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Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure

Open ArchivePublished:September 09, 2013DOI:https://doi.org/10.1016/j.jjcc.2013.07.012

      Abstract

      Background and purpose

      Hyponatremia is common and is associated with poor in-hospital outcomes in patients hospitalized with heart failure (HF). However, it is unknown whether hyponatremia is associated with long-term adverse outcomes. The purpose of this study was to clarify the characteristics, clinical status on admission, and management during hospitalization according to the serum sodium concentration on admission, and determine whether hyponatremia was associated with in-hospital as well as long-term outcomes in 1677 patients hospitalized with worsening HF on index hospitalization registered in the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).

      Methods and subjects

      We studied the characteristics and in-hospital treatment in 1659 patients hospitalized with worsening HF by using the JCARE-CARD database. Patients were divided into 2 groups according to serum sodium concentration on admission <135 mEq/mL (n = 176; 10.6%) or ≥135 mEq/mL (n = 1483; 89.4%).

      Results

      The mean age was 70.7 years and 59.2% were male. Etiology was ischemic in 33.9% and mean left ventricular ejection fraction was 42.4%. After adjustment for covariates, hyponatremia was independently associated with in-hospital death [adjusted odds ratio (OR) 2.453, 95% confidence interval (CI) 1.265–4.755, p = 0.008]. It was significantly associated also with adverse long-term (mean 2.1 ± 0.8 years) outcomes including all-cause death (OR 1.952, 95% CI 1.433–2.657), cardiac death (OR 2.053, 95% CI 1.413–2.983), and rehospitalization due to worsening HF (OR 1.488, 95% CI 1.134–1.953).

      Conclusions

      Hyponatremia was independently associated with not only in-hospital but also long-term adverse outcomes in patients hospitalized with worsening HF.

      Keywords

      Introduction

      Hyponatremia, usually defined as a serum sodium concentration <135 mEq/L, has been observed in ∼20% and consistently an independent risk for all-cause mortality as well as longer length of stay in hospitalized patients with worsening heart failure (HF) [
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      ]. However, most of these studies have been focused on short-term outcome with up to 90 days of follow-up. A recent study using a large individual patient data meta-analysis demonstrated that hyponatremia is a determinant of all-cause death during the follow-up of 3 years [
      • Rusinaru D.
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      • Doughty R.N.
      Relationship of serum sodium concentration to mortality in a wide spectrum of heart failure patients with preserved and with reduced ejection fraction: an individual patient data meta-analysis: Meta-Analysis Global Group in Chronic heart failure (MAGGIC).
      ]. This study analyzed only all-cause death and could not include cardiac death or hospitalization due to worsening HF for an inherent limitation of meta-analysis using the incorporated data from both randomized trials and observational studies [
      • Rusinaru D.
      • Tribouilloy C.
      • Berry C.
      • Richards A.M.
      • Whalley G.A.
      • Earle N.
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      Relationship of serum sodium concentration to mortality in a wide spectrum of heart failure patients with preserved and with reduced ejection fraction: an individual patient data meta-analysis: Meta-Analysis Global Group in Chronic heart failure (MAGGIC).
      ]. Therefore, little information has been available regarding the relationship between serum sodium concentration and adverse outcomes including cardiac death and hospitalization due to worsening HF. Moreover, most of these previous studies were performed mainly in the USA and Europe. Therefore, the impact of hyponatremia on outcomes has not been assessed in a broad cohort of HF patients encountered in routine clinical practice in Japan.
      The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied the characteristics, management, and the outcomes including death and rehospitalization in a broad sample of patients hospitalized with worsening HF in Japan [
      • Tsutsui H.
      • Tsuchihashi-Makaya M.
      • Kinugawa S.
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      Clinical characteristics and outcome of hospitalized patients with heart failure in Japan.
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      • Tsutsui H.
      Chronic kidney disease as an independent risk for long-term adverse outcomes in patients hospitalized with heart failure in Japan. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ,
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      • Kinugawa S.
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      • Takeshita A.
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      Effects of atrial fibrillation on long-term outcomes in patients hospitalized for heart failure in Japan: a report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
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      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      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).
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      • Hamaguchi S.
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      • Goto K.
      • Goto D.
      • Yokota T.
      • Yamada S.
      • Yokoshiki H.
      • Takeshita A.
      • Tsutsui H.
      Spironolactone use at discharge was associated with improved survival in hospitalized patients with systolic heart failure.
      ,
      • Hamaguchi S.
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      • Goto D.
      • Yokota T.
      • Kinugawa S.
      • Yokoshiki H.
      • Takeshita A.
      • Tsutsui H.
      Hyperuricemia predicts adverse outcomes in patients with heart failure.
      ,
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
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      • Goto K.
      • Goto D.
      • Furumoto T.
      • Yamada S.
      • Yokoshiki H.
      • Takeshita A.
      • Tsutsui H.
      Sex differences with respect to clinical characteristics, treatment, and long-term outcomes in patients with heart failure.
      ,
      • Hamaguchi S.
      • Kinugawa S.
      • Sobirin M.A.
      • Goto D.
      • Tsuchihashi-Makaya M.
      • Yamada S.
      • Yokoshiki H.
      • Tsutsui H.
      Mode of death in patients with heart failure and reduced vs preserved ejection fraction: report from the registry of hospitalized heart failure patients.
      ,
      • Goto D.
      • Kinugawa S.
      • Hamaguchi S.
      • Sakakibara M.
      • Tsuchihashi-Makaya M.
      • Yokota T.
      • Yamada S.
      • Yokoshiki H.
      • Tsutsui H.
      Clinical characteristics and outcomes of dilated phase of hypertrophic cardiomyopathy: report from the registry data in Japan.
      ]. The JCARE-CARD prospectively enrolled patients admitted with worsening HF in a web-based registry at 164 participating hospitals.
      The objectives of this study were to clarify the characteristics of patients, clinical status on admission, and management during hospitalization according to the serum sodium concentration on admission, and determine whether hyponatremia was associated with in-hospital as well as long-term outcomes in 1677 patients hospitalized with worsening HF on index hospitalization registered in the JCARE-CARD database [
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Tsutsui H.
      Weekend versus weekday hospital admission and outcomes during hospitalization for patients due to worsening heart failure: a report from Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ,
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Yamada S.
      • Yokoshiki H.
      • Tsutsui H.
      Characteristics, management, and outcomes for patients during hospitalization due to worsening heart failure – a report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ].

      Materials and methods

      The details of the JCARE-CARD have been described previously [
      • Tsutsui H.
      • Tsuchihashi-Makaya M.
      • Kinugawa S.
      • Goto D.
      • Takeshita A.
      Clinical characteristics and outcome of hospitalized patients with heart failure in Japan.
      ,
      • Tsuchihashi-Makaya M.
      • Hamaguchi S.
      • Kinugawa S.
      • Yokota T.
      • Goto D.
      • Yokoshiki H.
      • Kato N.
      • Takeshita A.
      • Tsutsui H.
      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).
      ,
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto K.
      • Goto D.
      • Yokota T.
      • Yamada S.
      • Yokoshiki H.
      • Takeshita A.
      • Tsutsui H.
      Spironolactone use at discharge was associated with improved survival in hospitalized patients with systolic heart failure.
      ,
      • Hamaguchi S.
      • Furumoto T.
      • Tsuchihashi-Makaya M.
      • Goto K.
      • Goto D.
      • Yokota T.
      • Kinugawa S.
      • Yokoshiki H.
      • Takeshita A.
      • Tsutsui H.
      Hyperuricemia predicts adverse outcomes in patients with heart failure.
      ,
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Tsutsui H.
      Weekend versus weekday hospital admission and outcomes during hospitalization for patients due to worsening heart failure: a report from Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ,
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Yamada S.
      • Yokoshiki H.
      • Tsutsui H.
      Characteristics, management, and outcomes for patients during hospitalization due to worsening heart failure – a report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ]. Briefly, it registered the patients hospitalized due to worsening HF as the primary cause of admission. The study hospitals were encouraged to register the patients as consecutively as possible. For each patient, baseline data included (1) demography; (2) causes of HF; (3) precipitating causes; (4) comorbidities; (5) complications; (6) clinical status; (7) electrocardiographic and echocardiographic findings; (8) laboratory data; and (9) treatments including discharge medications. The data were entered using a web-based electronic data capture (EDC) system licensed by the JCARE-CARD (www.jcare-card.jp).
      Using the database of 1677 patients registered in JCARE-CARD [
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Tsutsui H.
      Weekend versus weekday hospital admission and outcomes during hospitalization for patients due to worsening heart failure: a report from Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ,
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Yamada S.
      • Yokoshiki H.
      • Tsutsui H.
      Characteristics, management, and outcomes for patients during hospitalization due to worsening heart failure – a report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ], the present study analyzed the data of (1) patient demographics, clinical characteristics, vital signs, and laboratory data on admission [age, sex, cause of HF, medical history, prior hospitalization due to HF, New York Heart Association (NYHA) functional class, symptoms and signs, vital signs, laboratory data including serum sodium concentration, and echocardiographic parameters], (2) medication use before admission [angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), βblocker, diuretics, digitalis, Ca channel blocker, nitrate, antiarrhythmics, aspirin, warfarin, and statin], (3) in-hospital management (diuretics, inotropic agents, vasodilator agents, and non-pharmacological procedures), (4) clinical status during index hospitalization [admission from emergency room, stay at coronary care unit (CCU), length of CCU stay, length of stay, and in-hospital death], and (5) long-term outcomes (all-cause death, cardiac death, and rehospitalization due to HF). Eighteen (1.1%) patients were excluded with missing data of serum sodium concentration on admission, resulting in 1659 patients included in this analysis. Hyponatremia was defined as a serum sodium concentration on admission <135 mEq/L.

      Statistical analysis

      Patient characteristics and treatments were compared using Pearson chi-square test for categorical variables, Student's t-test for normally distributed continuous variables, and Mann–Whitney U test for continuous variables not normally distributed. Multivariable logistic regression was performed to determine the odds of in-hospital mortality. The covariates including medical history [hypertension, diabetes mellitus, ventricular tachycardia/ventricular fibrillation (VT/VF)], NYHA functional class on admission, medication use before hospitalization (ACE inhibitor, diuretics, aldosterone antagonist, and warfarin), laboratory data on admission [estimated glomerular filtration rate (eGFR), hemoglobin, and plasma B-type natriuretic peptide (BNP)] were used in developing the multivariable logistic regression model. The relationship between serum sodium concentration and long-term outcomes was evaluated among patients with the post-discharge Cox proportional hazard models. Relative risk was calculated after adjustment with covariables including age, ischemic etiology, medical history (hypertension, diabetes mellitus, sustained VT/VF, and prior stroke), NYHA functional class on admission, medication use on admission (ACE-inhibitor or ARB, βblocker, diuretics, aldosterone antagonist, and warfarin), and laboratory data on admission (eGFR, hemoglobin, and plasma BNP). SPSS version 16.0 J for Windows (Chicago, IL, USA) was used for all statistical analyses.

      Results

      Patient characteristics

      The distribution of serum sodium concentration on admission in the total cohort of study patients is shown in Fig. 1. The mean and median serum sodium concentrations on admission were 139.6 ± 4.5 mEq/L and 140.0 mEq/L, respectively, ranging from 114.0 to 156.0 mEq/L. Out of 1659 patients, 176 patients (10.6%) had hyponatremia, defined as serum sodium concentration on admission <135 mEq/L.
      Figure thumbnail gr1
      Fig. 1Distribution of serum sodium concentration on admission in patients hospitalized with worsening heart failure.
      Clinical characteristics for the total cohort of patients and those classified into 2 groups according to the presence or absence of hyponatremia are shown in Table 1. The mean age was 70.7 ± 13.5 years and 59.3% were men. The causes of HF were ischemic heart disease in 33.9%, valvular heart disease in 28.1%, hypertensive heart disease in 26.4%, and dilated cardiomyopathy in 16.9%. As expected, mean serum sodium concentration was 130.4 mEq/L in patients with hyponatremia and 140.7 mEq/L without it.
      Table 1Patient characteristics according to the presence or absence of hyponatremia.
      CharacteristicsTotalHyponatremiaNo hyponatremiap-Value
      n = 1659n = 176n = 1483
      Na, mEq/L139.7 ± 4.5130.4 ± 4.4140.7 ± 2.9<0.001
      Age, yrs (mean ± SD)70.7 ± 13.569.2 ± 14.970.9 ± 13.40.200
      Male, %59.362.058.90.441
      Causes of heart failure, %
       Ischemic33.937.333.50.327
       Valvular28.124.128.50.229
       Hypertensive26.425.326.50.737
       Dilated cardiomyopathy16.912.717.40.122
      Medical history, %
       Hypertension52.143.353.20.017
       Diabetes mellitus30.040.028.80.003
       Dyslipidemia25.922.826.20.350
       Hyperuricemia49.150.349.00.745
       Prior stroke16.421.815.80.047
       COPD5.93.06.20.098
       Smoking37.533.538.00.270
       Prior myocardial infarction28.231.727.80.297
       Atrial fibrillation34.933.935.00.780
       Sustained VT/VF6.815.75.8<0.001
      Prior hospitalization, %49.862.448.40.001
      NYHA functional class, %
       10.90.01.00.033
       210.56.611.0
       345.841.646.3
       442.751.841.7
      Symptoms, %
       Dyspnea on effort85.881.286.40.031
       Dyspnea at rest68.970.368.80.671
       Fatigue58.258.558.10.848
      Signs, %
       Jugular venous distension33.629.734.10.456
       III sound24.321.024.70.563
       Rale51.548.351.90.424
       Edema53.251.153.50.448
       Lung congestion79.481.179.20.707
       Pleural effusion56.552.657.00.266
      Hemodynamics
       Heart rate, bpm87.9 ± 24.484.7 ± 22.188.2 ± 24.60.165
       SBP, mmHg134.3 ± 30.3123.0 ± 29.5135.6 ± 30.1<0.001
       DBP, mmHg75.4 ± 18.268.6 ± 17.876.2 ± 18.1<0.001
      Laboratory data
       eGFR, mL/min/1.73 m252.5 ± 24.647.7 ± 28.953.1 ± 24.0<0.001
       Hemoglobin, g/dL12.4 ± 4.511.5 ± 2.312.5 ± 4.7<0.001
       Plasma BNP, pg/mL880 ± 9321078 ± 1035856 ± 9160.013
      Echocardiographic parameters
       LV EDD, mm55.8 ± 10.654.8 ± 10.255.9 ± 10.60.174
       LV ESD, mm44.0 ± 12.543.3 ± 13.444.0 ± 12.40.549
       LVEF, %42.4 ± 17.942.0 ± 19.442.5 ± 17.70.532
      COPD, chronic obstructive pulmonary disease; VT/VF, ventricular tachycardia/fibrillation; NYHA, New York Heart Association; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; BNP, B-type natriuretic peptide; LV, left ventricular; EDD, end-diastolic diameter; ESD, end-systolic diameter; EF, ejection fraction. Data are shown as percent or means ± SD.
      The mean age and causes of HF were comparable between 2 groups. Patients with hyponatremia more frequently had diabetes mellitus, prior stroke, sustained VT/VF, and prior hospitalization due to HF, but less hypertension. They had worse NYHA functional class and lower blood pressure on admission. eGFR and hemoglobin concentration were significantly lower in these patients and plasma BNP levels were significantly higher. Echocardiographic parameters including left ventricular ejection fraction (LVEF) were comparable between groups.
      Medication use before hospitalization was compared between groups of patients (Table 2). The use of ACE inhibitor, ARB, and βblocker was comparable between groups. The use of loop diuretics, aldosterone antagonist, antiarrhythmics, and warfarin was significantly higher in patients with hyponatremia.
      Table 2Medication use before hospitalization according to the presence or absence of hyponatremia.
      TotalHyponatremiaNo hyponatremiap-Value
      n = 1659n = 176n = 1483
      ACE inhibitor, %26.532.425.80.062
      ARB, %28.725.629.10.333
      ACE inhibitor or ARB, %51.051.151.00.968
      βblocker, %22.123.921.90.556
      Diuretics, %61.567.660.80.077
      Loop diuretics, %54.361.453.50.047
      Aldosterone antagonist, %24.136.922.6<0.001
      Digitalis, %26.427.826.30.651
      Ca channel blocker, %24.421.624.70.367
      Nitrates, %22.323.322.20.743
      Antiarrhythmics, %13.920.513.10.007
      Aspirin, %34.335.834.10.661
      Warfarin, %27.537.526.30.002
      Statin, %16.217.016.10.752
      ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker.

      In-hospital management

      The use of thiazide and spironolactone was significantly higher in patients with hyponatremia. Patients with hyponatremia were more often treated with catecholamines, PDE III inhibitor, and carperitide. Mechanical ventilation, PCI, and hemodialysis were also more frequently used in them (Table 3).
      Table 3In-hospital management according to the presence or absence of hyponatremia.
      TotalHyponatremiaNo hyponatremiap-Value
      n = 1659n = 176n = 1483
      Diuretics, %
       Loop, i.v.70.775.070.20.190
       Loop, p.o.88.886.989.00.409
       Thiazide5.49.14.90.020
       Spironolactone51.759.150.80.038
      Inotropic agents, %
       Digoxin, i.v.10.78.011.00.215
       Digoxin, p.o.33.835.833.60.561
       Dopamine20.334.718.6<0.001
       Dobutamine12.726.111.1<0.001
       Norepinephrine3.36.22.90.018
       PDE III inhibitor4.58.04.00.018
      Vasodilator agents, %
       Nitroglycerin, i.v.14.510.215.00.086
       Isosorbide dinitrate, i.v.12.113.611.90.498
       Nitroglycerin, p.o.3.12.33.20.513
       Isosorbide dinitrate, p.o.12.114.911.80.242
       Carperitide33.740.332.90.048
      Procedures, %
       Mechanical ventilation9.114.38.50.014
       PCI4.08.93.50.001
       CABG1.01.80.90.272
       Pacemaker4.47.24.00.058
       Hemodialysis3.17.82.6<0.001
       IABP1.01.80.90.268
       PCPS0.20.60.10.191
       LVAD0.10.60.10.066
      PDE, phosphodiesterase; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; DC, direct current cardioversion; IABP, intra-aortic balloon pumping; PCPS, percutaneous cardiopulmonary support; LVAD, left ventricular assist device.

      In-hospital outcomes

      Of the total cohort of patients, 37.7% were admitted from the emergency room; 34.8% of them stayed in the CCU, and mean length of CCU stay was 6.5 ± 10.2 days (median 4.0 days). Mean length of hospital stay was 33.8 ± 34.8 days and the median was 25.0 days. Crude in-hospital mortality was 5.7% (Table 4).
      Table 4In-hospital outcomes according to the presence or absence of hyponatremia.
      TotalHyponatremiaNo hyponatremiap-Value
      n = 1659n = 176n = 1483
      Visit to emergency room, %37.751.436.1<0.001
      Stay at CCU, %34.846.033.40.001
      Length of CCU stay, days6.5 ± 10.28.3 ± 14.96.2 ± 9.20.060
      Length of hospital stay, days33.8 ± 34.843.3 ± 37.032.8 ± 34.4<0.001
      In-hospital mortality, %5.713.34.6<0.001
      CCU, coronary care unit. Data are shown as percent or means ± SD.
      Patients with hyponatremia were more often admitted from emergency room (51.4% versus 36.1%, p < 0.001) and stayed in the CCU (46.0% versus 33.4%, p = 0.001). Moreover, their length of hospital stay was significantly longer (43.3 ± 37.0 days versus 32.8 ± 34.4 days, p < 0.001).
      Crude in-hospital mortality was significantly higher in patients with hyponatremia (13.3% versus 4.6%, p < 0.001). In logistic regression model with patients without hyponatremia as the reference, hyponatremia was significantly associated with in-hospital death [unadjusted odds ratio (OR) 3.029, 95% confidence interval (CI) 1.819–5.043, p < 0.001]. Even after adjustment for covariates, including medical history, NYHA functional class on admission, and medication use before hospitalization, hyponatremia was independently associated with in-hospital death (adjusted OR 2.453, 95% CI 1.265–4.755, p = 0.008).

      Long-term outcomes

      During the follow-up after hospital discharge (mean 776.6 ± 294.9 days, 2.1 ± 0.8 years), the rates of adverse outcomes were as follows: all-cause death 22.2%, cardiac death 14.7%, and rehospitalization due to worsening HF 35.6%. Hyponatremia was significantly associated also with adverse long-term outcomes including all-cause death (OR 1.952, 95% CI 1.433–2.657, p < 0.001), cardiac death (OR 2.053, 95% CI 1.413–2.983, p < 0.001), rehospitalization due to worsening HF (OR 1.488, 95% CI 1.134–1.953, p = 0.004), and all-cause death or rehospitalization due to worsening HF (OR 1.685, 95% CI 1.331–2.132, p < 0.001) (Table 5 and Fig. 2). Even after adjustment with covariables including age, ischemic etiology, medical history, NYHA functional class on admission, medication use on admission, and laboratory data on admission, hyponatremia was an independent risk factor for all-cause death (adjusted OR 1.658, 95% CI 1.112–2.473, p = 0.013), cardiac death (adjusted OR 1.775, 95% CI 1.075–2.929, p = 0.025), and all-cause death or rehospitalization due to worsening HF (adjusted OR 1.526, 95% CI 1.114–2.042, p = 0.004) (Table 5).
      Table 5Relative risk of long-term adverse outcomes associated with hyponatremia.
      OR (95% CI)p-Value
      All-cause death
       Unadjusted1.952 (1.433–2.657)<0.001
       Adjusted1.658 (1.112–2.473)0.013
      Cardiac death
       Unadjusted2.053 (1.413–2.983)<0.001
       Adjusted1.775 (1.075–2.929)0.025
      Rehospitalization due to heart failure
       Unadjusted1.488 (1.134–1.953)0.004
       Adjusted1.341 (0.955–1.884)0.090
      All-cause death or rehospitalization
       Unadjusted1.685 (1.331–2.132)<0.001
       Adjusted1.526 (1.114–2.042)0.004
      Relative risk was calculated after adjustment with covariables including age, ischemic etiology, medical history (hypertension, diabetes mellitus, sustained ventricular tachycardia/ventricular fibrillation, prior stroke), New York Heart Association functional class on admission, medication use on admission (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, βblocker, diuretics, aldosterone antagonist, warfarin), laboratory data on admission (estimated glomerular filtration rate, hemoglobin, plasma B-type natriuretic peptide). OR, odds ratio; CI, confidence interval.
      Figure thumbnail gr2
      Fig. 2Kaplan–Meier survival curves free from all-cause death (A), cardiac death (B), rehospitalization due to worsening heart failure (HF) (C), and all-cause death or rehospitalization (D) according to the presence or absence of hyponatremia.
      The results of subgroup analysis for all-cause death stratified by age (≥70 versus <70 years), sex, comorbidity (hypertension versus no hypertension and eGFR <60 mL/min/1.73 m2 versus ≥60 mL/min/1.73 m2), LVEF <40% versus ≥40%, and diuretic use versus no diuretic use are shown in Table 6. There was no significant interaction in any subgroups. These results showing that hyponatremia was associated with all-cause death in each subgroup were similar to those found on the primary analysis.
      Table 6Subgroup analysis for relative risk of all-cause death associated with hyponatremia.
      SubgroupnOR for all-cause death95% CIp-Value
      Na <135 mEq/L vs. ≥135 mEq/LBetween groupsInteraction
      Age <70 years old5582.2571.300–3.9200.0040.767
      Age ≥70 years old8052.0421.405–2.968<0.001
      Male8072.0461.396–2.998<0.0010.699
      Female5561.8271.080–3.0920.025
      Hypertension7081.9451.184–3.1970.0090.981
      No hypertension6461.9201.293–2.8520.001
      eGFR <60 mL/min/1.73 m28671.9401.395–2.696<0.0010.442
      eGFR ≥60 mL/min/1.73 m24941.3620.544–3.4130.510
      LVEF < 40%5921.5440.927–2.5730.0950.373
      LVEF ≥40%6292.1251.333–3.3860.002
      Diuretic use8382.0211.442–2.832<0.0010.355
      No diuretic use5251.3440.615–2.9380.459
      eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; OR, odds ratio; CI, confidence interval.

      Discussion

      The present study demonstrated by using the JCARE-CARD database that, among patients hospitalized with worsening HF, hyponatremia was seen in 10.6% of patients. Patients with hyponatremia had more comorbidities. Plasma BNP was significantly higher, and eGFR and hemoglobin concentration were lower in these patients. Importantly, the risks of adjusted in-hospital mortality as well as long-term adverse outcomes including all-cause death, cardiac death, and rehospitalization due to HF were significantly higher in patients with hyponatremia.
      The present study demonstrated that hyponatremia was associated with not only adverse in-hospital but also long-term outcomes in patients hospitalized with worsening HF. The present results were consistent with previous reports [
      • Klein L.
      • O’Connor C.M.
      • Leimberger J.D.
      • Gattis-Stough W.
      • Pina I.L.
      • Felker G.M.
      • Adams Jr., K.F.
      • Califf R.M.
      • Gheorghiade M.
      Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.
      ,
      • Gheorghiade M.
      • Abraham W.T.
      • Albert N.M.
      • Gattis Stough W.
      • Greenberg B.H.
      • O’Connor C.M.
      • She L.
      • Yancy C.W.
      • Young J.
      • Fonarow G.C.
      Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
      ,
      • Rusinaru D.
      • Tribouilloy C.
      • Berry C.
      • Richards A.M.
      • Whalley G.A.
      • Earle N.
      • Poppe K.K.
      • Guazzi M.
      • Macin S.M.
      • Komajda M.
      • Doughty R.N.
      Relationship of serum sodium concentration to mortality in a wide spectrum of heart failure patients with preserved and with reduced ejection fraction: an individual patient data meta-analysis: Meta-Analysis Global Group in Chronic heart failure (MAGGIC).
      ,
      • Gheorghiade M.
      • Rossi J.S.
      • Cotts W.
      • Shin D.D.
      • Hellkamp A.S.
      • Pina I.L.
      • Fonarow G.C.
      • DeMarco T.
      • Pauly D.F.
      • Rogers J.
      • DiSalvo T.G.
      • Butler J.
      • Hare J.M.
      • Francis G.S.
      • Stough W.G.
      • et al.
      Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial.
      ]. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study identified a substantial risk of short- and intermediate-term clinical events associated with decreasing serum sodium concentration in patients hospitalized for worsening HF [
      • Klein L.
      • O’Connor C.M.
      • Leimberger J.D.
      • Gattis-Stough W.
      • Pina I.L.
      • Felker G.M.
      • Adams Jr., K.F.
      • Califf R.M.
      • Gheorghiade M.
      Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.
      ]. Lower serum sodium concentrations on admission remained a predictor of increased number of days hospitalized for cardiovascular causes and increased mortality within 60 days of discharge even after adjustment for a variety of baseline variables [
      • Klein L.
      • O’Connor C.M.
      • Leimberger J.D.
      • Gattis-Stough W.
      • Pina I.L.
      • Felker G.M.
      • Adams Jr., K.F.
      • Califf R.M.
      • Gheorghiade M.
      Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.
      ]. In the OPTIMIZE-HF registry, low serum sodium was more common among patients with lower admission systolic blood pressure and a prior history of HF [
      • Gheorghiade M.
      • Abraham W.T.
      • Albert N.M.
      • Gattis Stough W.
      • Greenberg B.H.
      • O’Connor C.M.
      • She L.
      • Yancy C.W.
      • Young J.
      • Fonarow G.C.
      Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
      ]. After adjusting for differences with multivariable analysis, the risk of in-hospital death increased by 19.5%, for each 3 mmol/L decrease in patients with serum sodium <140 mmol/L [
      • Gheorghiade M.
      • Abraham W.T.
      • Albert N.M.
      • Gattis Stough W.
      • Greenberg B.H.
      • O’Connor C.M.
      • She L.
      • Yancy C.W.
      • Young J.
      • Fonarow G.C.
      Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.
      ]. The Italian Registry on Heart Failure Outcome (IN-HF) also demonstrated that hyponatremia (serum sodium concentration <136 mEq/L) was one of the independent predictors of in-hospital mortality (OR 2.00, 95% CI 1.26–3.19, p = 0.004) [
      • Oliva F.
      • Mortara A.
      • Cacciatore G.
      • Chinaglia A.
      • Di Lenarda A.
      • Gorini M.
      • Metra M.
      • Senni M.
      • Maggioni A.P.
      • Tavazzi L.
      Acute heart failure patient profiles, management and in-hospital outcome: results of the Italian Registry on Heart Failure Outcome.
      ]. However, these studies have primarily focused on in-hospital and early post-discharge mortality. Moreover, the OPTIME-CHF study, was performed using the patient data derived from a large clinical trial with restricted inclusion criteria, such as markedly reduced LVEF of ≤30%, lower serum creatinine levels of ≤3 mg/dL, and systolic blood pressure ≥80 mmHg [
      • Klein L.
      • O’Connor C.M.
      • Leimberger J.D.
      • Gattis-Stough W.
      • Pina I.L.
      • Felker G.M.
      • Adams Jr., K.F.
      • Califf R.M.
      • Gheorghiade M.
      Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.
      ]. The present study extended the prognostic impact of hyponatremia during the long-term follow-up over 2 years and more importantly to a non-selected HF population encountered in routine clinical practice by analyzing the registry data of hospitalized HF patients in Japan.
      There are several mechanisms of hyponatremia responsible for worsening clinical outcomes in HF. First, hyponatremia may directly reflect the reduction of cardiac output. Reduced cardiac output decreases renal perfusion and GFR. Previous studies [
      • Tokmakova M.P.
      • Skali H.
      • Kenchaiah S.
      • Braunwald E.
      • Rouleau J.L.
      • Packer M.
      • Chertow G.M.
      • Moye L.A.
      • Pfeffer M.A.
      • Solomon S.D.
      Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarction: the Survival And Ventricular Enlargement (SAVE) study.
      ,
      • Smith G.L.
      • Lichtman J.H.
      • Bracken M.B.
      • Shlipak M.G.
      • Phillips C.O.
      • DiCapua P.
      • Krumholz H.M.
      Renal impairment and outcomes in heart failure: systematic review and meta-analysis.
      ,
      • Heywood J.T.
      • Fonarow G.C.
      • Costanzo M.R.
      • Mathur V.S.
      • Wigneswaran J.R.
      • Wynne J.
      High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database.
      ] including our own [
      • Hamaguchi S.
      • Tsuchihashi-Makaya M.
      • Kinugawa S.
      • Yokota T.
      • Ide T.
      • Takeshita A.
      • Tsutsui H.
      Chronic kidney disease as an independent risk for long-term adverse outcomes in patients hospitalized with heart failure in Japan. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
      ] demonstrated that reduced GFR was associated with worsening outcomes in patients with HF. Second, hormonal abnormalities are also important factors of hyponatremia in HF. Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are activated in HF [
      • Francis G.S.
      The relationship of the sympathetic nervous system and the renin-angiotensin system in congestive heart failure.
      ,
      • Triposkiadis F.
      • Karayannis G.
      • Giamouzis G.
      • Skoularigis J.
      • Louridas G.
      • Butler J.
      The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.
      ]. Increased SNS and RAAS cause renal vasoconstriction and reduce GFR. These hormonal abnormalities also increase the retention of sodium and water, and induce the release of arginine vasopressin (AVP). AVP increases vascular resistance and also increase free water retention [
      • Sica D.A.
      Hyponatremia and heart failure – pathophysiology and implications.
      ,
      • Jao G.T.
      • Chiong J.R.
      Hyponatremia in acute decompensated heart failure: mechanisms, prognosis, and treatment options.
      ,
      • Bettari L.
      • Fiuzat M.
      • Felker G.M.
      • O’Connor C.M.
      Significance of hyponatremia in heart failure.
      ]. It also directly and adversely affects myocardial contractility and cell growth [
      • Goldsmith S.R.
      • Gheorghiade M.
      Vasopressin antagonism in heart failure.
      ]. Finally, hyponatremia may also result from the use of diuretics. Diuretic use has been consistently reported to be associated with long-term adverse outcomes in previous studies [
      • Cooper H.A.
      • Dries D.L.
      • Davis C.E.
      • Shen Y.L.
      • Domanski M.J.
      Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction.
      ,
      • Hasselblad V.
      • Gattis Stough W.
      • Shah M.R.
      • Lokhnygina Y.
      • O’Connor C.M.
      • Califf R.M.
      • Adams Jr., K.F.
      Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial.
      ] including our own [
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Yamada S.
      • Yokoshiki H.
      • Takeshita A.
      • Tsutsui H.
      Loop diuretic use at discharge is associated with adverse outcomes in hospitalized patients with heart failure: a report from the Japanese cardiac registry of heart failure in cardiology (JCARE-CARD).
      ]. Therefore, it is not clear whether hyponatremia is directly associated with adverse outcomes in HF or only a marker of more advanced status of HF which requires the use of diuretics.
      Given the prognostic role of hyponatremia in HF, the treatment of hyponatremia may improve outcomes in patients with HF. Tolvaptan is a V2 receptor antagonist approved for the treatment of hyponatremia (serum sodium <125 mEq/L) in patients with cirrhosis, HF, and syndrome of inappropriate anti-diuretic hormone secretion in the USA and also fluid retention in HF patients in Japan. Tolvaptan significantly increased serum sodium concentration in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST). However, it had no beneficial effects on long-term mortality or HF-related morbidity [
      • Konstam M.A.
      • Gheorghiade M.
      • Burnett Jr., J.C.
      • Grinfeld L.
      • Maggioni A.P.
      • Swedberg K.
      • Udelson J.E.
      • Zannad F.
      • Cook T.
      • Ouyang J.
      • Zimmer C.
      • Orlandi C.
      Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.
      ]. Furthermore, in the subanalysis of the EVEREST study for HF patients with hyponatremia (11.5% of total cohort), tolvaptan use was associated with greater likelihood of normalization of serum sodium, greater weight reduction at day 1 and discharge, and greater relief of dyspnea than placebo. However, long-term outcomes were comparable between patients with tolvaptan and placebo. Only in 92 patients with pronounced hyponatremia (<130 mEq/mL), tolvaptan was associated with reduced cardiovascular morbidity and mortality after discharge (p = 0.04) [
      • Hauptman P.J.
      • Burnett J.
      • Gheorghiade M.
      • Grinfeld L.
      • Konstam M.A.
      • Kostic D.
      • Krasa H.B.
      • Maggioni A.
      • Ouyang J.
      • Swedberg K.
      • Zannad F.
      • Zimmer C.
      • Udelson J.E.
      Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan.
      ]. Further clinical studies are clearly needed to determine the effects of tolvaptan on the outcomes of hyponatremic HF patients. Moreover, tolvaptan is not necessarily a therapeutic tool for hyponatremia, and is one of diuretics. Thus, it may not be easy to clarify the effects of a therapeutic intervention against hyponatremia by analyzing the effects of tolvaptan.

      Study limitations

      Several limitations inherent in the design of the registry should be considered in this study. First, the documentation of serum sodium concentration levels on admission might not accurately reflect those after discharge or their changes over time. Second, the present study was not a prospective randomized trial and, despite covariate adjustment, other measured and unmeasured factors might have influenced outcomes. Third, we did not collect information regarding the dose of loop diuretics and cannot assess its relation to prognosis. Loop diuretic use can induce hyponatremia and has been demonstrated to be associated with worse outcomes in our previous study [
      • Hamaguchi S.
      • Kinugawa S.
      • Tsuchihashi-Makaya M.
      • Goto D.
      • Yamada S.
      • Yokoshiki H.
      • Takeshita A.
      • Tsutsui H.
      Loop diuretic use at discharge is associated with adverse outcomes in hospitalized patients with heart failure: a report from the Japanese cardiac registry of heart failure in cardiology (JCARE-CARD).
      ]. Finally, data were dependent on the accuracy of documentation and abstraction by individual cardiologists that participated in this study.

      Conclusions

      Hyponatremia was observed in 10% of patients hospitalized with worsening HF. It was independently associated with in-hospital as well as long-term adverse outcomes in these patients. Further studies are needed to establish serum sodium concentration as a potential therapeutic target for HF.

      Acknowledgments

      The JCARE-CARD was supported by the Japanese Circulation Society and the Japanese Society of Heart Failure and by grants from Health Sciences Research Grants from the Japanese Ministry of Health, Labor and Welfare (Comprehensive Research on Cardiovascular Diseases) , the Japan Heart Foundation , and Japan Arteriosclerosis Prevention Fund . The JCARE-CARD Investigators and participating cardiologists are listed in the Appendix of our previous publication [
      • Tsutsui H.
      • Tsuchihashi-Makaya M.
      • Kinugawa S.
      • Goto D.
      • Takeshita A.
      Clinical characteristics and outcome of hospitalized patients with heart failure in Japan.
      ]. This study could not have been carried out without the help, cooperation, and support of the cardiologists in the survey institutions. We thank them for allowing us to obtain the data.

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