Hyponatremia and In-Hospital Mortality in Patients Admitted for Heart Failure (from the ATTEND Registry)

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1 Hyponatremia and In-Hospital Mortality in Admitted for Heart Failure (from the ATTEND Registry) Naoki Sato, MD a, *, Mihai Gheorghiade, MD b, Katsuya Kajimoto, MD c, Ryo Munakata, MD d, Yuichiro Minami, MD e, Masayuki Mizuno, MD e, Toshiyuki Aokage, MD d, Kuniya Asai, MD d, Yasushi Sakata, MD f, Dai Yumino, MD e, Kyoichi Mizuno, MD d, and Teruo Takano, MD d, on Behalf of the ATTEND Investigators Hyponatremia is known to be a poor prognostic factor in patients hospitalized with heart failure (HF), however not well studied in Japan. The aims of this study were to characterize hyponatremic hospitalized patients with HF and to clarify the relations between hyponatremia and detailed in-hospital outcomes in Japan. Among 4,837 hospitalized patients with HF enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, patient characteristics and in-hospital mortality in those with hyponatremia were examined. Hyponatremia (sodium <135 meq/l) was observed in 11.6% of patients. with hyponatremia were of similar age, included fewer men, and had a higher proportion of previous hospitalizations for HF compared to those with normonatremia. On admission, lower heart rates and blood pressures and higher brain natriuretic peptide levels were observed in patients with hyponatremia. During hospitalization, inotrope levels and mechanical device use were significantly higher in patients with hyponatremia. Rates of allcause and cardiac death were significantly higher in patients with hyponatremia, 15.0% and 11.4%, respectively, compared to 5.3% and 3.6%, respectively, in those with normonatremia. In hyponatremic hospitalized patients with HF, cardiac death accounted for 76.2% of all-cause death. In conclusion, the present study demonstrates that in Japan hyponatremia in patients hospitalized with HF is relatively common and is associated with a very high in-hospital mortality. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;111:1019e1025) It is known that hyponatremia, defined as a serum sodium concentration <135 meq/l, is a relatively common finding in patients hospitalized with heart failure (HF), with an incidence of 20% to 25%, 1e6 and it is among the most important predictors of short- and long-term mortality. 5,6 However, these data and analyses regarding hyponatremia were derived from North America and Europe populations, but not from Asian registries except Korea. 7,8 Accordingly, the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, which is a prospective multicenter observational cohort study of patients hospitalized with HF in Japan, 9 provides a unique opportunity to examine the prevalence and prognostic value of hyponatremia and the a Internal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan; b Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois; c Division of Cardiology, Sensoji Hospital, Tokyo, Japan; d Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan; e Department of Cardiology, Tokyo Women s Medical University, Japan; and f Department of Cardiology, Osaka University Graduate School of Medicine, Osaka, Japan. Manuscript received September 2, 2012; revised manuscript received and accepted December 12, This study was funded by the Japan Heart Foundation, Tokyo, Japan. See page 1024 for disclosure information. *Corresponding author: Tel: þ ; fax: þ address: nms-ns@nms.ac.jp (N. Sato). mode of in-hospital death of patients with hyponatremia in Asia Thus, the objective of the present study was to fully characterize patients with hyponatremia admitted for HF in Japan. Methods The ATTEND registry is a nationwide, multicenter, patient-based, prospective cohort study involving 52 medical hospitals throughout Japan (clinical registration with the University Hospital Medical Information Network: UMIN ). The objectives and protocol of the ATTEND registry have been described in more detail previously 9 and are summarized briefly here. hospitalized for HF who met the modified Framingham criteria 9 were eligible for the registry. aged <20 years and those who were not considered suitable for inclusion in the registry by the attending physicians were excluded. The present study excluded patients with acute coronary syndromes. The data included in the present study were collected from April 1, 2007, and December 31, On admission, the patient s history was obtained, and a physical examination was performed to assess New York Heart Association functional class, paroxysmal nocturnal dyspnea, orthopnea, rales, third heart sound, jugular venous distention, edema, coldness of the extremities, oxygen saturation by pulse oximetry, systolic and diastolic blood pressures, and heart rate /13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.

2 1020 The American Journal of Cardiology ( Table 1 Characteristics of patients with hyponatremia and those with normonatremia Variable Total (n ¼ 4,837) Hyponatremia (n ¼ 561) (n ¼ 4,276) Age (yrs) Men 2,801 (57.9%) 297 (52.9%) 2,504 (58.6%) Ischemic cause of HF 1,503 (31.1%) 164 (29.2%) 1,339 (31.3%) Medical history Previous hospitalization for HF 1,748 (36.1%) 245 (43.7%) 1,503 (35.1%) <0.001 Hypertension 3,354 (69.3%) 338 (60.2%) 3,016 (70.5%) <0.001 Dyslipidemia 1,767 (36.5%) 176 (31.4%) 1,591 (37.2%) Diabetes mellitus 1,633 (33.8%) 203 (36.2%) 1,430 (33.4%) Smokers 2,051 (42.4%) 214 (38.1%) 1,837 (43.0%) Atrial flutter or fibrillation 1,914 (39.6%) 242 (43.1%) 1,672 (39.1%) Ventricular tachycardia or ventricular fibrillation 502 (10.4%) 92 (16.4%) 410 (9.6%) <0.001 Chronic respiratory disease 458 (9.5%) 52 (9.3%) 406 (9.5%) Stroke/transient ischemic attack 678 (14.0%) 99 (17.6%) 579 (13.5%) Pacemaker/implantable cardioverter-defibrillator 440 (9.1%) 63 (11.2%) 377 (8.8%) Cardiac resynchronization therapy 110 (2.3%) 30 (5.3%) 80 (1.9%) <0.001 Clinical profile on admission Paroxysmal nocturnal dyspnea 2,560 (52.9%) 271 (48.3%) 2,289 (53.5%) Orthopnea 3,060 (63.3%) 356 (63.5%) 2,704 (63.2%) Rales 3,443 (71.2%) 384 (68.4%) 3,059 (71.5%) Third heart sound 1,745 (36.1%) 217 (38.7%) 1,528 (35.7%) Jugular venous distension 2,559 (52.9%) 324 (57.8%) 2,235 (52.3%) Peripheral edema 3,235 (66.9%) 392 (69.9%) 2,843 (66.5%) Cold extremities 1,111 (23.0%) 200 (35.7%) 911 (21.3%) <0.001 Left ventricular ejection fraction 40% 2,581 (53.4%) 320 (57.0%) 2,261 (52.9%) New York Heart Association functional class I 81 (1.7%) 7 (1.2%) 74 (1.7%) II 756 (15.6%) 65 (11.6%) 691 (16.2%) III 1,826 (37.8%) 210 (37.4%) 1,616 (37.8%) IV 2,108 (43.6%) 274 (48.8%) 1,834 (42.9%) Atrial fibrillation 1,736 (35.9%) 210 (37.4%) 1,526 (35.7%) Heart rate (beats/min) Systolic blood pressure (mm Hg) <0.001 Diastolic blood pressure (mm Hg) <0.001 BNP (pg/ml) 707 (361e1,285) 814 (410e1,493) 697 (355e1,265) Blood urea nitrogen (mg/dl) <0.001 Serum creatinine (mg/dl) Serum sodium (meq/l) <0.001 Hemoglobin (g/dl) <0.001 Anemia (World Health Organization criteria) 2,797 (57.8%) 371 (66.1%) 2,426 (56.7%) <0.001 C-reactive protein (mg/dl) 0.58 (0.20e1.80) 1.21 (0.35e4.67) 0.50 (0.19e1.61) <0.001 Total bilirubin (mg/dl) 0.7 (0.5e1.1) 0.8 (0.5e1.4) 0.7 (0.5e1.1) <0.001 Data are expressed as mean SD, as number (percentage), or as median (interquartile range). Echocardiography was also performed on admission to evaluate for a reduced left ventricular ejection fraction (40%). Blood chemistry tests were done on admission to measure blood urea nitrogen, serum creatinine, serum sodium, hemoglobin, C-reactive protein, total bilirubin, and brain natriuretic peptide (BNP). In-hospital mortality was defined as (1) death from any cause, (2) death from cardiac causes including sudden cardiac death and HF death, and (3) death from cerebral or vascular causes. Death was considered to be cardiac (defined as HF death, sudden death, or other cardiac death) unless a specific noncardiac cause was identified by each primary physician. The end point classification committee (2 experienced cardiologists who were not study investigators) reviewed the data and, if any problems were encountered, asked the primary physician to confirm the cause of death. Figure 1. Distribution of serum sodium levels on admission. The proportion of patients with hyponatremia (<135 meq/l) was 11.6% (n ¼ 561).

3 Heart Failure/Hyponatremia in Hospitalized Heart Failure 1021 Table 2 Management in patients with hypoatremia and those with normonatremia Variable Total (n ¼ 4,837) Hyponatremia (n ¼ 561) (n ¼ 4,276) Intravenous therapy Diuretics 3,692 (76.3%) 439 (78.3%) 3,253 (76.1%) Vasodilators 3,788 (78.3%) 404 (72.0%) 3,384 (79.1%) <0.001 Inotropes 896 (18.5%) 185 (33.0%) 711 (16.6%) <0.001 In-hospital management Oxygen supplementation 3,061 (63.3%) 388 (69.2%) 2,673 (62.5%) Noninvasive positive pressure ventilation 1,182 (24.4%) 137 (24.4%) 1,045 (24.4%) Intubation 361 (7.5%) 42 (7.5%) 319 (7.5%) Swan-Ganz catheterization 807 (16.7%) 102 (18.2%) 705 (16.5%) Pacemaker 185 (3.8%) 26 (4.6%) 159 (3.7%) 0.3 Cardiac resynchronization therapy 109 (2.3%) 22 (3.9%) 87 (2.0%) Implantable cardioverter-defibrillator 124 (2.6%) 22 (3.9%) 102 (2.4%) Hemodialysis 144 (3.0%) 18 (3.2%) 126 (2.9%) Continuous hemodiafiltration 125 (2.6%) 32 (5.7%) 93 (2.2%) <0.001 Revascularization therapy 449 (9.3%) 47 (8.4%) 402 (9.4%) Valve replacement 121 (2.5%) 21 (3.7%) 100 (2.3%) Intra-aortic balloon pump 123 (2.5%) 29 (5.2%) 94 (2.2%) <0.001 Percutaneous cardiopulmonary support 33 (0.7%) 11 (2.0%) 22 (0.5%) <0.001 Left ventricular assist system 17 (0.4%) 8 (1.4%) 9 (0.2%) <0.001 Outpatient medications before admission Loop diuretics 2,216 (45.8%) 300 (53.5%) 1,916 (44.8%) <0.001 Spironolactone 871 (18.0%) 174 (31.0%) 697 (16.3%) <0.001 Thiazide diuretics 331 (6.8%) 86 (15.3%) 245 (5.7%) <0.001 Angiotensin-converting enzyme inhibitors or 2,264 (46.8%) 254 (45.3%) 2,010 (47.0%) 0.44 angiotensin II receptor blockers Calcium channel blockers 1,384 (28.6%) 147 (26.2%) 1,237 (28.9%) b blockers 1,615 (33.4%) 211 (37.6%) 1,404 (32.8%) Digitalis 610 (12.6%) 92 (16.4%) 518 (12.1%) Nitrates 854 (17.7%) 96 (17.1%) 758 (17.7%) 0.72 Aspirin 1,570 (32.5%) 160 (28.5%) 1,410 (33.0%) Warfarin 1,181 (24.4%) 164 (29.2%) 1,017 (23.8%) Amiodarone 227 (4.7%) 50 (8.9%) 177 (4.1%) <0.001 Pimobendan 164 (3.4%) 51 (9.1%) 113 (2.6%) <0.001 Statins 1,125 (23.3%) 109 (19.4%) 1,016 (23.8%) Length of hospital stay (days) Median (interquartile range) 21 (14e32) 27 (15e45) 20 (13e31) <0.001 Mean SD <0.001 Data are expressed as mean SD or as number (percentage) except as indicated. Finally, the committee categorized each event for use in the present analysis. The study was conducted on the basis of the Declaration of Helsinki and the Japanese ethical guidelines for clinical studies. Of the 4,842 subjects registered, 5 patients with missing serum sodium levels on admission or incomplete data were excluded, leaving 4,837 patients for analysis. Analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina). Data are presented as mean SD and as medians with interquartile ranges. Student s t tests were used to compare groups with respect to normally distributed continuous variables, and Mann- Whitney U tests were used for other variables. Chi-square tests were used to compare nominally scaled variables. To evaluate the influence of hyponatremia with respect to inhospital mortality, a logistic regression model was applied, and heterogeneity of the influence, or interaction, was evaluated in the model. Two-tailed p values <0.05 were considered to indicate statistically significant differences. All analyses were performed at an independent biostatistics and data center (STATZ Institute, Inc., Tokyo, Japan). Results In 4,837 hospitalized patients with HF, hyponatremia (<135 meq/l) was observed in 11.6% (n ¼ 561) (Table 1). The distribution of serum sodium levels is shown in Figure 1. Comparison of patient characteristics between patients with hyponatremia and those with normonatremia are listed in Table 1. Compared to those with normonatremia, patients with hyponatremia were of similar age (73 years), included slightly fewer men, less commonly had hypertensive heart disease, and had higher proportions of history of hospitalization for HF and

4 1022 The American Journal of Cardiology ( Figure 2. Relation between admission serum sodium level and in-hospital allcause (left) and cardiac (right) deaths in all patients. Both causes of death were significantly (p <0.001) different between patients with hyponatremia and those with normonatremia. In Japan, the mean length of hospitalization is 30 days, quite different from that of Western countries. *p < cardiac resynchronized therapy. On admission, heart rates and blood pressures were significantly lower in patients with hyponatremia than in those with normonatremia. Plasma BNP levels were significantly (p ¼ 0.001) higher in patients with hyponatremia than in those with normonatremia. Impaired renal function and anemia were observed more commonly in hyponatremic hospitalized patients with HF. Before admission, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and calciumchannel blocker use was not different between patients with hyponatremia and those with normonatremia, but diuretic use was more common, especially thiazide diuretics and spironolactone, and b-blocker use was slightly higher in patients with hyponatremia (Table 2). During hospitalization, inotropes use was significantly higher and vasodilator use significantly lower in patients with hyponatremia. Nonpharmacologic management, such as cardiac resynchronization therapy, implantable cardioverter-defibrillators, continuous hemodiafiltration, intra-aortic balloon pumps, percutaneous cardiopulmonary support, and left ventricular assist systems, were used more commonly in hyponatremic patients with HF, although the use of noninvasive positive pressure ventilation, intubation, and Swan-Ganz catheterization were not different between the 2 groups. In patients with hyponatremia, a significantly longer length of hospital stay was observed (Table 2). The all-cause death rate was significantly higher in patients with hyponatremia at 15.0% compared with 5.3% in those with normonatremia. All-cause death rates in patients with hyponatremia and those with normonatremia at 7 days after admission were 1.4% and 1.0%, respectively, and cardiac death rates were 1.4% and 0.8%, respectively. The 2 rates were not statistically different between patients with hyponatremia and those with normonatremia. Furthermore, cardiac death rates were also significantly higher in hyponatremic patients with HF, as shown in Figure 2. In hyponatremic patients with HF, cardiac death accounted for 76.2% of all-cause death, higher than in normonatremic patients with HF (68.0%). In patients with hyponatremia who died from cardiac causes, systolic blood pressure at admission, known as a powerful independent risk factor for HF death, was significantly lower ( mm Hg) than in patients with noncardiac causes of death ( mm Hg) (p <0.001). To evaluate the heterogeneity of the prognostic value of hyponatremia on admission with respect to all-cause and cardiac mortality, subgroup analysis was performed. As listed in Tables 3 and 4, there were interactions for age, C- reactive protein, and BNP in all-cause and cardiac death. Also, an interaction existed for serum creatinine regarding cardiac death. Given these findings, age, renal function, C- reactive protein, and BNP should be considered from the viewpoint of the clinical significance of hyponatremia in cardiac death. Discussion The present study clearly demonstrates that hyponatremic hospitalized patients with HF are in more critical condition, requiring more intensive care, and have a poorer prognosis in terms of cardiac death as well as all-cause death. In hospitalized patients with HF, previous studies have revealed the relation between serum sodium concentration and all-cause death, but not cardiac death. To our knowledge, the present study is the first registry report to clarify the clinical impact of admission hyponatremia on cardiac mortality, with much higher in-hospital mortality of 11.4% compared to 3.6% in normonatremic hospitalized patients with HF. In Japan, the mean length of hospital stay is 30 days, quite different from that of Western countries. In the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study, in-hospital mortality during a mean 8-day hospital stay was 5.9% in hyponatremic patients with HF. 2 In the present study, 7-day mortality was 1.4%, relatively lower than that in the OPTIME-CHF study. In contrast, 30-day mortality in Japan, at 15.4%, might be relatively higher compared to that of the OPTIME-CHF study (i.e., about 10%). 2 However, the patient characteristics between the 2 studies were quite different; for example, the mean systolic blood pressure was 130 mm Hg in the present study compared to 114 mm Hg in the OPTIME-CHF study. Therefore, a simple comparison would be meaningless. It is known that hyponatremia on admission is independently associated with increased in-hospital mortality in acute emergency medical patients. 10 In the present study, 76.2% of hyponatremic hospitalized patients with HF died from cardiac causes. Chawla et al 11 demonstrated that the nature of the underlying illness, rather than the severity of hyponatremia, best explains mortality associated with hyponatremia, using data from 45,693 admitted patients. Taken together, the increased mortality is due mainly to hyponatremia in hospitalized patients with HF. The pathogenesis of hyponatremia in HF is multifactorial as follows: (1) Low cardiac output causes impairment of the kidneys ability to excrete diluted urine, (2) The decrease in cardiac output activates through baroreceptors the sympathetic nervous system and the renin-angiotensin-aldosterone

5 Heart Failure/Hyponatremia in Hospitalized Heart Failure 1023 Table 3 Subgroup analysis of the prognostic value of hyponatremia in the prediction of all-cause death Stratum Hyponatremia Odds Ratio 95% Confidence Interval for Interaction Total (15.0) 4, (5.3) 3.13 (2.39e4.09) <0.001 Age (yrs) (12.0) 2, (2.3) 5.84 (3.61e9.45) < (17.0) 2, (8.0) 2.37 (1.70e3.30) <0.001 Gender Female (14.8) 1, (5.8) 2.84 (1.91e4.21) <0.001 NS (0.530) Male (15.2) 2, (5.0) 3.37 (2.34e4.85) <0.001 Ischemic Absent (15.7) 2, (4.8) 3.70 (2.69e5.09) <0.001 NS (0.086) Present (13.4) 1, (6.6) 2.20 (1.34e3.63) History of HF Absent (11.2) 2, (4.3) 2.79 (1.87e4.14) <0.001 NS (0.559) Present (19.6) 1, (6.9) 3.28 (2.26e4.76) <0.001 Edema Absent (14.5) 1, (5.1) 3.14 (1.91e5.14) <0.001 NS (0.964) Present (15.1) 2, (5.3) 3.18 (2.31e4.39) <0.001 Left ventricular ejection fraction (%) (14.7) 2, (5.8) 2.78 (1.95e3.96) <0.001 NS (0.340) > (15.4) 1, (4.8) 3.63 (2.39e5.51) <0.001 Systolic blood pressure (mm Hg) (19.4) 2, (7.7) 2.88 (2.13e3.90) <0.001 NS (0.428) > (6.0) 2, (2.9) 2.15 (1.11e4.15) Serum creatinine (mg/dl) (13.7) 3, (4.2) 3.63 (2.58e5.11) <0.001 NS (0.060) > (17.4) 1, (8.9) 2.14 (1.39e3.30) <0.001 C-reactive protein (mg/dl) (12.7) 2, (2.9) 4.81 (3.13e7.41) <0.001 <0.001 > (17.1) 1, (9.9) 1.88 (1.33e2.65) <0.001 BNP (pg/ml) 1, (15.9) 2, (3.7) 4.96 (3.44e7.14) <0.001 <0.001 >1, (14.8) 1, (8.6) 1.84 (1.20e2.81) system and thus the release of arginine vasopressin, which enhances renal water retention, and (3) Diuretics, especially thiazide, are commonly prescribed to patients with HF. 5 In patients with hyponatremia, diuretics were prescribed more than in those with normonatremia before admission. From these findings, pharmacologic management of HF should be considered to prevent hyponatremia and also to appropriately treat hyponatremia once a patient is determined to be hyponatremic. Hyponatremia is well known as an independent risk factor in hospitalized patients with HF in Western countries. The present study has demonstrated higher mortality in hospitalized patients with HF with hyponatremia compared with normonatremia in Japan. 7 From the findings of Korean 7 and the present registries, it should be recognized that hyponatremia on admission is an important and universal risk factor in hospitalized patients with HF. It is also important to clarify how to prevent and treat hyponatremia in hospitalized patients with HF. In this respect, a vasopressin antagonist, tolvaptan, is an appropriate drug to address this issue, 12,13 although a large clinical trial, the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, could not demonstrate improved prognosis in patients hospitalized for worsening HF, which included just 8% with hyponatremia. 14 The role of vasopressin antagonists in hospitalized patients with HF with hyponatremia remains to be tested. Therefore, a prospective study using a vasopressin antagonist should be conducted for hyponatremic hospitalized patients with HF. 15 There were several limitations to the present study in terms of confirming the pathogenesis of hyponatremia. First, there were no data regarding diuretic doses, which are related to the severity of hyponatremia. Second, there were no supportive biochemical data regarding hyponatremia (e.g., concentration of arginine vasopressin). However, these issues are well known. 5 Another limitation of the present study was the lack of long-term follow-up data. However, the primary aim of the present study was to investigate the relation between hyponatremia and cardiac death in the short term. Regarding long-term assessment, further study is required. In conclusion, the present study demonstrates that in Japan hyponatremia in patients hospitalized with HF is relatively common and is associated with a very high inhospital mortality.

6 1024 The American Journal of Cardiology ( Table 4 Subgroup analysis of the prognostic value of hyponatremia in the prediction of cardiac death Stratum Hyponatremia Odds Ratio 95% Confidence Interval for Interaction Total (11.4) 4, (3.6) 3.42 (2.52e4.65) <0.001 Age (yrs) (9.2) 2, (1.5) 6.49 (3.72e11.32) < (12.9) 2, (5.5) 2.56 (1.75e3.73) <0.001 Gender Female (11.4) 1, (4.1) 2.98 (1.91e4.66) <0.001 NS (0.430) Male (11.4) 2, (3.3) 3.82 (2.51e5.81) <0.001 Ischemic Absent (11.9) 2, (3.5) 3.73 (2.60e5.37) <0.001 NS (0.409) Present (10.4) 1, (4.0) 2.81 (1.58e4.97) <0.001 History of HF Absent (8.3) 2, (2.8) 3.12 (1.97e4.95) <0.001 NS (0.687) Present (15.5) 1, (4.9) 3.54 (2.34e5.38) <0.001 Edema Absent (10.9) 1, (3.4) 3.47 (1.97e6.14) <0.001 NS (0.992) Present (11.5) 2, (3.6) 3.48 (2.41e5.04) <0.001 Left ventricular ejection fraction (%) (11.3) 2, (4.1) 2.96 (1.97e4.43) <0.001 NS (0.296) > (11.4) 1, (3.0) 4.14 (2.55e6.73) <0.001 Systolic blood pressure (mm Hg) (15.6) 2, (5.6) 3.13 (2.23e4.37) <0.001 NS (0.258) > (2.7) 2, (1.6) 1.75 (0.68e4.52) Serum creatinine (mg/dl) (11.1) 3, (2.6) 4.58 (3.11e6.76) < > (12.1) 1, (6.8) 1.89 (1.15e3.12) C-reactive protein (mg/dl) (9.1) 2, (2.1) 4.60 (2.79e7.59) < > (13.4) 1, (6.4) 2.24 (1.51e3.32) <0.001 BNP (pg/ml) 1, (13.1) 2, (2.4) 6.10 (4.03e9.23) <0.001 <0.001 >1, (10.0) 1, (6.1) 1.72 (1.04e2.84) Acknowledgment: We thank all investigators for their contributors (see the Appendix). Disclosures The authors have no conflicts of interest to disclose. Supplementary Data Supplementary data related to this article can be found at 1. De Luca L, Klein L, Udelson JE, Orlandi C, Sardella G, Fedele F, Gheorghiade M. Hyponatremia in patients with heart failure. Am J Cardiol 2005;96(suppl):19Le23L. 2. Klein L, O Connor CM, Leimberger JD, Gattis-Stough W, Piña IL, Felker GM, Adams KF Jr, Califf RM, Gheorghiade M; OPTIME-CHF Investigators. Lower serum sodium is associated with increased shortterm mortality in hospitalized patients with worsening heart failure. Results from the outcome of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (OPTIME-CHF) study. Circulation 2005;111:2454e Gheorghiade M, Rossi JS, Cotts W, Shin DD, Hellkamp AS, Piña IL, Fonarow GC, DeMarco T, Pauly DF, Rogers J, DiSalvo TG, Butler J, Hare JM, Francis GS, Stough WG, O Connor CM. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE trial. Arch Intern Med 2007;167: 1998e Friedewald VE, Emmett M, Gheorghiade M, Roberts WC. The editor s roundtable: pathophysiology and management of hyponatremia and the role of vasopressin antagonists. Am J Cardiol 2011;107:1357e Farmakis D, Filippatos G, Parissis J, Kremastions DT, Gheorghiade M. Hyponatremia in heart failure. Heart Fail Rev 2009;14:59e Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O Connor CM, She L, Yancy CW, Young J, Fonarow GC; OPTIMIZE-HF Investigators and Coordinators. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE- HF registry. Eur Heart J 2007;28:980e Choi D-J, Han S, Jeon E-S, Kim JJ, Yoo BS, Shin MS, Seong IW, Ahn Y, Kang SM, Kim YJ, Kim HS, Chae SC, Oh BH, Lee MM, Ryu KH; on behalf of the KorHF Registry. Characteristics, outcomes and predictors of long-term mortality for patients hospitalized for acute heart failure: a report from the Korean Heart Failure Registry. Korean Circ J 2011;41:363e Antherton JJ, Hayward CS, Wan Ahmad WA, Kwok B, Jorge J, Hernandez AF, Liang L, Kociol RD, Krum H; ADHERE InternationaleAsia Pacific Scientific Advisory Committee. Patient characteristics from a regional multicenter database of acute decompensated heart failure in Asia Pacific (ADHERE InternationaleAsia Pacific). J Cardiac Fail 2012;18:82e Sato N, Kajimoto K, Asai K, Mizuno M, Minami Y, Nagashima M, Murai K, Muanakata R, Yumino D, Meguro T, Kawana M, Nejima J, Satoh T, Mizuno K, Tanaka K, Kasanuki H, Takano T; ATTEND Investigators.

7 Heart Failure/Hyponatremia in Hospitalized Heart Failure 1025 Acute Decompensated Heart Failure Syndromes (ATTEND) registry. A prospective observational multicenter cohort study: rationale, design, and preliminary data. Am Heart J 2010;159:949e Whelan B, Bennett K, O Riordan D, Silke B. Serum sodium as a risk factor for in-hospital mortality in acute unselected general medical patients. QJM 2009;102:175e Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol 2011;6:960e Gheorghiade M, Gottlieb SS, Udelson JE, Konstam MA, Czerwiec F, Ouyang J, Orlandi C; Tolvaptan Investigators. Vasopressin V 2 receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia. Am J Cardiol 2006;97:1064e Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V 2 -receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099e Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure. The EVEREST Outcome Trial. JAMA 2007;297:1319e Brandimarte F, Fedele F, De Luca L, Fonarow GC, Gheorghiade M. Hyponatremia in acute heart failure syndromes: a potential therapeutic target. Curr Heart Fail Rep 2007;4:207e213.