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Clinical characteristics and long-term clinical outcomes of Japanese heart failure patients with preserved versus reduced left ventricular ejection fraction: A prospective cohort of Shinken Database 2004–2011

Open ArchivePublished:June 03, 2013DOI:https://doi.org/10.1016/j.jjcc.2013.03.013

      Abstract

      Background

      Clinical data on the mortality and morbidity of unselected Japanese patients with heart failure (HF) are limited. In this study, we aimed to determine the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with preserved or reduced left ventricular ejection fraction (LVEF).

      Methods and results

      We used a single hospital-based cohort from the Shinken Database 2004–2011 that comprised all new patients (n = 17,517) visiting the Cardiovascular Institute Hospital. A total of 1,525 patients diagnosed with symptomatic HF at the initial visit were included in the analysis. Of these, 1121 patients (74%) exhibited a preserved LVEF (>50%) and 404 patients (26%) had a reduced LVEF (≤50%). HF patients with preserved LVEF (HFpEF) were older and more often female than patients with reduced LVEF (HFrEF). Kaplan–Meier curves and log-rank test results showed that HFpEF patients had a better prognosis than HFrEF patients. However, there were no significant differences in clinical outcomes between HFpEF and HFrEF patients when the analysis was limited to inpatients. Cox regression analysis showed that HFpEF patients had a significantly lower risk of all-cause death (p = 0.027; hazard ratio, 0.547, 95% confidence interval, 0.321–0.933). Multivariate analyses performed separately showed that the independent predictors of all-cause death in HFrEF were advanced age, lower body mass index, diabetes mellitus, and the absence of statin treatment, whereas those for HFpEF were advanced age, absence of dyslipidemia, anemia, and left ventricular hypertrophy.

      Conclusions

      This prospective cohort study identified the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with reduced and preserved ejection fractions in a real-world clinical setting.

      Keywords

      Introduction

      In Japan's rapidly aging population, heart failure (HF) has become a common and deteriorating condition [
      • Shiba N.
      • Shimokawa H.
      Chronic heart failure in Japan: implications of the CHART studies.
      ]. In addition to the increased prevalence of HF, HF with a preserved ejection fraction (HFpEF) is increasingly being recognized as a public health problem. The prevalence of HFpEF is similar to that of HF with reduced ejection fraction (HFrEF). HFpEF is associated with poor clinical outcomes, which are believed to be slightly better than those of HFrEF.
      The epidemiology of HF in Japan is different from that in Western countries with respect to ethnic background and etiology. However, there are few Japanese hospital-based reports about preserved left ventricular ejection fraction (LVEF) [
      • Tsutsui H.
      • Tsuchihashi M.
      • Takeshita A.
      Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.
      ,
      • Ramadan M.M.
      • Okura Y.
      • Ohno Y.
      • Suzuki K.
      • Taneda K.
      • Hoyano M.
      • Hao K.
      • Kimura S.
      • Kodama M.
      • Aizawa Y.
      Comparative analysis of systolic and isolated diastolic dysfunction: Sado Heart Failure Study.
      ,
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
      • Kinugawa S.
      • Yokota T.
      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      JCARE-CARD Investigators
      Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ], and the prevalence and prognosis of HF with preserved LVEF are not well known. Tsuchihashi-Makaya et al. examined patients from the Japanese Cardiac Registry of Heart Failure in Cardiology who were hospitalized for HF and demonstrated that patients with HFpEF had similar mortality rates and equally high rates of rehospitalization as those with HFrEF [
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
      • Kinugawa S.
      • Yokota T.
      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      JCARE-CARD Investigators
      Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ]. However, the patients enrolled in these studies had severe HF that required hospitalization. To our knowledge, the differences in clinical characteristics, outcomes, and prognostic factors between patients with HFpEF and those with HFrEF in an unselected Japanese HF population that includes both inpatients and outpatients with mild symptoms have not been examined. Therefore, we examined a hospital-based cohort from the Shinken Database using data obtained between 2004 and 2011. The registry was initiated in 2004, and patients have since been continually registered to the database annually. In the present study, we aimed to clarify the differences in clinical characteristics, outcomes, and prognostic factors between patients with HFpEF and those with HFrEF in an unselected cohort of Japanese HF patients by using the Shinken Database.

      Methods

      Study patients

      The Shinken Database includes all patients (inpatients and outpatients) who were examined at the Cardiovascular Institute in Tokyo, Japan (“Shinken” is a Japanese abbreviation for the name of the hospital), and excludes patients who are foreign travelers and those with active cancer. This hospital-based database was established to investigate the prevalence and prognosis of cardiovascular diseases in the urban areas of Japan [
      • Suzuki S.
      • Yamashita T.
      • Ohtsuka T.
      • Sagara K.
      • Uejima T.
      • Oikawa Y.
      • Yajima J.
      • Koike A.
      • Nagashima K.
      • Kirigaya H.
      • Ogasawara K.
      • Sawada H.
      • Aizawa T.
      Prevalence and prognosis of patients with atrial fibrillation in Japan: a prospective cohort of Shinken Database 2004.
      ,
      • Kaneko H.
      • Koike A.
      • Senoo K.
      • Tanaka S.
      • Suzuki S.
      • Nagayama O.
      • Sagara K.
      • Otsuka T.
      • Matsuno S.
      • Funada R.
      • Uejima T.
      • Oikawa Y.
      • Yajima J.
      • Nagashima K.
      • Kirigaya H.
      • et al.
      Role of cardiopulmonary dysfunction and left atrial remodeling in development of acute decompensated heart failure in chronic heart failure with preserved left ventricular ejection fraction.
      ]. The registry began in June 2004, and patients have been continually registered to the database annually. The present study analyzed data from this database collected between June 2004 and March 2012 (Shinken Database 2004–2011) and included 17,517 new visiting patients. In the present study, HF patients were defined as those with symptomatic HF [New York Heart Association (NYHA) classes II–IV] coexistent with structural heart diseases, which were diagnosed using cardiovascular diagnostic tests such as echocardiography, nuclear scanning, and angiography. We defined HFpEF patients as those with symptomatic HF and preserved LVEF (i.e. LVEF > 50%), and HFrEF patients as those with symptomatic HF and reduced LVEF (i.e. LVEF ≤ 50%), as previously described [
      • Goda A.
      • Yamashita T.
      • Suzuki S.
      • Ohtsuka T.
      • Uejima T.
      • Oikawa Y.
      • Yajima J.
      • Koike A.
      • Nagashima K.
      • Kirigaya H.
      • Sagara K.
      • Ogasawara K.
      • Isobe M.
      • Sawada H.
      • Aizawa T.
      Heart failure with preserved versus reduced left ventricular systolic function: a prospective cohort of Shinken Database 2004–2005.
      ]. We excluded patients with valvular heart disease. Valvular heart disease was defined as long-standing mitral or aortic valve involvement as documented by physical examination and echocardiography, angiography, or history of surgical repair. We defined inpatients as patients who were admitted to or transferred to our hospital because of HF (not for examination) at their first hospital visit, whereas outpatients are patients who have symptomatic HF and visited the outpatient clinic of our hospital without hospital admission at their first hospital visit.

      Ethics

      The ethical committee of the Cardiovascular Institute approved this study, and all the patients provided written informed consent.

      Data collection

      For each patient, after undergoing electrocardiography and chest radiography, cardiovascular status was evaluated by echocardiography, an exercise test, 24-h Holter recordings, and blood laboratory data as prescribed by the attending physician within 3 months after the first visit. As initial clinical parameters, collected data included gender, age, body mass index (BMI), drug information, and coexisting conditions, including hypertension, atrial fibrillation, diabetes mellitus, and dyslipidemia. In most patients, additional echocardiographic parameters included left ventricular diameter of the diastole (LVDd), left ventricular diameter of the systole (LVDs), interventricular septum thickness (IVST), posterior wall thickness (PWT), and LVEF using M-mode echocardiography. Left ventricular (LV) hypertrophy was defined by echocardiography (IVST or PWT ≥ 13 mm). Anemia was defined as a hemoglobin level of <11 g/dL. An estimated glomerular filtration rate (eGFR) was calculated using the eGFR equation for the Japanese population: eGFR = 194 × (serum creatinine)−1.094 × (age)−0.287 × (0.739, if the patient is female) [
      • Matsuo S.
      • Imai E.
      • Horio M.
      • Yasuda Y.
      • Tomita K.
      • Nitta K.
      • Yamagata K.
      • Tomino Y.
      • Yokoyama H.
      • Hishida A.
      Collaborators developing the Japanese equation for estimated GFR
      Revised equations for estimated GFR from serum creatinine in Japan.
      ]. A baseline eGFR < 60 mL min−1·1.73 m−2 was used for defining chronic kidney disease (CKD) [
      • Tonelli M.
      • Jose P.
      • Curhan G.
      • Sacks F.
      • Braunwald E.
      • Pfeffer M.
      Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial.
      ]. Idiopathic dilated cardiomyopathy was diagnosed by the presence of global LV dilatation with impaired systolic function occurring in the absence of known cardiac causes. Hypertrophic cardiomyopathy was diagnosed by echocardiography when hypertrophy (IWST or PWT > 12 mm) without hypertension was present. We confirmed the deaths of study patients by the medical records of our hospital or by the information obtained during follow-up. We defined cardiovascular death as death resulting from acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, or death due to other cardiovascular causes. HF admission was defined as exacerbation of chronic HF requiring hospitalization and was determined by the outpatient clinic physician according to the presenting symptoms, physical examination results, laboratory data, and chest radiography findings.

      Patient follow-up

      The health status and incidence of cardiovascular events and mortality of patients are maintained in the database by linking to the medical records of the hospital and through study documents that were sent once per year to those who stopped hospital visits or who were referred to other hospitals.
      We excluded the follow-up data obtained after April 1, 2012, from data analysis. Therefore, the end of the follow-up period was defined as one of the following: (1) the date of death, if the date was before March 31, 2012; (2) the final hospital visit or the final response to our study documents involving prognosis with confirmation of being alive before March 31, 2012; (3) March 31, 2012, when the date of death, the final hospital visit, or the final response to our study documents involving prognosis were later than April 1, 2012.

      Statistical analysis

      Categorical and consecutive data regarding patient background are presented as numbers (%) and means ± standard deviation, respectively. The chi-square test was used for comparisons between groups, and the unpaired t-test was used for comparison of consecutive variables. Long-term, event-free survival was estimated using Kaplan–Meier curves and the log-rank test to assess the significance of differences between the 2 groups. Cox regression analysis was used to identify the effects of HFpEF on long-term clinical outcomes. Univariate Cox regression analysis was used to identify the co-factors with significant effects on all-cause mortality. Step-wise multivariate Cox regression analysis was performed to determine the independent prognostic factors for all-cause death. For subanalysis, patients with HF were segregated into outpatients and inpatients. Clinical outcomes were compared between patients with HFpEF and HFrEF in the outpatient and inpatient groups, respectively. A probability value of <0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA), version 19.0 software.

      Results

      Patient characteristics

      Of the 17,517 patients who had visited our hospital, 1,525 patients were diagnosed with symptomatic HF without valvular heart disease. These patients were followed for an average period of 1135 ± 764 days. Patients were divided into HFpEF (LVEF > 50%; 1,121 patients, 74%) and HFrEF (LVEF ≤ 50%; 404 patients, 26%). There were 1,330 outpatients (HFpEF: 1,048 patients, 79%; HFrEF: 282 patients, 21%), and 195 inpatients (HFpEF: 73 patients, 37%; HFrEF: 122 patients, 63%). Compared with patients with HFrEF, patients with HFpEF were older, more often female, less likely to have diabetes mellitus, hyperuricemia, CKD, anemia, a prior history of myocardial infarction, dilated cardiomyopathy, or atrial fibrillation, and had a higher rate of dyslipidemia. Ultrasound cardiography results showed that IVST, PWT, LVDd, and LVDs were greater in HFrEF patients than in HFpEF patients. LVEF and left ventricular fractional shortening were greater in HFpEF patients than in HFrEF patients. The mean B-type natriuretic peptide (BNP) level was significantly lower in patients with preserved LVEF than in those with reduced LVEF. The use of beta-blockers, renin–angiotensin-system inhibitors (RAS-Is), diuretics, and digitalis was more common among HFrEF patients, whereas use of calcium channel blockers, statins, and nitrates was more common in HFpEF patients. The HFpEF group had a higher prevalence of NYHA II, but a lower prevalence of NYHA III and IV heart failure than the HFrEF group (Table 1).
      Table 1Characteristics of patients.
      HFrEF (n = 404)HFpEF (n = 1,121)p-Value
      Age (years)63.0 ± 13.865.6 ± 11.7<.001
      Male sex81.276.2.039
      BMI (kg/m2)24.6 ± 4.824.3 ± 3.6.209
      Hypertension59.964.5.100
      Dyslipidemia51.766.8<.001
      Diabetes mellitus39.932.4.007
      Hyperuricemia19.611.4<.001
      Cigarette28.624.2.144
      CKD46.527.6<.001
      Anemia14.39.7.013
      Prior MI26.29.6<.001
      DCM24.50.4<.001
      HCM2.03.9.065
      AF19.39.0<.001
      BNP (pg/mL)671.0 ± 772.7232.6 ± 460.5<.001
      UCG
      IVST (mm)9.4 ± 2.210.0 ± 2.2<.001
      PWT (mm)8.7 ± 1.89.1 ± 1.5<.001
      LVDd (mm)57.3 ± 8.646.0 ± 4.6<.001
      LVDs (mm)48.0 ± 9.928.9 ± 4.7<.001
      LVFS (%)16.7 ± 6.237.4 ± 5.8<.001
      LVEF (%)34.0 ± 11.767.0 ± 7.5<.001
      LVH8.69.7.542
      NYHA class
      II55.478.6<.001
      III23.815.7<.001
      IV20.85.7<.001
      Medications
      Beta-blockers55.037.7<.001
      Calcium channel blockers19.130.5<.001
      ACE-Is27.713.4<.001
      ARBs49.834.9<.001
      RAS-Is71.044.8<.001
      Statins43.654.9<.001
      Diuretics63.619.1<.001
      Digitalis15.63.4<.001
      Nitrate39.660.8<.001
      HFrEF, heart failure with reduced left ventricular ejection fraction; HFpEF, heart failure with preserved left ventricular ejection fraction; BMI; body mass index; CKD, chronic kidney disease; IHC, ischemic heart disease; prior MI, prior history of myocardial infarction; DCM, idiopathic dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; AF, atrial fibrillation; BNP, brain natriuretic peptide; UCG, ultrasound cardiography; IVST, interventricular septum thickness; PWT, posterior wall thickness; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVFS, left ventricular fractional shortening; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; NYHA, New York Heart Association; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; RAS-I, renin–angiotensin system inhibitor. Data are expressed as mean ± standard deviation, or percentage.

      Clinical outcomes

      All-cause death occurred in 4.5% of patients in the HFpEF group, and 11.4% of patients in the HFrEF group. Cardiovascular death (HF death) occurred in 1.7% (0.8%) of the patients in the HFpEF group, and 5.2% (2.0%) of the patients in the HFrEF group. Admission for HF occurred in 4.1% of the patients with HFpEF and 15.8% of the patients with HFrEF (Table 2). Kaplan–Meier curves and log-rank test results showed that frequency of all-cause death, cardiovascular death, HF death, and HF admission, were significantly higher in HFrEF patients than in HFpEF patients (Fig. 1).
      Table 2Clinical outcomes.
      HFrEF (n = 404)HFpEF (n = 1,121)p-Value
      All-cause death11.44.5<.001
      Heart failure death2.00.8.053
      Cardiovascular death5.21.7<.001
      Heart failure admission15.84.1<.001
      HFrEF, heart failure with reduced left ventricular ejection fraction; HFpEF, heart failure with preserved left ventricular ejection fraction. Data are expressed as percentage.
      Figure thumbnail gr1
      Figure 1Kaplan–Meier curves for all-cause death-free survival rate (A), cardiovascular death-free survival rate (B), heart failure death-free survival rate (C), and heart failure admission-free survival rate (D). HFpEF, heart failure patients with preserved left ventricular ejection fraction; HFrEF, heart failure patients with reduced left ventricular ejection fraction.
      Cox regression analysis showed that HFpEF was associated with a lower incidence of all-cause death [p < 0.001; hazard ratio (HR) 0.369, 95% confidence interval (95% CI) 0.247–0.549], cardiovascular death (p < 0.001; HR 0.307, 95% CI 0.165–0.571), and HF admission (p < 0.001; HR 0.222, 95% CI 0.152–0.324). The Cox regression model was used in the analysis to adjust for the following covariates: age, sex, dyslipidemia, diabetes mellitus, hyperuricemia, CKD, anemia, prior history of myocardial infarction, dilated cardiomyopathy, atrial fibrillation, BNP level, LVEF, NYHA III/IV, beta blockers, calcium channel blockers, RAS-Is, statins, diuretics, digitalis, and nitrate. It showed that patients with HFpEF had a comparable risk for cardiovascular death (p = 0.436; HR 0.730, 95% CI 0.331–1.611), HF death (p = 0.452, HR 0.626, 95% CI 0.184–2.126), and HF admission (p = 0.360, HR 1.456, 95% CI 0.652–3.237), but had a significantly lower risk for all-cause death (p = 0.027, HR 0.547, 95% CI 0.321–0.933) (Table 3).
      Table 3Hazard ratios of clinical outcomes of patients with HFpEF.
      p-ValueHazard ratio95% CI
      All-cause death
       Unadjusted HR<.001.369.247–.549
       Adjusted HR.027.547.321–.933
      Cardiovascular death
       Unadjusted HR<0.001.307.165–.571
       Adjusted HR.436.730.331–1.611
      HF death
       Unadjusted HR.054.392.151–1.016
       Adjusted HR.452.626.184–2.126
      HF admission
       Unadjusted HR<.001.222.152–.324
       Adjusted HR.3601.456.652–3.237
      HFpEF, heart failure with preserved left ventricular ejection fraction; HR, hazard ratio; CI, confidence interval; HF, heart failure.

      Predictors for all-cause death

      Univariate Cox regression analysis showed that age, BMI, dyslipidemia, diabetes mellitus, cigarette smoking, CKD, anemia, statins, and BNP level were associated with all-cause death in HF with HFrEF (Table 4). Multivariate Cox regression analysis, including the significant predictors identified in the univariate model, showed that older age, lower BMI, diabetes mellitus, and the absence of statin treatment were independent predictors of all-cause death in HFrEF (Table 4). Univariate Cox regression analysis showed that age, BMI, dyslipidemia, hyperuricemia, CKD, anemia, AF, statins, diuretics, NYHA III/IV, BNP level, and LV hypertrophy were associated with all-cause death in HFpEF (Table 5). Multivariate Cox regression analysis, including the significant predictors, identified in the univariate model showed that advanced age, absence of dyslipidemia, anemia, and LV hypertrophy were independent predictors of all-cause death in HFpEF (Table 5).
      Table 4Predictors for death in HFrEF.
      p-ValueHazard ratio95% CI
      Univariate
      Age<.0011.0651.039–1.092
      Male.7901.116.499–2.495
      BMI.001.863.791–.942
      Hypertension.537.833.466–1.489
      Dyslipidemia.018.480.262–.881
      Diabetes mellitus.0062.2751.265–4.092
      Hyperuricemia.094.416.149–1.162
      Cigarette.006.133.032–.552
      CKD<.0014.4362.250–8.743
      Anemia<.0014.2712.345–7.782
      Prior MI.1481.565.853–2.872
      DCM.475.767.370–1.589
      HCM.2362.357.571–9.728
      AF.571.792.354–1.772
      Beta-blockers.299.736.413–1.313
      Calcium channel blockers.5071.258.639–2.478
      RAS-Is.151.641.349–1.177
      Statins.002.337.167–.679
      Diuretics.700.890.492–1.610
      Nitrate.4831.231.689–2.200
      NYHA III/IV.1431.541.564–2.748
      BNP<.0011.0011.000–1.001
      LVH.2111.733.732–4.101
      LVEF.298.987.964–1.011
      Multivariate
      Age.0111.0521.012–1.095
      BMI.024.852.741–.980
      DM.0063.5041.431–8.578
      Statin.019.323.125–.831
      BMI, body mass index; CKD, chronic kidney disease; IHD, ischemic heart disease; prior MI, prior history of myocardial infarction; DCM, idiopathic dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; AF, atrial fibrillation; RAS-I, renin–angiotensin system inhibitor; NYHA, New York Heart Association; BNP, brain natriuretic peptide; LVH, left ventricular hypertrophy; LVEF, left ventricular ejection fraction; DM, diabetes mellitus. CI, confidence interval.
      Table 5Predictors for death in HFpEF.
      p-ValueHazard ratio95% CI
      Univariate
      Age<.0011.1171.085–1.149
      Male.062.574.320–1.028
      BMI<.000.812.736–.895
      Hypertension.6671.134.638–2.017
      Dyslipidemia<.001.304.172–.536
      Diabetes mellitus.2741.366.782–2.385
      Hyperuricemia.0412.0571.030–4.110
      Cigarette.660.828.356–1.922
      CKD<.0014.1302.357–7.237
      Anemia<.00110.7456.109–18.896
      Prior MI.452.676.243–1.877
      DCM.855.050.000–4.596
      HCM.415.047.000–72.407
      AF.0132.4911.212–5.121
      Beta-blockers.759.913.521–1.609
      Calcium channel blockers.7621.094.611–1.959
      RAS-Is.7051.112.642–1.926
      Statins<.001.259.140–.479
      Diuretics<.0012.7981.569–4.990
      Nitrate.937.977.550–1.737
      NYHA III or IV<.0013.9182.257–6.802
      BNP<.0011.0011.001–1.001
      LVH<.0014.2002.181–8.089
      LVEF.064.966.932–1.002
      Multivariate
      Age.0011.0761.030–1.125
      Dyslipidemia.041.445.204–.969
      Anemia<.0015.5272.450–12.466
      LVH.0182.8201.192–6.672
      BMI, body mass index; CKD, chronic kidney disease; IHD, ischemic heart disease; prior MI, prior history of myocardial infarction; DCM, idiopathic dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; AF, atrial fibrillation; RAS-I, renin–angiotensin system inhibitor; NYHA, New York Heart Association; BNP, brain natriuretic peptide; LVH, left ventricular hypertrophy; LVEF, left ventricular ejection fraction. CI, confidence interval.

      Subanalysis

      Kaplan–Meier curves and the log-rank test results revealed that the frequencies of all-cause death, cardiovascular death, HF death, and HF admission were significantly higher in HFrEF than in HFpEF outpatients (Fig. 2), whereas these were all comparable among inpatients (Fig. 3).
      Figure thumbnail gr2
      Figure 2Kaplan–Meier curves for all-cause death-free survival rate (A), cardiovascular death-free survival rate (B), heart failure death-free survival rate (C), and heart failure admission-free survival rate (D). HFpEF, heart failure patients with preserved left ventricular ejection fraction; HFrEF, heart failure patients with reduced left ventricular ejection fraction.
      Figure thumbnail gr3
      Figure 3Kaplan–Meier curves for all-cause death-free survival rate (A), cardiovascular death-free survival rate (B), heart failure death-free survival rate (C), and heart failure admission-free survival rate (D). HFpEF, heart failure patients with preserved left ventricular ejection fraction; HFrEF, heart failure patients with reduced left ventricular ejection fraction.

      Discussion

      The present study analyzed data from an observational cohort of HF patients to determine the mortality and morbidity of unselected Japanese HF patients in a real-world clinical setting. The major findings of the present study were as follows:
      • (1)
        HFpEF was present in approximately 74% of all of the HF inpatients (37%) and outpatients (79%) visiting a cardiovascular hospital in Japan.
      • (2)
        Patients with HFpEF showed a better prognosis than those with HFrEF. However, our sub-analysis showed that among inpatients, the clinical outcomes of HFpEF and HFrEF patients were comparable.
      • (3)
        In HFrEF, older age, lower BMI, diabetes mellitus, and the absence of statin treatment were independent predictors of all-cause death, whereas older age, absence of dyslipidemia, anemia, and LV hypertrophy were independent predictors of all-cause death in HFpEF.
      The prevalence of HFpEF, which has increased with time in Western countries [
      • Roger V.L.
      • Weston S.A.
      • Redfield M.M.
      • Hellermann-Homan J.P.
      • Killian J.
      • Yawn B.P.
      • Jacobsen S.J.
      Trends in heart failure incidence and survival in a community-based population.
      ], varies according to age, race, and the cutoff value for LVEF. Nevertheless, there is widespread agreement that HFpEF is noted in more than one-third of all patients admitted with HF [
      • Tsutsui H.
      • Tsuchihashi M.
      • Takeshita A.
      Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.
      ,
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • Jacobsen S.J.
      • Roger V.L.
      • Redfield M.M.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      ,
      • Bhatia R.S.
      • Tu J.V.
      • Lee D.S.
      • Austin P.C.
      • Fang J.
      • Haouzi A.
      • Gong Y.
      • Liu P.P.
      Outcome of heart failure with preserved ejection fraction in a population-based study.
      ,
      • Redfield M.M.
      • Jacobsen S.J.
      • Burnett Jr., J.C.
      • Mahoney D.W.
      • Bailey K.R.
      • Rodeheffer R.J.
      Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.
      ,
      • Devereux R.B.
      • Roman M.J.
      • Liu J.E.
      • Welty T.K.
      • Lee E.T.
      • Rodeheffer R.
      • Fabsitz R.R.
      • Howard B.V.
      Congestive heart failure despite normal left ventricular systolic function in a population-based sample: the Strong Heart Study.
      ,
      • Kupari M.
      • Lindroos M.
      • Iivanainen A.M.
      • Heikkila J.
      • Tilvis R.
      Congestive heart failure in old age: prevalence, mechanisms and 4-year prognosis in the Helsinki Ageing Study.
      ,
      • Malki Q.
      • Sharma N.D.
      • Afzal A.
      • Ananthsubramaniam K.
      • Abbas A.
      • Jacobson G.
      • Jafri S.
      Clinical presentation, hospital length of stay, and readmission rate in patients with heart failure with preserved and decreased left ventricular systolic function.
      ,
      • Cohen-Solal A.
      • Desnos M.
      • Delahaye F.
      • Emeriau J.P.
      • Hanania G.
      A national survey of heart failure in French hospitals. The Myocardiopathy and Heart Failure Working Group of the French Society of Cardiology, the National College of General Hospital Cardiologists and the French Geriatrics Society.
      ,
      • Masoudi F.A.
      • Havranek E.P.
      • Smith G.
      • Fish R.H.
      • Steiner J.F.
      • Ordin D.L.
      • Krumholz H.M.
      Gender, age, and heart failure with preserved left ventricular systolic function.
      ,
      • Smith G.L.
      • Masoudi F.A.
      • Vaccarino V.
      • Radford M.J.
      • Krumholz H.M.
      Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline.
      ,
      • Lenzen M.J.
      • Scholte op Reimer W.J.
      • Boersma E.
      • Vantrimpont P.J.
      • Follath F.
      • Swedberg K.
      • Cleland J.
      • Komajda M.
      Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey.
      ]. A recent study conducted by Tsuchihashi-Makaya et al. reported that HFpEF is present in one-third of all admitted HF patients [
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
      • Kinugawa S.
      • Yokota T.
      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      JCARE-CARD Investigators
      Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ]. In our study, the prevalence of HFpEF was 72%, which was significantly higher than that of previous reports in both Western countries and Japan. This could be attributed to the HF outpatients that were included in our cohort. In fact, 40% of the inpatients with HF had preserved LVEF, which was in agreement with the findings of previous studies. The high prevalence of HFpEF suggests that this type of HF merits further attention.
      Patients with HFpEF are older, more often female, and more frequently have hypertension compared to patients with HFrEF [
      • Tsutsui H.
      • Tsuchihashi M.
      • Takeshita A.
      Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.
      ,
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • Jacobsen S.J.
      • Roger V.L.
      • Redfield M.M.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      ,
      • Bhatia R.S.
      • Tu J.V.
      • Lee D.S.
      • Austin P.C.
      • Fang J.
      • Haouzi A.
      • Gong Y.
      • Liu P.P.
      Outcome of heart failure with preserved ejection fraction in a population-based study.
      ,
      • Malki Q.
      • Sharma N.D.
      • Afzal A.
      • Ananthsubramaniam K.
      • Abbas A.
      • Jacobson G.
      • Jafri S.
      Clinical presentation, hospital length of stay, and readmission rate in patients with heart failure with preserved and decreased left ventricular systolic function.
      ,
      • Cohen-Solal A.
      • Desnos M.
      • Delahaye F.
      • Emeriau J.P.
      • Hanania G.
      A national survey of heart failure in French hospitals. The Myocardiopathy and Heart Failure Working Group of the French Society of Cardiology, the National College of General Hospital Cardiologists and the French Geriatrics Society.
      ,
      • Masoudi F.A.
      • Havranek E.P.
      • Smith G.
      • Fish R.H.
      • Steiner J.F.
      • Ordin D.L.
      • Krumholz H.M.
      Gender, age, and heart failure with preserved left ventricular systolic function.
      ,
      • Smith G.L.
      • Masoudi F.A.
      • Vaccarino V.
      • Radford M.J.
      • Krumholz H.M.
      Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline.
      ,
      • Lenzen M.J.
      • Scholte op Reimer W.J.
      • Boersma E.
      • Vantrimpont P.J.
      • Follath F.
      • Swedberg K.
      • Cleland J.
      • Komajda M.
      Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey.
      ,
      • Senni M.
      • Redfield M.M.
      Heart failure with preserved systolic function. A different natural history?.
      ]. Similar background differences were demonstrated in Japanese HF patients in both inpatient-based and community-based cohorts [
      • Ramadan M.M.
      • Okura Y.
      • Ohno Y.
      • Suzuki K.
      • Taneda K.
      • Hoyano M.
      • Hao K.
      • Kimura S.
      • Kodama M.
      • Aizawa Y.
      Comparative analysis of systolic and isolated diastolic dysfunction: Sado Heart Failure Study.
      ,
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
      • Kinugawa S.
      • Yokota T.
      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      JCARE-CARD Investigators
      Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ]. The differences in patients’ backgrounds in our study were almost identical to those of previous reports, and patients with HFpEF were older and more often female.
      Whether the long-term clinical outcomes of HFpEF and HFrEF patients differ is not clear. Smith et al. and Solomon et al. reported that patients with HFpEF had a significantly better prognosis than those with HFrEF [
      • Smith G.L.
      • Masoudi F.A.
      • Vaccarino V.
      • Radford M.J.
      • Krumholz H.M.
      Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline.
      ,
      • Solomon S.D.
      • Anavekar N.
      • Skali H.
      • McMurray J.J.
      • Swedberg K.
      • Yusuf S.
      • Granger C.B.
      • Michelson E.L.
      • Wang D.
      • Pocock S.
      • Pfeffer M.A.
      Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators
      Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients.
      ]. However, no significant differences in mortality between patients with preserved and reduced LVEF were reported by other studies [
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • Jacobsen S.J.
      • Roger V.L.
      • Redfield M.M.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      ,
      • Bhatia R.S.
      • Tu J.V.
      • Lee D.S.
      • Austin P.C.
      • Fang J.
      • Haouzi A.
      • Gong Y.
      • Liu P.P.
      Outcome of heart failure with preserved ejection fraction in a population-based study.
      ,
      • Senni M.
      • Tribouilloy C.M.
      • Rodeheffer R.J.
      • Jacobsen S.J.
      • Evans J.M.
      • Bailey K.R.
      • Redfield M.M.
      Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991.
      ]. Previous studies conducted in Japan found no significant differences in prognosis between 3 groups divided on the basis of LVEF [
      • Tsutsui H.
      • Tsuchihashi M.
      • Takeshita A.
      Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.
      ,
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
      • Kinugawa S.
      • Yokota T.
      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      JCARE-CARD Investigators
      Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ]. In the present study, patients with HFpEF had a significantly better prognosis than those with HFrEF. Interestingly, no significant differences in clinical outcomes between HFpEF and HFrEF patients were detected when the analysis was limited to inpatients. This was in agreement with the results of previous studies [
      • Tsutsui H.
      • Tsuchihashi M.
      • Takeshita A.
      Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.
      ,
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
      • Kinugawa S.
      • Yokota T.
      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      JCARE-CARD Investigators
      Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ,
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • Jacobsen S.J.
      • Roger V.L.
      • Redfield M.M.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      ,
      • Bhatia R.S.
      • Tu J.V.
      • Lee D.S.
      • Austin P.C.
      • Fang J.
      • Haouzi A.
      • Gong Y.
      • Liu P.P.
      Outcome of heart failure with preserved ejection fraction in a population-based study.
      ,
      • Senni M.
      • Tribouilloy C.M.
      • Rodeheffer R.J.
      • Jacobsen S.J.
      • Evans J.M.
      • Bailey K.R.
      • Redfield M.M.
      Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991.
      ] that included hospitalized HF patients and showed that the prognoses of HFpEF and HFrEF were comparable. On the other hand, Solomon et al. reported that LVEF was a powerful predictor of cardiovascular outcome in a broad spectrum of patients with HF, including outpatients and inpatients [
      • Solomon S.D.
      • Anavekar N.
      • Skali H.
      • McMurray J.J.
      • Swedberg K.
      • Yusuf S.
      • Granger C.B.
      • Michelson E.L.
      • Wang D.
      • Pocock S.
      • Pfeffer M.A.
      Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators
      Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients.
      ]. The findings of this study suggested that although patients with HFpEF generally had favorable outcomes, the prognosis of HFpEF does not differ from that of HFrEF in patients with decompensated HF requiring hospital admission.
      Previous studies identified the prognostic factors for HF, including older age, the severity of HF [
      Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
      ,
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
      ], anemia [
      • Anand I.
      • McMurray J.J.
      • Whitmore J.
      • Warren M.
      • Pham A.
      • McCamish M.A.
      • Burton P.B.
      Anemia and its relationship to clinical outcome in heart failure.
      ], the presence of CKD [
      • Shiba N.
      • Matsuki M.
      • Takahashi J.
      • Tada T.
      • Watanabe J.
      • Shimokawa H.
      Prognostic importance of chronic kidney disease in Japanese patients with chronic heart failure.
      ,
      • Go A.S.
      • Yang J.
      • Ackerson L.M.
      • Lepper K.
      • Robbins S.
      • Massie B.M.
      • Shlipak M.G.
      Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.
      ,
      • Hosoda J.
      • Ishikawa T.
      • Matsushita K.
      • Matsumoto K.
      • Kimura Y.
      • Miyamoto M.
      • Ogawa H.
      • Takamura T.
      • Sugano T.
      • Ishigami T.
      • Uchino K.
      • Kimura K.
      • Umemura S.
      Impact of renal insufficiency on long-term clinical outcome in patients with heart failure treated by cardiac resynchronization therapy.
      ] and lower LVEF [
      • Bettencourt P.
      • Ferreira A.
      • Dias P.
      • Pimenta J.
      • Frioes F.
      • Martins L.
      • Cerqueira-Gomes M.
      Predictors of prognosis in patients with stable mild to moderate heart failure.
      ]. However, whether these predictors could be applied to both preserved and reduced LVEF remained unclear. In the present study, multivariate analyses demonstrated that the independent predictors of all-cause death in HFrEF were older age, lower BMI, diabetes mellitus, and the absence of statin treatment, whereas, older age, the absence of dyslipidemia, anemia, and LV hypertrophy were independent predictors of all-cause death in HFpEF. Hence, older age was a common risk factor of reduced and preserved LVEF. On the other hand, the effect of other factors differed between the reduced and preserved LVEF groups. Therefore, our results underscore that different factors should be paid more attention to, according to reduced or preserved LVEF.

      Study limitations

      The present study had several limitations. First, this study was a single center-based study. Because our hospital is a single-department cardiovascular facility, the results of this study cannot be generalized to all medical centers. Second, the definition of HFrEF and HFpEF in the present study was based on LVEF, and it therefore remains unknown whether the study population had objective evidence of diastolic dysfunction, as defined by guidelines for the diagnosis of HFpEF [
      • Bhatia R.S.
      • Tu J.V.
      • Lee D.S.
      • Austin P.C.
      • Fang J.
      • Haouzi A.
      • Gong Y.
      • Liu P.P.
      Outcome of heart failure with preserved ejection fraction in a population-based study.
      ]. Third, the proportion of patients treated with drugs known to be effective for the treatment of HF was lower in the present study than in other studies.

      Conclusion

      The present study analyzed an observational cohort of Japanese patients with HF to determine the real-world clinical characteristics and long-term mortality and morbidity of HF with respect to HFpEF and HFrEF status. Long-term clinical outcomes were better in patients with HFpEF than in those with HFrEF. Interestingly, no significant differences in clinical outcomes between HFpEF and HFrEF patients were detected when the analysis was limited to inpatients. Multivariate analysis showed that older age, lower BMI, diabetes mellitus, and the absence of statin treatment were the independent predictors of all-cause death in HFrEF patients, whereas older age, absence of dyslipidemia, anemia, and LV hypertrophy were the independent predictors of all-cause death in HFpEF patients—suggesting that various factors should be considered for preserved or reduced LVEF.

      Acknowledgments

      We thank Shiro Ueda and Nobuko Ueda of Medical Edge Co. Ltd., for assembling the database by Clinical Study Supporting System (CliSSS), and Ineko Hayakawa, Hiroaki Arai, and Hiroshi Aoki for data management and system administration.

      References

        • Shiba N.
        • Shimokawa H.
        Chronic heart failure in Japan: implications of the CHART studies.
        Vasc Health Risk Manage. 2008; 4: 103-113
        • Tsutsui H.
        • Tsuchihashi M.
        • Takeshita A.
        Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.
        Am J Cardiol. 2001; 88: 530-533
        • Ramadan M.M.
        • Okura Y.
        • Ohno Y.
        • Suzuki K.
        • Taneda K.
        • Hoyano M.
        • Hao K.
        • Kimura S.
        • Kodama M.
        • Aizawa Y.
        Comparative analysis of systolic and isolated diastolic dysfunction: Sado Heart Failure Study.
        Int Heart J. 2008; 49: 459-469
        • Tsuchihashi-Makaya M.
        • Hamaguchi S.
        • Kinugawa S.
        • Yokota T.
        • Goto D.
        • Yokoshiki H.
        • Kato N.
        • Takeshita A.
        • Tsutsui H.
        • JCARE-CARD Investigators
        Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
        Circ J. 2009; 73: 1893-1900
        • Suzuki S.
        • Yamashita T.
        • Ohtsuka T.
        • Sagara K.
        • Uejima T.
        • Oikawa Y.
        • Yajima J.
        • Koike A.
        • Nagashima K.
        • Kirigaya H.
        • Ogasawara K.
        • Sawada H.
        • Aizawa T.
        Prevalence and prognosis of patients with atrial fibrillation in Japan: a prospective cohort of Shinken Database 2004.
        Circ J. 2008; 72: 914-920
        • Kaneko H.
        • Koike A.
        • Senoo K.
        • Tanaka S.
        • Suzuki S.
        • Nagayama O.
        • Sagara K.
        • Otsuka T.
        • Matsuno S.
        • Funada R.
        • Uejima T.
        • Oikawa Y.
        • Yajima J.
        • Nagashima K.
        • Kirigaya H.
        • et al.
        Role of cardiopulmonary dysfunction and left atrial remodeling in development of acute decompensated heart failure in chronic heart failure with preserved left ventricular ejection fraction.
        J Cardiol. 2012; 59: 359-365
        • Goda A.
        • Yamashita T.
        • Suzuki S.
        • Ohtsuka T.
        • Uejima T.
        • Oikawa Y.
        • Yajima J.
        • Koike A.
        • Nagashima K.
        • Kirigaya H.
        • Sagara K.
        • Ogasawara K.
        • Isobe M.
        • Sawada H.
        • Aizawa T.
        Heart failure with preserved versus reduced left ventricular systolic function: a prospective cohort of Shinken Database 2004–2005.
        J Cardiol. 2010; 55: 108-116
        • Matsuo S.
        • Imai E.
        • Horio M.
        • Yasuda Y.
        • Tomita K.
        • Nitta K.
        • Yamagata K.
        • Tomino Y.
        • Yokoyama H.
        • Hishida A.
        • Collaborators developing the Japanese equation for estimated GFR
        Revised equations for estimated GFR from serum creatinine in Japan.
        Am J Kidney Dis. 2009; 53: 982-992
        • Tonelli M.
        • Jose P.
        • Curhan G.
        • Sacks F.
        • Braunwald E.
        • Pfeffer M.
        Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial.
        BMJ. 2006; 332: 1426
        • Roger V.L.
        • Weston S.A.
        • Redfield M.M.
        • Hellermann-Homan J.P.
        • Killian J.
        • Yawn B.P.
        • Jacobsen S.J.
        Trends in heart failure incidence and survival in a community-based population.
        JAMA. 2004; 292: 344-350
        • Owan T.E.
        • Hodge D.O.
        • Herges R.M.
        • Jacobsen S.J.
        • Roger V.L.
        • Redfield M.M.
        Trends in prevalence and outcome of heart failure with preserved ejection fraction.
        N Engl J Med. 2006; 355: 251-259
        • Bhatia R.S.
        • Tu J.V.
        • Lee D.S.
        • Austin P.C.
        • Fang J.
        • Haouzi A.
        • Gong Y.
        • Liu P.P.
        Outcome of heart failure with preserved ejection fraction in a population-based study.
        N Engl J Med. 2006; 355: 260-269
        • Redfield M.M.
        • Jacobsen S.J.
        • Burnett Jr., J.C.
        • Mahoney D.W.
        • Bailey K.R.
        • Rodeheffer R.J.
        Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.
        JAMA. 2003; 289: 194-202
        • Devereux R.B.
        • Roman M.J.
        • Liu J.E.
        • Welty T.K.
        • Lee E.T.
        • Rodeheffer R.
        • Fabsitz R.R.
        • Howard B.V.
        Congestive heart failure despite normal left ventricular systolic function in a population-based sample: the Strong Heart Study.
        Am J Cardiol. 2000; 86: 1090-1096
        • Kupari M.
        • Lindroos M.
        • Iivanainen A.M.
        • Heikkila J.
        • Tilvis R.
        Congestive heart failure in old age: prevalence, mechanisms and 4-year prognosis in the Helsinki Ageing Study.
        J Intern Med. 1997; 241: 387-394
        • Malki Q.
        • Sharma N.D.
        • Afzal A.
        • Ananthsubramaniam K.
        • Abbas A.
        • Jacobson G.
        • Jafri S.
        Clinical presentation, hospital length of stay, and readmission rate in patients with heart failure with preserved and decreased left ventricular systolic function.
        Clin Cardiol. 2002; 25: 149-152
        • Cohen-Solal A.
        • Desnos M.
        • Delahaye F.
        • Emeriau J.P.
        • Hanania G.
        A national survey of heart failure in French hospitals. The Myocardiopathy and Heart Failure Working Group of the French Society of Cardiology, the National College of General Hospital Cardiologists and the French Geriatrics Society.
        Eur Heart J. 2000; 21: 763-769
        • Masoudi F.A.
        • Havranek E.P.
        • Smith G.
        • Fish R.H.
        • Steiner J.F.
        • Ordin D.L.
        • Krumholz H.M.
        Gender, age, and heart failure with preserved left ventricular systolic function.
        J Am Coll Cardiol. 2003; 41: 217-223
        • Smith G.L.
        • Masoudi F.A.
        • Vaccarino V.
        • Radford M.J.
        • Krumholz H.M.
        Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline.
        J Am Coll Cardiol. 2003; 41: 1510-1518
        • Lenzen M.J.
        • Scholte op Reimer W.J.
        • Boersma E.
        • Vantrimpont P.J.
        • Follath F.
        • Swedberg K.
        • Cleland J.
        • Komajda M.
        Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey.
        Eur Heart J. 2004; 25: 1214-1220
        • Senni M.
        • Redfield M.M.
        Heart failure with preserved systolic function. A different natural history?.
        J Am Coll Cardiol. 2001; 38: 1277-1282
        • Solomon S.D.
        • Anavekar N.
        • Skali H.
        • McMurray J.J.
        • Swedberg K.
        • Yusuf S.
        • Granger C.B.
        • Michelson E.L.
        • Wang D.
        • Pocock S.
        • Pfeffer M.A.
        • Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators
        Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients.
        Circulation. 2005; 112: 3738-3744
        • Senni M.
        • Tribouilloy C.M.
        • Rodeheffer R.J.
        • Jacobsen S.J.
        • Evans J.M.
        • Bailey K.R.
        • Redfield M.M.
        Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991.
        Circulation. 1998; 98: 2282-2289
      1. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
        N Engl J Med. 1987; 316: 1429-1435
      2. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
        N Engl J Med. 1991; 325: 293-302
        • Anand I.
        • McMurray J.J.
        • Whitmore J.
        • Warren M.
        • Pham A.
        • McCamish M.A.
        • Burton P.B.
        Anemia and its relationship to clinical outcome in heart failure.
        Circulation. 2004; 110: 149-154
        • Shiba N.
        • Matsuki M.
        • Takahashi J.
        • Tada T.
        • Watanabe J.
        • Shimokawa H.
        Prognostic importance of chronic kidney disease in Japanese patients with chronic heart failure.
        Circ J. 2008; 72: 173-178
        • Go A.S.
        • Yang J.
        • Ackerson L.M.
        • Lepper K.
        • Robbins S.
        • Massie B.M.
        • Shlipak M.G.
        Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.
        Circulation. 2006; 113: 2713-2723
        • Hosoda J.
        • Ishikawa T.
        • Matsushita K.
        • Matsumoto K.
        • Kimura Y.
        • Miyamoto M.
        • Ogawa H.
        • Takamura T.
        • Sugano T.
        • Ishigami T.
        • Uchino K.
        • Kimura K.
        • Umemura S.
        Impact of renal insufficiency on long-term clinical outcome in patients with heart failure treated by cardiac resynchronization therapy.
        J Cardiol. 2012; 60: 301-305
        • Bettencourt P.
        • Ferreira A.
        • Dias P.
        • Pimenta J.
        • Frioes F.
        • Martins L.
        • Cerqueira-Gomes M.
        Predictors of prognosis in patients with stable mild to moderate heart failure.
        J Card Fail. 2000; 6: 306-313