was 1157pg/mL. All-cause mortality after admission was significantly higher in patients with high BNP levels (>1157pg/mL) than in those with low BNP levels (≤1157pg/mL) (median follow-up: 508days, log-rank P<0.001). Subgroup analyses were performed to evaluate the heterogeneity of the prognostic significance of BNP levels. The effect of high BNP levels on the risk of all-cause mortality was significantly greater in the subgroup of patients with a non-hypertensive etiology, low creatinine levels (<1.3mg/dL), and high sodium levels (≥135mEq/L) than in those without these factors (P=0.024, P<0.001, and P<0.001 for the interaction, respectively). CONCLUSIONS: The present analysis shows that underlying etiology of heart failure (i.e., hypertensive), renal function, and sodium levels should be considered for assessing the clinical significance of elevated BNP levels on admission in relation to the risk of adverse outcome after hospitalization for AHFS.

eGFR and Outcomes in Patients with Acute Decompensated Heart Failure with or without Elevated BUN.

BACKGROUND AND OBJECTIVES: In patients with heart failure, the association of renal dysfunction and BUN levels with outcomes is unclear. The aim of our study was to investigate the association between the eGFR at discharge and outcomes in patients with heart failure with or without an elevated BUN level at discharge. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Of 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes Registry, 4449 patients discharged alive after hospitalization for acute decompensated heart failure were investigated to assess the association of eGFR in the context of serum BUN level at discharge with all-cause mortality. The enrolled patients were divided into four groups on the basis of the discharge levels of eGFR (<45 or ≥45 ml/min per 1.73 m(2)) and BUN (≥25 or <25 mg/dl). The median follow-up period after discharge was 517 (381-776) days. RESULTS: The all-cause mortality rate after discharge was 19.1%. After adjustment for multiple comorbidities, an eGFR<45 ml/min per 1.73 m(2) was associated with a significantly higher risk of all-cause mortality in patients with a BUN≥25 mg/dl (hazard ratio, 1.58; 95% confidence interval, 1.33 to 1.88; P<0.001) but not in patients with a BUN<25 mg/dl (hazard ratio, 0.97; 95% confidence interval, 0.76 to 1.26; P=0.84) relative to those with an eGFR≥45 ml/min per 1.73 m(2) and a BUN<25 mg/dl. Among patients with an eGFR≥45 ml/min per 1.73 m(2), a BUN≥25 mg/dl was associated with a significantly higher risk of all-cause mortality than a BUN<25 mg/dl (hazard ratio, 1.34; 95% confidence interval, 1.04 to 1.73; P=0.02). CONCLUSIONS: We showed that elevation of BUN at discharge significantly modified the relation between eGFR at discharge and the risk of all-cause mortality after discharge, suggesting that the association between eGFR and outcomes may be largely dependent on concomitant elevation of BUN.

Clinical profile, management, and mortality in very-elderly patients hospitalized with acute decompensated heart failure: An analysis from the ATTEND registry.

BACKGROUND: Acute decompensated heart failure (ADHF) is a leading cause of hospitalization among the elderly. Discussion of optimal management of ADHF in older patients is a growing health care priority. The aim of this study was to examine the clinical profile, management, and mortality in patients admitted with ADHF according to age. METHODS: We analyzed 4824 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry from April 2007 to December 2011. Patient characteristics, management, and in-hospital outcomes were compared among four age groups (<65, 65-74, 75-84, and ≥85 years). RESULTS: The mean age of the overall population was 73 years; approximately 20% were aged ≥85 years. Older patients were more likely to be women and have preserved left ventricular ejection fraction (LVEF) and decreased renal function. Intravenous treatments were well administered in both young and elderly patients irrespective of LVEF. Invasive procedures were less frequently performed in the eldest group. The median length of hospital stay was 21 days, and in-hospital cardiac death in the eldest group was four-fold higher than that in the youngest group (2.2% vs. 8.9%, P<0.001). CONCLUSIONS: Clinical characteristics of ADHF differ considerably with age, and cardiac death increases linearly with age. Despite a higher rate of preserved systolic function in very-elderly individuals aged ≥85 years, in-hospital mortality was higher, suggesting that more suitable treatments for the elderly might be needed.

Association of anemia and renal dysfunction with in-hospital mortality among patients hospitalized for acute heart failure syndromes with preserved or reduced ejection fraction.

BACKGROUND: The aim of this study was to evaluate the association of anemia and renal dysfunction with in-hospital outcomes in acute heart failure syndromes patients with preserved or reduced ejection fraction. METHODS AND RESULTS: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4693 patients were evaluated to investigate the association among anemia, renal dysfunction, a preserved or reduced ejection fraction and in-hospital mortality. They were divided into four groups based on hemoglobin and estimated glomerular filtration rate at admission. The in-hospital mortality rate was 5.9% and 6.9% of the preserved and reduced ejection fraction groups, respectively. After adjustment for multiple comorbidities, there was no association of either anemia or renal dysfunction alone with in-hospital mortality in preserved ejection fraction patients, but the combination of anemia and renal dysfunction was associated with a somewhat higher risk of in-hospital mortality than that without either condition (odds ratio (OR), 2.75; 95% confidence interval (CI), 0.72-10.41; p=0.137). In reduced ejection fraction patients, adjusted analysis showed that a significantly higher risk of in-hospital mortality was associated with anemia alone (OR, 2.56; 95% CI, 1.10 -5.94; p=0.029) and with anemia plus renal dysfunction (OR, 2.34; 95% CI, 1.09-5.03; p=0.029) relative to the risk without either condition. CONCLUSIONS: Our findings demonstrate that anemia combined with renal dysfunction is not a risk factor for in-hospital mortality in patients with a preserved ejection fraction, whereas anemia is an independent predictor of in-hospital mortality risk in reduced ejection fraction patients regardless of renal dysfunction.

Association of age and baseline systolic blood pressure with outcomes in patients hospitalized for acute heart failure syndromes.

BACKGROUND: Baseline systolic blood pressure (SBP) is one of the most important prognostic indicators for patients with acute heart failure syndromes (AHFS). However, the association among age, baseline SBP, and outcomes of AHFS is unclear. This study was performed to evaluate the relation between baseline SBP and outcomes to increasing age in patients hospitalized for AHFS. METHODS: Of the 4842 patients entered into the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4828 patients with in-hospital and postdischarge follow-up data were included. The patients were divided into quartiles of age (<65, 65 to 75, 76 to 82, and ≥83 years), and each age group was divided into quartiles of baseline SBP. Then the 1-year all-cause mortality was compared among the baseline SBP quartiles in the each age quartile. RESULTS: After adjustment for multiple comorbidities, patients aged <65 years, 65 to 75 years, and 76 to 82 years showed no significant increase in the relative risk of all-cause mortality as the baseline SBP declined until the lowest SBP quartile (SBP<112 mmHg, <120 mmHg, and <120 mmHg, respectively). In contrast, among patients aged ≥83 years, the lower three SBP quartiles (SBP<122 mmHg, 122 to <142 mmHg, and 142 to <165 mmHg) were associated with a significantly higher risk of all-cause mortality than the highest SBP quartile. CONCLUSIONS: In patients hospitalized for AHFS, the relation between baseline SBP and all-cause mortality is markedly associated with increasing age, which means that baseline SBP is more important for very elderly patients with AHFS.

Association between anemia, clinical features and outcome in patients hospitalized for acute heart failure syndromes.

BACKGROUND: It remains unclear in which patients hospitalized for acute heart failure syndromes (AHFS) the presence of anemia increases the risk of morbidity or mortality because of the heterogeneity of this patient population. The aim of this study was to evaluate the influence of anemia on the clinical outcome in subgroups of patients hospitalized for AHFS. METHODS AND RESULTS: The study included patients from the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, a nationwide hospital-based prospective observational multicenter cohort of 4842 patients with AHFS admitted to 53 hospitals in Japan. The primary endpoint was all-cause death after admission and the secondary endpoint was a composite of all-cause death and readmission for heart failure (HF). Anemia was detected in 58% of the patients. The all-cause death rate after admission was significantly higher in patients with anemia (31.3%) than in those without anemia (15.5%). To identify the predictors that influence the effect of anemia on all-cause mortality, subgroup analyses were performed. As a result, the presence of anemia on admission was associated with a significantly increased risk of all-cause death in patients aged <75 years, male patients, patients with new-onset heart failure (HF) and patients with a reduced ejection fraction (EF). CONCLUSIONS: The present subgroup analysis demonstrated that age, gender, prior hospitalization for HF and the EF (preserved or reduced) should be considered in patients with AHFS when assessing the clinical significance of anemia at admission in relation to the risk of all-cause mortality.

Relation of left ventricular ejection fraction and clinical features or co-morbidities to outcomes among patients hospitalized for acute heart failure syndromes.

The aim of this study was to evaluate the heterogeneity of the association of a preserved or reduced ejection fraction (EF) with the increased risk of outcomes among patients with acute heart failure syndromes. Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry in Japan, 4,720 patients were evaluated to investigate the association of EF and clinical features or co-morbidities with all-cause mortality after admission. The median follow-up period after admission was 519 (388 to 781) days. The all-cause mortality rate did not differ between the reduced EF and preserved EF groups (24.9% and 24.5%, respectively). To evaluate the heterogeneity of the influence of a preserved or reduced EF on all-cause mortality, subgroup analyses were performed. As a result, there were significant interactions in the association of a preserved or reduced EF with all-cause mortality when the patients were stratified by an ischemic cause, a hypertensive cause, previous hospitalization for heart failure, diabetes mellitus, and anemia. The influence of a nonischemic cause, a hypertensive cause, or new-onset heart failure on the risk of all-cause mortality was significantly greater in patients with preserved EF than in those with reduced EF. In contrast, the influence of diabetes mellitus or anemia on the risk of all-cause mortality was significantly greater in patients with reduced EF than in those with preserved EF. In conclusion, the present analysis demonstrated that the association of a preserved or reduced EF with the clinical outcome differs markedly in relation to the clinical features or co-morbidities of these patients.

Associations of anemia and renal dysfunction with outcomes among patients hospitalized for acute decompensated heart failure with preserved or reduced ejection fraction.

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.