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

    Serum sodium concentration, blood urea nitrogen, and outcomes in patients hospitalized for acute decompensated heart failure Katsuya Kajimoto, Yuichiro Minami, Naoki Sato, Teruo Takano PII: DOI: Reference:

S0167-5273(16)31651-5 doi: 10.1016/j.ijcard.2016.07.255 IJCA 23222

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

31 March 2016 27 July 2016 30 July 2016

Please cite this article as: Kajimoto Katsuya, Minami Yuichiro, Sato Naoki, Takano Teruo, Serum sodium concentration, blood urea nitrogen, and outcomes in patients hospitalized for acute decompensated heart failure, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.07.255

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Serum sodium concentration, blood urea nitrogen, and outcomes

RI P

T

in patients hospitalized for acute decompensated heart failure

SC

Katsuya Kajimoto, MDa, Yuichiro Minami, MDb, Naoki Sato, MDc, Teruo Takano, MDd on behalf of

Division of Cardiology, Sekikawa Hospital, Tokyo; bDepartment of Cardiology, Tokyo Women’s

MA

a

NU

the investigators of the Acute Decompensated Heart Failure Syndromes (ATTEND) registry

Medical University, Tokyo; cInternal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical

ED

School Musashi-Kosugi Hospital, Kanagawa; and dDepartment of Internal Medicine,

AC CE

PT

Nippon Medical School, Tokyo.

Keywords: heart failure; serum sodium; blood urea nitrogen; outcomes assessment. Funding: This work was supported by the Japan Heart Foundation. Conflict of interest: None declared.

Address for correspondence: Katsuya Kajimoto, MD, Division of Cardiology, Sekikawa Hospital, 1-4-1, Nishi-Nippori, Arakawa-ku, Tokyo, 116-0013, Japan, Phone: +81-3-3803-5151, Fax: +81-3-3806-6808, E-mail: [email protected]

ACCEPTED MANUSCRIPT

Abstract

RI P

T

Background: This study investigated the association of a low serum sodium and elevated blood urea nitrogen (BUN) with outcomes in acute decompensated heart failure (HF) patients.

SC

Methods: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes

NU

(ATTEND) registry, 4438 patients discharged after hospitalization for acute decompensated HF were investigated to assess the association of a low serum sodium and/or elevated BUN at discharge with

MA

all-cause mortality. The patients were divided into four groups based on serum sodium (>136 or ≤136 mEq/l) and BUN (<25 or ≥25 mg/dl) at discharge. The median follow-up period after discharge was

ED

517 (381-776) days.

PT

Results: According to multivariate analysis, a low serum sodium (≤136 mEq/l) or an elevated BUN

AC CE

(≥25 mg/dl) was significantly associated with a higher risk of all-cause death compared with patients who had neither (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.22 to 1.94; P <0.001 and HR, 1.44; 95% CI, 1.19 to 1.73; P <0.001, respectively). Patients with both low serum sodium and elevated BUN had a higher risk of all-cause death relative to patients with neither (HR, 2.64; 95% CI, 2.17 to 3.20; P <0.001) and also relative to patients with either low serum sodium alone or elevated BUN alone (HR, 1.72; 95% CI, 1.36 to 2.18; P <0.001 and HR, 1.84; 95% CI, 1.53 to 2.21; P<0.001, respectively).

Conclusion: These findings demonstrated that a low serum sodium and an elevated BUN may be additive risk factors for postdischarge mortality in acute decompensated HF patients. 2

ACCEPTED MANUSCRIPT

Introduction

RI P

T

Hyponatremia is a well-known predictor of mortality in patients with heart failure (HF) [1-8]. This is probably because hyponatremia in patients with exacerbation of HF is likely to be related to

SC

hypervolemia due to sympathetic nervous overactivity, activation of the renin-angiotensin-aldosterone

NU

system (RAAS), and release of arginine vasopressin [2-4]. It was recently suggested that vasopressin enhances urea transport in the renal collecting ducts, thereby increasing blood urea nitrogen (BUN)

MA

[9,10]. Elevated BUN levels have been shown to be associated with low blood pressure, low serum sodium, and worse clinical outcomes of HF, indicating that a low serum sodium concentration may be

ED

related to an elevated BUN level in HF patients [1,11]. However, the association of serum sodium and

PT

BUN levels with outcomes is unclear in HF patients. Furthermore, very few registries of hospitalized

AC CE

HF patients collect data on the outcomes after discharge, although the majority of adverse events are known to occur after patients leave hospital [12,13]. The aim of the present study was to investigate the association of a low serum sodium concentration and/or elevated BUN level at the time of discharge from hospital with outcomes in patients who were discharged after hospitalization for acute decompensated HF.

Methods Study design and data collection The Acute Decompensated Heart Failure Syndromes (ATTEND) registry was a nationwide hospital3

ACCEPTED MANUSCRIPT

based prospective observational multicenter cohort study of patients with acute decompensated HF

RI P

T

admitted to 53 hospitals in all regions of Japan between April 1, 2007 and December 31, 2011. Patients were enrolled at their first admission and then followed, so that data collection was

SC

patient-based and not event-based. The study design, study methods, and patient profile have been

NU

described previously [14,15]. Briefly, the ATTEND registry study was designed to clarify the profile of patients with acute decompensated HF, including their demographic and clinical characteristics,

MA

treatment, in-hospital mortality, and morbidity/mortality after discharge from hospital. Management of acute decompensated HF was not specified, and treatment was selected by the attending physicians.

ED

Information obtained for each registered patient included demographic data, medical history, baseline

PT

characteristics, initial evaluation, treatment, procedures, hospital course, and disposition. This study

AC CE

was conducted in accordance with the principles of the Declaration of Helsinki. Institutional review board approval was obtained at each participating medical center prior to commencement of the study, and all patients gave written informed consent to enrollment. The endpoint classification committee (two experienced cardiologists who were not investigators) reviewed all endpoint data and asked the primary physician to confirm the cause of death if any problems were encountered.

Patients and definitions The ATTEND registry study enrolled consecutive eligible patients with a discharge diagnosis of acute decompensated HF, in whom acute decompensated HF was the primary reason for admission. Acute 4

ACCEPTED MANUSCRIPT

decompensated HF was defined according to the modified Framingham criteria. Patients aged less than

RI P

T

20 years old, those with acute coronary syndrome, and others considered unsuitable by their attending physicians were excluded from the study. Patients on hemodialysis were also excluded from this

SC

analysis. A preserved ejection fraction (EF) was defined as a documented EF >40% at admission,

NU

while a reduced EF was defined as an EF ≤40% at admission. Patients were divided into four groups based on their serum sodium and BUN values at discharge. In order to define the optimum cut-off

MA

values of serum sodium and BUN for predicting all-cause death after discharge, Receiver operating characteristics (ROC) analysis with the Youden index was employed. As shown in Figure 1, this

ED

analysis demonstrated that the area under the ROC curve (AUC) for serum sodium at discharge was

PT

0.60 and a cut-off value of 136 mEq/l had a sensitivity of 39% and specificity of 77% for predicting

AC CE

all-cause death after discharge. On the other hand, ROC analysis showed that the AUC for BUN at discharge was 0.63 and that a cut-off value of 25 mg/dl had a sensitivity of 60% and specificity of 61% for predicting all-cause death after discharge. In the present study, a low serum sodium concentration was defined as serum sodium ≤136 mEq/l and an elevated BUN level was defined as BUN ≥25 mg/dl. Accordingly, outcomes were evaluated in subgroups stratified by serum sodium >136 or ≤136 mEq/l at discharge and BUN <25 or ≥25 mg/dl at discharge. Patients assigned to group 1 had a serum sodium >136 mEq/l and BUN <25 mg/dl, group 2 had a serum sodium >136 mEq/l and BUN ≥25

mg/dl, group 3 had a serum sodium ≤136 mEq/l and BUN <25 mg/dl, and group 4 had a serum

sodium ≤136 mEq/l and BUN ≥25 mg/dl. Using these four groups, we evaluated the association of a 5

ACCEPTED MANUSCRIPT

low serum sodium and/or an elevated BUN at discharge with outcomes in patients who were

RI P

T

discharged after hospitalization for acute decompensated HF. The primary endpoint was all-cause death after discharge, while the secondary endpoints were cardiac death after discharge and a

SC

combination of all-cause death and readmission for HF after discharge.

NU

Statistical analysis

MA

Data are presented as the mean (SD), as the median with interquartile range, or as proportions. ROC curves with the Youden index were constructed to identify the optimum cut-off values of serum

ED

sodium and BUN for predicting outcomes after discharge. One-way ANOVA was used for comparison

PT

of continuous variables with a normal distribution among the four groups, while the Kruskal-Wallis

AC CE

H-test was used for comparison of skewed continuous variables or discrete variables. The chi-square test was employed to compare nominal scale variables. Cumulative probability of event curves were estimated by the Kaplan–Meier method and were compared with the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed to assess the association of candidate variables with postdischarge outcomes. The multivariate model included variables that were significant predictors of outcomes according to univariate analysis, as well as other factors known to influence postdischarge outcomes, including the age, gender, ischemic etiology, hypertension, diabetes, readmission for HF, left ventricular EF, atrial fibrillation, body mass index, systolic blood pressure, New York Heart Association functional class, hemoglobin, and use of the following drugs at discharge: 6

ACCEPTED MANUSCRIPT

loop diuretics, spironolactone, angiotensin-converting enzyme inhibitors, and angiotensin II receptor

RI P

T

blockers. The proportional hazards assumption was confirmed by calculating the log value (log survival function), and the influence of profile, interaction, and multicollinearity in these models was

SC

examined by regression diagnostic analysis. A probability (P) value of less than 0.05 (two-tailed) was

NU

considered to indicate statistical significance. An independent statistical data center (STATZ Institute, Inc., Tokyo, Japan) performed all analyses using SAS system ver. 9.3 software (SAS Institute, Cary,

ED

MA

NC, USA).

Results

PT

Baseline characteristics of all patients and subgroups stratified by serum sodium and BUN

AC CE

Among the 4842 patients enrolled in the ATTEND registry, 4530 patients were discharged after hospitalization for acute decompensated HF. Of these 4530 patients, 4438 patients were included in this analysis since data on serum sodium and BUN at discharge were available, as well as postdischarge follow-up data (Table 1). The median follow-up period after discharge was 517 (381-776) days. The all-cause mortality rate after discharge was 19.1%, while the composite endpoint (all-cause mortality and readmission for HF) was reached by 37.4% of patients. Of the 4438 patients analyzed, 1148 patients (25.8%) had a low serum sodium level (≤136 mEq/l) at discharge and 1819 (40.9%) had an elevated BUN level (≥25 mg/dl) at discharge. As shown in Figure 2, there was a modest inverse correlation between serum sodium and BUN at discharge (R=-0.18; P <0.001). The 7

ACCEPTED MANUSCRIPT

baseline clinical characteristics of the four groups of patients stratified by serum sodium and BUN at

RI P

T

discharge are shown in Table 2. In patients with a serum sodium >136 mEq/l (groups 1 and 2) or ≤136 mEq/l (groups 3 and 4), serum sodium concentrations were similar between BUN ≥25 mg/dl and BUN

SC

<25 mg/dl. There were no significant differences among the four groups with respect to gender,

NU

preserved or reduced EF, and use of beta-blockers at discharge. Patients with a BUN level ≥25 mg/dl at discharge (groups 2 and 4) were significantly older, had a higher rate of ischemic or valvular

MA

etiology, a higher frequency of a history of hospitalization for HF, were more likely to be using loop or thiazide diuretics at discharge, and had a lower hemoglobin at discharge than the patients with a BUN

ED

level <25 mg/dl (groups 1 and 3). In addition, patients with a serum sodium ≤136 mEq/l (groups 3 and

PT

4) were more likely to have a history of chronic obstructive pulmonary disease, less likely to have a

AC CE

history of hypertension or dyslipidemia, and less likely to be using angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker at discharge than the patients with a serum sodium >136 mEq/l (groups 1 and 2).

Outcomes stratified by serum sodium and BUN at discharge Figure 3 shows the unadjusted hazard ratios for the relationship between the serum sodium concentration and all-cause death after discharge in patients with and without elevation of BUN at discharge. There was a significantly higher risk of all-cause death after discharge in patients who had a low serum sodium level (≤136 mEq/l), an elevated BUN level (≥25 mg/dl), or both compared with 8

ACCEPTED MANUSCRIPT

patients who had neither an elevated BUN level nor a low serum sodium level (Table 2). After

RI P

T

adjustment for multiple comorbidities, either a low serum sodium level or an elevated BUN level was still significantly associated with a higher risk of all-cause mortality relative to patients with neither

SC

of these parameters (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.22 to 1.94; P <0.001, and

NU

HR, 1.44; 95% CI, 1.19 to 1.73; P <0.001, respectively). In addition, the combination of a low serum sodium level and an elevated BUN level was significantly associated with a higher risk of all-cause

MA

mortality relative to patients with neither parameter (HR, 2.64; 95% CI, 2.17 to 3.20; P <0.001), as well as relative to patients with either low serum sodium alone or elevation of BUN alone (HR, 1.72;

ED

95% CI, 1.36 to 2.18; P <0.001 and HR, 1.84; 95% CI, 1.53 to 2.21; P<0.001, respectively). On the

PT

other hand, a serum sodium level ≤136 mEq/l without elevation of BUN was not associated with a

AC CE

higher risk of all-cause mortality than a serum sodium >136 mEq/l combined with elevation of BUN (HR, 1.07; 95% CI, 0.85 to 1.35; P=0.577). Figure 4 shows the unadjusted relationship between serum sodium and cardiac death after discharge in patients with or without elevation of BUN at discharge. This multivariate analysis revealed the same trends for cardiac death after discharge as those reported above for all-cause death after discharge (Table 2). Furthermore, Figure 5 shows the unadjusted relationship between serum sodium and the composite endpoint (all-cause death and readmission for HF) in patients with or without elevation of BUN at discharge. This multivariate analysis revealed the same trends for the composite endpoint as those reported above for all-cause or cardiac death after discharge (Table 2). Furthermore, there was no evidence for the interaction between serum sodium and 9

ACCEPTED MANUSCRIPT

BUN with respect to all-cause death, cardiac death, or the composite endpoint (P=0.221, P=0.325, and

RI P

T

P=0.960 for the interaction, respectively).

SC

Discussion

NU

A novel finding of the present study was that a low serum sodium concentration and elevated BUN level at discharge may have an additive effect on the subsequent risk of adverse outcomes

MA

among patients discharged after hospitalization for acute decompensated HF. In the setting of acute decompensated HF, a low serum sodium level or elevated BUN level is a

ED

well-known predictor of adverse outcomes [1-3,10]. However, the association of serum sodium and

PT

BUN with outcomes has been unclear in patients with compensated HF (i.e., after stabilization of

AC CE

acute decompensated HF). We found that either a low serum sodium concentration (≤136 mEq/l) or elevation of BUN (≥25 mg/dl) at discharge was associated with a higher risk of all-cause mortality by 1.4- to 1.5-fold relative to that of patients with neither parameter, while the combination of low serum sodium and elevated BUN was associated with a higher risk of adverse events by 2.6-fold relative to patients with neither parameter. Additionally, we found no interaction between serum sodium and BUN with respect to adverse outcomes, indicating that serum sodium and BUN had effects that were independent in terms of predicting adverse outcomes. Taken together, low serum sodium and elevated BUN may have an additive effect as risk factors in HF patients. We do not have a clear explanation for this finding, but the following point can be suggested. Recently, Klein et al. suggested that marked 10

ACCEPTED MANUSCRIPT

activation of neurohormonal factors, particularly vasopressin, may be the cause of low serum sodium

RI P

T

and high BUN levels in HF patients [3]. It was also reported that elevation of BUN is associated with low blood pressure, a low serum sodium concentration, and worse outcomes in HF patients [1,11].

SC

Consistently, we found a modest inverse correlation between serum sodium and BUN at discharge. In

NU

addition, some previous studies have indicated that HF patients with hyponatremia have higher circulating levels of neurohormones (catecholamines, renin, angiotensin II, aldosterone, and

MA

vasopressin) than normonatremic HF patients, suggesting that hyponatremia in the setting of HF may be a marker of increased neurohormonal activation and greater severity of disease [2,16-21]. On the

ED

other hand, elevated BUN levels reflect the cumulative effects of hemodynamic and neurohormonal

PT

alternations that results in renal hypoperfusion [10,22-24]. In addition, BUN levels are affected by not

AC CE

only tubular reabsorption due to neurohormonal activation but also dietary protein intake and catabolism of endogenous proteins [10,22,24,25]. Recently, it has been suggested that lower body mass index is associated with a worse prognosis of HF [26,27]. It was also reported that BUN is a significant determinant of adiponectin, which is decreased in obesity, suggesting that a higher BUN level is related to a lower body mass index [28]. Taken together, it is possible that an elevated BUN level may identify HF patients who have a higher risk of developing adverse effects related to a low serum sodium concentration. However, there is a complex relationship between sodium and water reabsorption, neurohormonal activation, and BUN in the setting of HF patients [22]. Accordingly, further study will be needed to clarify the implications of this finding. 11

ACCEPTED MANUSCRIPT

The present study also revealed that 25.8% of the enrolled patients had a low serum sodium

RI P

T

(≤136 mEq/l) at discharge. Patients with acute decompensated HF and hyponatremia at admission are likely to also have hypervolemia [1,17], whereas patients with hyponatremia at discharge are likely to

SC

be euvolemic or hypovolemic since most patients had little evidence of fluid overload at discharge

NU

[17]. Although we could not determine the causes of discharge hyponatremia in our study cohort, it seems possible that hyponatremia at discharge (after stabilization of acute decompensated HF) may be

MA

related to diuretic therapy [17,29]. Previous reports have suggested that hyponatremia associated with diuretic use can be accompanied by multiple other abnormalities (such as hypokalemia,

ED

hypomagnesemia, and loop diuretic-induced neurohormonal activation) that could increase morbidity

PT

and mortality [17,29], However, the association between the serum sodium concentration and

AC CE

outcomes is complex in the setting of compensated HF [17,30]. Accordingly, further investigation will be needed to clarify the mechanism underlying the relation between a low serum sodium concentration at discharge and outcomes in HF patients. There are several limitations that need to be considered when interpreting the results of this study. First, serum sodium and BUN were measured at a single time point (at discharge), and it is unknown whether the values obtained were persistent or transient in the study population. Second, we could not investigate the causes of a low discharge serum sodium level in our patients (such as renal dysfunction, diuretic hyponatremia, etc.). Third, BUN is influenced by several factors, including dietary protein intake, basal protein catabolism, glucocorticoid-dependent catabolism, and upper 12

ACCEPTED MANUSCRIPT

gastrointestinal bleeding. Accordingly, the BUN levels of our HF patients need to be interpreted by

RI P

T

taking these factors into account.

In conclusion, the present study demonstrated that low serum sodium and elevation of BUN

SC

at discharge may have an additive effect on the risk of adverse outcomes in patients admitted to

NU

hospital for acute decompensated HF. Accordingly, improvement of both sodium and BUN by the time of discharge may be an appropriate therapeutic target for HF patients with a low serum sodium

MA

concentration and/or elevated BUN level at admission. However, further investigation will be needed to clarify the mechanisms underlying the association between low serum sodium combined with

Acknowledgments

AC CE

PT

ED

elevation of BUN at discharge and outcomes in patients with acute decompensated HF.

We thank the study investigators for their contributions. We also express our appreciation to

Katsunori Shimada, PhD (STATZ Institute, Inc., Tokyo, Japan) for his expert assistance with the statistical analysis.

Funding sources: The study was supported by the Japan Heart foundation based on the basis of a statement issued by the International Committee of Medical Journal Editors (ICMJE) in September of 2004. The funding for statistical support and administration in the study was accepted. Before the launch of the Acute Decompensated Heart Failure Syndromes (ATTEND) Registry, information on the 13

ACCEPTED MANUSCRIPT

objectives of this study, its social significance, and an abstract are provided to the society from the

RI P

T

University Hospital Medical Information Network (UMIN; Clinical Trial Registration Identification

AC CE

PT

ED

MA

NU

SC

No. UMIN000000736). The Japan Heart Foundation had no role in the conduct of the study.

14

ACCEPTED MANUSCRIPT

References

T

Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O'Connor CM,

RI P

㹙1㹛

She L, Yancy CW, Young J, Fonarow GC; OPTIMIZE-HF Investigators and Coordinators.

SC

Relationship between admission serum sodium concentration and clinical outcomes in patients

NU

hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J. 28 (2007) 980-988.

Ghali JK. Hyponatraemia in heart failure: a call for redefinition. Eur Heart J. 28 (2007)

MA

㹙2㹛

920-921.

Klein L, O'Connor CM, Leimberger JD, Gattis-Stough W, Piña IL, Felker GM, Adams KF Jr,

ED

㹙3㹛

PT

Califf RM, Gheorghiade M; OPTIME-CHF Investigators. Lower serum sodium is associated with

AC CE

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. Circulation. 111 (2005) 2454-2460. 㹙4㹛

Madan VD, Novak E, Rich MW. Impact of change in serum sodium concentration on

mortality in patients hospitalized with heart failure and hyponatremia. Circ Heart Fail. 4 (2011) 637-643. 㹙5㹛

Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and

severe hyponatremia. Am J Med. 122 (2009) 857-865. 㹙6㹛

Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated 15

ACCEPTED MANUSCRIPT

hyponatremia on selected outcomes. Arch Intern Med. 170 (2010) 294-302. Sajadieh A, Binici Z, Mouridsen MR, Nielsen OW, Hansen JF, Haugaard SB. Mild

RI P

T

㹙7㹛

hyponatremia carries a poor prognosis in community subjects. Am J Med. 122 (2009) 679-686. Sato N, Gheorghiade M, Kajimoto K, Munakata R, Minami Y, Mizuno M, Aokage T, Asai K,

SC

㹙8㹛

NU

Sakata Y, Yumino D, Mizuno K, Takano T; ATTEND Investigators. Hyponatremia and in-hospital mortality in patients admitted for heart failure (from the ATTEND registry). Am J Cardiol. 111

㹙9㹛

MA

(2013) 1019-1025.

Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart

Schrier RW. Blood urea nitrogen and serum creatinine; not married in heart failure. Circ

PT

㹙10㹛

ED

failure. Clin J Am Soc Nephrol. 4 (2009) 2013-2026.

AC CE

Heart Fail. 1 (2008) 2-5. 㹙11㹛

Klein L, Massie BM, Leimberger JD, O'Connor CM, Piña IL, Adams KF Jr, Califf RM,

Gheorghiade M; OPTIME-CHF Investigators. Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF). Circ Heart Fail. 1 (2008) 25-33. 㹙12㹛

Logeart D, Thabut G, Jourdain P, Chavelas C, Beyne P, Beauvais F, Bouvier E, Solal AC.

Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol. 43 (2004) 635-641. 16

ACCEPTED MANUSCRIPT

㹙13㹛

Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, Nodari S,

RI P

T

Lam CS, Sato N, Shah AN, Gheorghiade M. The Global Health and Economic Burden of Hospitalizations for Heart Failure: Lessons Learned From Hospitalized Heart Failure Registries. J

Sato N, Kajimoto K, Asai K, Mizuno M, Minami Y, Nagashima M, Murai K, Muanakata R,

NU

㹙14㹛

SC

Am Coll Cardiol 63 (2014) 1123-1133.

Yumino D, Meguro T, Kawana M, Nejima J, Satoh T, Mizuno K, Tanaka K, Kasanuki H, Takano

MA

T; ATTEND Investigators. Acute Decompensated Heart Failure Syndromes (ATTEND) Registry Prospective Observational Multicenter Cohort Study: Rationale, design, and preliminary data. Am

Kajimoto K, Sato N, Takano T; ATTEND investigators. eGFR and Outcomes in Patients with

PT

㹙15㹛

ED

Heart J. 159 (2010) 949-955.

AC CE

Acute Decompensated Heart Failure with or without Elevated BUN. Clin J Am Soc Nephrol. 11 (2016) 405-412. 㹙16㹛

Dzau VJ. Renal and circulatory mechanisms in congestive heart failure. Kidney Int. 31

(1987) 1402-1415. 㹙17㹛

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. 167 (2007) 1998-2005. 㹙18㹛

Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin17

ACCEPTED MANUSCRIPT

aldosterone system to clinical state in congestive heart failure. Circulation. 63 (1981) 645-651.

T

Levine TB, Franciosa JA, Vrobel T, Cohn JN. Hyponatraemia as a marker for high renin

RI P

㹙19㹛

heart failure. Br Heart J. 47 (1982) 161-166.

Dzau VJ, Packer M, Lilly LS, Swartz SL, Hollenberg NK, Williams GH. Prostaglandins in

SC

㹙20㹛

NU

severe congestive heart failure. Relation to activation of the renin--angiotensin system and hyponatremia. N Engl J Med. 310 (1984) 347-352.

Lilly LS, Dzau VJ, Williams GH, Rydstedt L, Hollenberg NK. Hyponatremia in congestive

MA

㹙21㹛

heart failure: implications for neurohumoral activation and responses to orthostasis. J Clin

Lindenfeld J, Schrier RW. Blood urea nitrogen a marker for adverse effects of loop diuretics?

PT

㹙22㹛

ED

Endocrinol Metab. 59 (1984) 924-930.

AC CE

J Am Coll Cardiol. 58 (2011) 383-385. 㹙23㹛

Schrier RW. Role of diminished renal function in cardiovascular mortality: marker or

pathogenetic factor? J Am Coll Cardiol. 47 (2006) 1-8. 㹙24㹛

Aronson D, Mittleman MA, Burger AJ. Elevated blood urea nitrogen level as a predictor of

mortality in patients admitted for decompensated heart failure. Am J Med. 116 (2004) 466-473. 㹙25㹛

Smith GL, Shlipak MG, Havranek EP, Foody JM, Masoudi FA, Rathore SS, Krumholz HM.

Serum urea nitrogen, creatinine, and estimators of renal function: mortality in older patients with cardiovascular disease. Arch Intern Med. 166 (2006) 1134-1142. 㹙26㹛

Shah R, Gayat E, Januzzi JL Jr, Sato N, Cohen-Solal A, diSomma S, Fairman E, Harjola VP, 18

ACCEPTED MANUSCRIPT

Ishihara S, Lassus J, Maggioni A, Metra M, Mueller C, Mueller T, Parenica J, Pascual-Figal D,

RI P

T

Peacock WF, Spinar J, van Kimmenade R, Mebazaa A; GREAT (Global Research on Acute Conditions Team) Network. Body mass index and mortality in acutely decompensated heart

Fonarow GC, Srikanthan P, Costanzo MR, Cintron GB, Lopatin M; ADHERE Scientific

NU

㹙27㹛

SC

failure across the world: a global obesity paradox. J Am Coll Cardiol. 63 (2014) 778-785.

Advisory Committee and Investigators. An obesity paradox in acute heart failure: analysis of

MA

body mass index and inhospital mortality for 108,927 patients in the Acute Decompensated Heart Failure National Registry. Am Heart J. 153 (2007) 74-81. Biolo A Shibata R, Ouchi N, Kihara S, Sonoda M, Walsh K, Sam F. Determinants of

ED

㹙28㹛

AC CE

1147-1152.

PT

adiponectin levels in patients with chronic systolic heart failure. Am J Cardiol. 105 (2010)

㹙29㹛

Testani JM, Cappola TP, Brensinger CM, Shannon RP, Kimmel SE. Interaction between loop

diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure. J Am Coll Cardiol. 58 (2011) 375-382. 㹙30㹛

Mohammed AA, van Kimmenade RR, Richards M, Bayes-Genis A, Pinto Y, Moore SA,

Januzzi JL Jr. Hyponatremia, natriuretic peptides, and outcomes in acutely decompensated heart failure: results from the International Collaborative of NT-proBNP Study. Circ Heart Fail. 3 (2010) 354-361.

19

ACCEPTED MANUSCRIPT

Figure legends

at discharge (B) predicting the all-cause death after discharge.

SC

Open circles indicate the optimum cut-off values

RI P

T

Figure 1: Receiver-operating characteristic (ROC) curves of serum sodium at discharge (A) and BUN

NU

BUN = blood urea nitrogen, HF = heart failure, AUC = area under the receiver-operating characteristic

MA

curve. CI = confidence interval.

PT

BUN = blood urea nitrogen.

ED

Figure 2: Correlation between serum sodium and BUN values at discharge.

AC CE

Figure 3: Kaplan-Meier estimates of all-cause death after discharge in four groups stratified by the serum sodium (Na) and BUN at discharge. BUN = blood urea nitrogen.

Figure 4: Kaplan-Meier estimates of cardiac death after discharge in four groups stratified by the serum sodium (Na) and BUN at discharge. BUN = blood urea nitrogen.

Figure 5: Kaplan-Meier estimates of the composite endpoint (all-cause death and readmission for HF 20

ACCEPTED MANUSCRIPT

after discharge) in four groups stratified by the serum sodium (Na) and BUN at discharge.

AC CE

PT

ED

MA

NU

SC

RI P

T

HF = heart failure, BUN = blood urea nitrogen.

21

AC CE

PT

ED

MA

NU

SC

RI P

T

ACCEPTED MANUSCRIPT

22

AC CE

PT

ED

MA

NU

SC

RI P

T

ACCEPTED MANUSCRIPT

23

AC CE

PT

ED

MA

NU

SC

RI P

T

ACCEPTED MANUSCRIPT

24

AC CE

PT

ED

MA

NU

SC

RI P

T

ACCEPTED MANUSCRIPT

25

AC CE

PT

ED

MA

NU

SC

RI P

T

ACCEPTED MANUSCRIPT

26

No. of patients Age, yrs Gender (% male) Etiology, % Ischemic Hypertensive Valvular Idiopathic dilated Medical history, % Prior hospitalization for heart failure Hypertension Dyslipidemia Diabetes Chronic obstructive pulmonary disease Stroke Reduced EF (≤40%), % Atrial fibrillation, %

Variables

27.4 19.1 17.2 14.2 26.5 68.3 37.5 32.3 10.2 11.5 54.4 30.4

35.2 69.5 37.2 33.8 11.8 13.5 53.6 31.2

ED

PT

2090 69.3±14.6 58.3

30.6 18.1 18.9 13.1

4438 72.5±13.8 58.2

Total

AC CE

41.6 77.9 39.9 36.3 12.4 15.0 50.8 31.4

㻌

34.6 60.1 32.5 31.0 14.0 14.0 54.1 28.4

T

53.2 65.1 34.7 36.5 14.1 17.1 55.7 35.7

33.1 13.4 21.5 15.3

619 75.5±11.6 61.2

RI P

SC

29.1 13.4 18.9 17.0

529 72.2±14.4 58.8

Serum sodium 䍸136 mEq/l BUN <25 mg/dl BUN 䍹25 mg/dl (Group 3) (Group 4)

NU

MA

35.3 21.0 20.4 8.5

1200 76.7±11.7 56.2

Serum sodium >136 mEq/l BUN <25 mg/dl BUN 䍹25 mg/dl (Group 1) (Group 2)

Table 1. Baseline characteristics of four groups stratified by serum sodium and BUN at discharge

<0.001 <0.001 0.017 0.025 0.011 <0.001 0.152 0.022

<0.001 <0.001 0.036 <0.001

<0.001 0.216

P value

ACCEPTED MANUSCRIPT

㻌

Medications at discharge, % Loop diuretic Thiazide diuretic Spironolactone or eplerenone ACE-I or ARB Beta-blocker Aspirin Warfarin Body mass index at discharge, kg/m2 Systolic BP at discharge, mmHg Diastolic BP at discharge, mmHg Heart rate at discharge, beats/min BUN at discharge, mg/dl Serum creatinine at discharge, mg/dl Serum sodium at discharge, mEq/l Hemoglobin at discharge, g/dl NYHA class at discharge, % I or II III or IV 㻌

㻌

28

96.4 3.6

94.3 5.7

ED

PT

AC CE

76.5 3.8 50.9 78.9 70.0 44.5 43.5 22.3±4.4 115.6±16.8 65.5±11.5 70.5±11.9 17.4±4.4 1.01±1.00 140.3±2.3 12.6±2.3

82.7 8.9 49.1 75.9 68.2 45.7 43.6 21.6±4.2 114.8±17.6 63.9±14.1 70.3±11.9 27.3±18.2 1.35±1.20 138.4±4.0 12.0±2.3

㻌

92.8 7.2 㻌

㻌

93.0 7.0

㻌

88.0 12.0

T

91.4 22.1 53.2 71.1 67.9 43.0 48.0 20.5±3.8 110.4±18.0 61.6±24.6 70.2±12.3 45.5±24.5 1.84±1.26 133.2±3.4 11.4±2.2

RI P

SC

85.1 9.1 59.9 70.1 66.2 43.3 43.5 20.4±3.9 109.9±17.1 61.6±10.4 71.8±12.1 18.2±4.5 1.03±1.07 133.4±3.1 12.1±2.2

NU

MA

88.0 10.7 39.1 75.6 66.0 50.1 41.7 21.4±3.9 117.7±18.2 63.5±11.5 69.2±11.5 39.3±18.7 1.81±1.29 140.0±2.6 11.3±2.2

㻌

<0.001 <0.001

<0.001 <0.001 <0.001 <0.001 0.077 0.004 0.084 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

ACCEPTED MANUSCRIPT

29

ED

PT

AC CE

T

RI P

SC

NU

MA

Values are the mean ± SD or proportion (%). BUN = blood urea nitrogen; EF = ejection fraction; ACE-I = Angiotensin-converting enzyme inhibitor, ARB = Angiotensin II receptor blocker, BP = blood pressure, NYHA = New York Heart Association.

ACCEPTED MANUSCRIPT

AC CE

1200 529

Na >136 and BUN ≥25

Na ≤136 and BUN <25

619

Na ≤136 and BUN ≥25 2090

529

Na ≤136 and BUN <25

Na >136 and BUN <25

1200

Na >136 and BUN ≥25

Cardiac death

2090

Group

All-cause death Na >136 and BUN <25

Endpoint

58 (11.0)

135 (11.3)

125 (6.0)

221 (35.7)

107 (20.2)

272 (22.7)

249 (11.9)

No. of No. of patients Patients with events (%)

30

2.00

2.06

1.00

3.99

1.87

2.10

1.00

(1.47 - 2.74)

(1.62 - 2.63)

(3.33 - 4.78)

(1.49 - 2.35)

(1.77 - 2.50)

㻌

<0.001

<0.001

<0.001

<0.001

1.59

1.54

1.00

2.64

(95% CI)

(1.15 - 2.19)

(1.19 - 1.99)

<0.001

<0.001

<0.001

P value

0.005

0.001

T

RI P

(2.17 - 3.20)

(1.22 - 1.94)

(1.19 - 1.73)

SC

1.53

1.44

1.00

Adjusted HR

NU

<0.001

P value

MA

(95% CI)

ED

Unadjusted HR

PT

㻌

Table 2. Unadjusted and adjusted risk of post-discharge outcomes stratified by serum sodium (Na) and BUN at discharge

0.325

0.221

P value for interaction

ACCEPTED MANUSCRIPT

1200 529 619

Na >136 and BUN ≥25

Na ≤136 and BUN <25

Na ≤136 and BUN ≥25 㻌

2090

Na >136 and BUN <25

㻌

146 (23.6)

㻌

㻌

1.89

1.27

1.40

1.00

3.30

㻌

<0.001

0.005

<0.001

<0.001

T

RI P

㻌

(1.64 - 2.18)

(1.08 - 1.50)

(1.23 - 1.58)

(2.55 - 4.27)

SC

NU

㻌

<0.001

<0.001

<0.001

<0.001

MA

㻌

(2.39 - 3.14)

(1.26 - 1.74)

(1.71 - 2.16)

(4.06 - 6.55)

ED

31

㻌

㻌 㻌

㻌

2.74

1.48

PT

1.92

1.00

5.15

335 (54.1)

197 (37.2)

551 (45.9)

578 (27.7)

AC CE

619

BUN = blood urea nitrogen, HR = hazard ratio, CI = confidence interval.

㻌

Composite endpoint

Na ≤136 and BUN ≥25

㻌

0.960

ACCEPTED MANUSCRIPT