Heart Failure

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
Liviu Klein, MD; Christopher M. O’Connor, MD; Jeffrey D. Leimberger, PhD;
Wendy Gattis-Stough, PharmD; Ileana L. Piña, MD; G. Michael Felker, MD; Kirkwood F. Adams, Jr, MD;
Robert M. Califf, MD; Mihai Gheorghiade, MD; for the OPTIME-CHF Investigators

Background—The prognostic value of serum sodium in patients hospitalized for worsening heart failure has not been well
defined.
Methods and Results—The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart
Downloaded from http://circ.ahajournals.org/ by guest on November 26, 2017

Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction hospitalized for worsening heart
failure to receive 48 to 72 hours of intravenous milrinone or placebo in addition to standard therapy. In a retrospective
analysis, we investigated the relationship between admission serum sodium and the primary end point of days
hospitalized for cardiovascular causes within 60 days of randomization, as well as the secondary end points of
in-hospital mortality, 60-day mortality, and 60-day mortality/rehospitalization. The number of days hospitalized for
cardiovascular causes was higher in the lowest sodium quartile: 8.0 (4.5, 18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus
6 (4, 12) days (P⬍0.015 for comparison with the lowest quartile). Lower serum sodium was associated with higher
in-hospital and 60-day mortality: 5.9% versus 1% versus 2.3% versus 2.3% (P⬍0.015) and 15.9% versus 6.4% versus
7.8% versus 7% (P⫽0.002), respectively. There was a trend toward higher mortality/rehospitalization for patients who
were in the lowest sodium quartile. Multivariable-adjusted Cox proportional hazards analysis showed that serum sodium
on admission, when modeled linearly, predicted increased 60-day mortality: sodium (per 3-mEq/L decrease) had a
hazard ratio of 1.18 with a 95% CI of 1.03 to 1.36 (P⫽0.018).
Conclusions—In patients hospitalized for worsening heart failure, admission serum sodium is an independent predictor of
increased number of days hospitalized for cardiovascular causes and increased mortality within 60 days of discharge.
(Circulation. 2005;111:2454-2460.)
Key Words: heart failure 䡲 prognosis 䡲 sodium 䡲 risk factors

A lthough recent clinical trials1– 4 demonstrated that hos-

pitalized heart failure patients have relatively low in-
hospital mortality (3% to 4%), their readmission for cardio-
vascular causes and all-cause mortality rates within 60 days
of discharge are as high as 25% and 10%, respectively. The
mortality and morbidity appear to be significantly higher
during this postdischarge phase than during a comparable
period for patients with severe disease that does not require
hospitalization.5 Despite the clinical significance of worsen-
ing heart failure that results in hospitalization, this phase of
the syndrome has received little attention in the cardiovascu-
lar community,6 and risk stratification for these patients has
not been well defined.
Serum sodium has been shown to be a prognostic factor in
outpatients with heart failure7; however, its significance in
hospitalized patients has not been well defined. In a retrospective
analysis of the Outcomes of a Prospective Trial of Intravenous
Milrinone for Exacerbations of Chronic Heart Failure
(OPTIME-CHF), we investigated the association between serum
sodium and all-cause mortality and readmissions for cardiovas-
cular causes in hospitalized patients with heart failure.
Methods
Study Design
The study design8 and primary results of OPTIME-CHF have been
published previously.1 The OPTIME-CHF study randomized 949

Received June 8, 2004; revision received January 26, 2005; accepted February 3, 2005.
From Northwestern University Feinberg School of Medicine (L.K., M.G.), Chicago, Ill; Duke Clinical Research Institute (C.M.O., J.D.L., W.G.-S.,
G.M.F., R.M.C.), Durham, NC; Case Western Reserve University (I.L.P.), Cleveland, Ohio; and University of North Carolina (K.F.A.), Chapel Hill, NC.
Correspondence to Mihai Gheorghiade, MD, Division of Cardiology, Northwestern University Feinberg School of Medicine, Galter 10-240, 201 E
Huron St, Chicago, IL 60611. E-mail m-gheorghiade@northwestern.edu
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000165065.82609.3D

2454
 Klein et al Hyponatremia in Hospitalized Heart Failure Patients
patients with systolic dysfunction and worsening heart failure to
receive 48 to 72 hours of intravenous milrinone (0.5 ␮g · kg⫺1 · min⫺1
without a loading dose) or placebo in a double-blinded fashion.
Patients requiring inotropic support and those with evidence of active
myocardial ischemia within the prior 3 months, serum creatinine
⬎3.0 mg/dL, systolic blood pressure ⬍80 mm Hg, or unstable
arrhythmias were excluded. Background therapy was left to the
discretion of the treating physician, but specific recommendations
for optimal medical therapy based on published guidelines were
included with the study protocol.8 The primary end point was the
total number of days hospitalized for cardiovascular causes within 60
days of randomization.8 Days lost to follow-up and days deceased
were included prospectively in the primary end point to avoid bias
toward a therapy with increased mortality.1 For instance, a patient
hospitalized initially for 7 days after randomization who then died on
day 45 of the 60-day follow-up would have 22 days as the primary
end point. Important secondary end points were 60-day mortality, the
composite of death and rehospitalizations at 60-days, the ability to
reach target dosing of ACE inhibitors at discharge, and quality of life
(QOL). The latter was assessed with a visual analog scale from 0
(worst) to 100 (best) and a subjective health status questionnaire that
assessed activity limitations, symptoms, and emotions as better,
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worse, or the same.8 End points for the present analysis were the
same as those in the overall OPTIME-CHF study, as described
previously.
Data Analysis
Continuous variables are presented as median values with 25th and
75th percentiles, whereas categorical variables are shown as percent-
ages of nonmissing values. The data are displayed in quartiles. All
analyses were performed on the basis of the intention-to-treat
principle.
Contingent on the assumptions of normality, ANOVA or Kruskal-
Wallis tests were used to explore the relationship between continu-
ous baseline and outcomes variables and serum sodium across
quartiles. Because of the nonnormality of the primary end point, the
Kruskal-Wallis test was used for this outcome. Pearson ␹2 statistics
or Fisher exact test were used to examine the association between
serum sodium quartiles and baseline categorical variables. If the
overall test for differences among quartiles was significant at
the 0.05 level, we examined the differences between the first and the
other quartiles. For dichotomous outcomes measures, logistic regres-
sion analysis was used to examine the overall association of serum
sodium and outcome with indicator variables for the higher 3
quartiles. If the overall model was significant at the 0.05 level, we
examined the significance of the higher 3 quartiles using the first
quartile as the referent group. A similar approach was used to assess
the relationship between serum sodium and 60-day mortality with
Cox proportional hazards regression. Multivariable analysis was
used to assess the independent risk of serum sodium on clinical end
points. For the multivariable analysis, 41 candidate variables were
considered that reflected demographics, cardiac history, comorbidi-
ties, bedside clinical assessment, and laboratory studies. Within each
category, the most likely predictors were identified by backwards-
variable selection, and variables were removed from the model at a
probability value ⬎0.05. The significant predictors from each of
these 5 groups were combined, and 6 prespecified covariates were
added if they had not already been included: age, gender, ethnicity,
ejection fraction, etiology, and systolic blood pressure. These covari-
ates were included on the basis of the high theoretical likelihood that
they would be associated with outcomes. Backward stepwise vari-
able selection was again performed, and a final model was generated.
Two-sided values of P⬍0.05 were considered significant for all
analyses. Analyses were performed with SAS version 8.2 (SAS
Institute Inc).
Results
Baseline Characteristics
The baseline characteristics of the study patients across serum
sodium quartiles are presented in Table 1. Patients with lower
2455
serum sodium were more likely to have more severe heart
failure (higher number of admissions in the previous year)
and tended to have a longer duration of their disease. These
patients also had lower systolic blood pressure and higher
blood urea nitrogen (BUN). However, left ventricular ejec-
tion fraction, degree of congestion, symptoms (New York
Heart Association [NYHA] functional class), and heart fail-
ure score8 were similar across quartiles.
Outcomes by Serum Sodium Concentrations
The primary end point of days hospitalized for cardiovascular
causes within 60 days of randomization was higher in the
lowest sodium quartile than in the other quartiles: 8.0 (4.5,
18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus 6 (4, 12) days
(P⬍0.001 overall; P⬍0.015 for any quartile compared with
first; Table 2). The in-hospital and 60-day mortality rates
were also increased in the lowest quartile of serum sodium:
5.9% versus 1% versus 2.3% versus 2.3% (P⫽0.015) and
15.9% versus 6.4% versus 7.8% versus 7% (P⫽0.002),
respectively (Figure 1). Patients in the lowest sodium quartile
trended toward higher rates of death or rehospitalization at 60
days: 41% versus 30.4% versus 33.5% versus 33.6%
(P⫽0.095). The primary end point had a moderate correlation
with the 60-day mortality and 60-day death/rehospitalization
rates (r⫽0.48 and 0.64, respectively, by Spearman rank
correlation).
There were no differences observed across serum sodium
quartiles in the rates of treatment failure (defined as sustained
hypotension for ⬎30 minutes that required intervention,
myocardial ischemia and arrhythmias, worsening heart fail-
ure, and failure to achieve adequate clinical improvement at
48 hours after study-drug infusion) while patients were taking
the study drug. However, significantly more patients with low
serum sodium developed sustained hypotension that necessi-
tated intervention (Table 2). There was no association be-
tween serum sodium concentration and the ability to reach
target dosing of ACE inhibitors by discharge.
Baseline QOL scores were comparable across sodium
quartiles, and all patients had substantial and similar improve-
ment over baseline in the visual analog QOL by hospital
discharge that was maintained at 60-day follow-up. There
was no difference in the QOL by the subjective health status
questionnaire in the 4 quartiles, with an equal percentage of
patients feeling better or the same by 60 days (Table 2).
Changes in Serum Sodium Concentration
Although on average, serum sodium increased by discharge
in the lowest admission quartile, it decreased in the other 3
quartiles: ⫹1 (⫺2, 3) versus ⫺1 (⫺3, 1) versus ⫺2 (⫺3, 0)
versus ⫺3 (⫺6, ⫺2; P⬍0.001). Thirty-eight percent (93/244)
of the patients who were in the lowest serum sodium quartile
at baseline were discharged with serum sodium concentration
⬎135 mEq/L. Their 60-day mortality rate was 10.75%
compared with 17.22% among patients who remained hy-
ponatremic at discharge (P⫽0.19). The 60-day mortality rates
in the other 3 quartiles were 6.4% versus 7.8% versus 7%,
respectively.
 2456 Circulation May 17, 2005

TABLE 1. Baseline Characteristics by Serum Sodium Quartiles

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile
(n⫽256) (n⫽207) (n⫽220) (n⫽260) P
Demographics
Age, y 68 (53–76) 65 (55–74) 68 (57–76) 69 (59–77) 0.06
Women, % 32 35 33 35 0.92
Ethnicity, %
White 72 66 64 58 0.041
Black 25 32 34 39
Medical history
Ischemic etiology, % 55 50 55 45 0.06
Myocardial infarction, % 45 51 50 47 0.59
Coronary artery bypass surgery, % 38 29 31 27 0.041
Hypertension, % 62 68 69 71 0.18
Atrial fibrillation, % 31 30 34 32 0.82
Ventricular tachycardia, % 11 10 11 8 0.65
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Months since heart failure diagnosis 39.5 (17.5–75) 37 (11–69) 39 (12–70) 30.5 (9–65) 0.054
Hospitalizations in prior 12 months, n 2 (1–3) 1 (0–3) 1 (0–2) 1 (0–3) 0.003*
Clinical characteristics
Ejection fraction, % 21 (17.5–30) 22 (17–30) 22.5 (19.5–30) 24.5 (20–30) 0.21
NYHA class, %
III 47 45 49 42 0.12
IV 49 49 45 47
Systolic blood pressure, mm Hg 114 (100–130) 120 (105–136) 120 (107–132) 123 (110–138) ⬍0.001*
Diastolic blood pressure, mm Hg 70 (60–78) 70 (60–80) 70 (62–80) 70 (60–80) 0.11
Baseline heart rate, bpm 84 (72–96) 84 (72–97) 85 (76–95) 81 (70–94) 0.11
Jugular venous pressure ⬎6 cm, % 76 72 73 70 0.57
Pulmonary rales, % 83 79 80 82 0.67
Systolic murmur, % 52 47 43 51 0.24
Third heart sound, % 59 61 56 58 0.76
Heart failure score (4–10) 6 (5–7) 6 (5–7) 6 (5–7) 6 (5–7) 0.72
Laboratory values
Serum sodium, mEq/L 134 (132–135) 138 (137–138) 140 (139–140) 142 (141–144) ⬍0.001*
Serum potassium, mEq/L 4.2 (3.9–4.6) 4.1 (3.8–4.5) 4 (3.8–4.4) 4 (3.8–4.4) 0.012*
Serum BUN, mg/dL 33 (20–49) 24 (17–39) 23 (16–37) 24 (18–35) ⬍0.001*
Serum creatinine, mg/dL 1.4 (1.1–1.8) 1.4 (1–1.8) 1.3 (1–1.7) 1.4 (1.1–1.7) 0.069
Admission medications, %
Diuretics 92 93 89 88 0.27
ACE inhibitors 70 70 67 74 0.35
Angiotensin receptor blockers 13 14 17 8 0.022
␤-Blockers 21 20 25 23 0.53
Digoxin 77 82 71 63 ⬍0.001*
Calcium channel blockers 12 10 15 17 0.086
Amiodarone 16 15 16 15 0.98
Continuous variables are presented as median (interquartile range). ANOVA or Kruskal-Wallis test was used to test for overall
differences between continuous variables. Pearson ␹2 statistics or Fisher exact test was used to test differences between categorical
variables.
*All individual quartiles vs first quartile, P⬍0.05.

Effect of Milrinone Treatment
There was no difference observed in the number of days
hospitalized for cardiovascular causes within 60 days of
randomization regardless of the treatment assignment (mil-
rinone or placebo) for any of the serum sodium quartiles.
The 60-day mortality rate was also similar across sodium
quartiles among patients treated with milrinone compared
with placebo (Table 3). The interaction between treatment
assignment and serum sodium was not significant for any
outcome (P⬎0.35), which indicates that the relationship
 Klein et al Hyponatremia in Hospitalized Heart Failure Patients 2457

TABLE 2. Outcomes by Serum Sodium Quartiles (Unadjusted Analysis)

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile
(n⫽256) (n⫽207) (n⫽220) (n⫽260) P
Primary end point, d 8 (4.5–18.5) 6 (4–13) 6 (4–11.5) 6 (4–12) 0.001*
Mortality, n (%)
In hospital 15 (5.9) 2 (1) 5 (2.3) 6 (2.3) 0.015*
OR (95% CI) Referent 0.16 (0.035–0.69) 0.37 (0.13–1.05) 0.38 (0.15–0.99)
60 Days† 40 (15.9) 13 (6.4) 17 (7.8) 18 (7) 0.002*
OR (95% CI) Referent 0.38 (0.2–0.72) 0.47 (0.27–0.82) 0.42 (0.24–0.74)
Rehospitalization/death within 60 days, n (%)† 103 (41) 62 (30.4) 73 (33.5) 87 (33.6) 0.095
OR (95% CI) Referent 0.63 (0.43–0.9) 0.72 (0.5–1.06) 0.73 (0.51–1.04)
Treatment failures (during infusion), % 17.9 13.2 13.8 13.1 0.4
In-hospital complications (any) 14.8 9.2 9.1 16.9 0.018
Sustained hypotension 10.5 3.9 5 6.9 0.022*
New atrial arrhythmias 4.3 3.4 0.9 3.5 0.11
Sustained ventricular tachycardia 0.8 1.5 1.8 3.8 0.09
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Ventricular fibrillation 1.2 1.9 0.9 0.8 0.7

Reached target ACE dosing by discharge, % 39.1 41.1 42.3 46.9 0.32
Visual analog QOL score (0–100)
Baseline 40 (25–50) 40 (25–55) 40 (25–50) 50 (30–60) 0.053
Change at discharge 25 (10–40) 26.5 (10–50) 30 (15–45) 25 (10–40) 0.051
Change at 30 days 20 (2.5–40) 25 (5–40) 23.5 (5–40) 20 (0–38) 0.72
Change at 60 days 21 (5–45) 30 (7–45) 25 (5–40) 25 (5–40) 0.72
Subjective health questionnaire (better/same)
Change at discharge, % 99 99 100 99 0.41
Change at 30 days, % 85 88 90 88 0.5
Change at 60 days, % 87 84 88 88 0.68
Continuous variables are presented as median (interquartile range). ANOVA or Kruskal-Wallis test was used to test for overall
differences between continuous variables. Cox proportional hazards regression with indicator variables was used to analyze 60-day
mortality. Categorical variables were analyzed with logistic regression. P value in last column represents overall relationship with
serum sodium for regression models.
*All individual quartiles vs first quartile, P⬍0.05.
†Raw percentages of patients followed up to 60-day visit.

between serum sodium and end points did not differ 1.22 to 3.04, P⫽0.004), and elevated BUN (HR⫽1.33 per
between treatment groups (Table 3). 5-mg/dL increase, 95% CI 1.19 to 1.47, P⬍0.001).

Multivariable Analysis Discussion

The findings of the Cox proportional hazards model were
consistent with those of the unadjusted analysis for the
primary end point and for the 60-day mortality rate. After
adjustment for baseline differences, serum sodium on admis-
sion remained a significant predictor of the number of days
hospitalized for cardiovascular causes within 60 days of
randomization (P⫽0.03). Serum sodium, when modeled lin-
early, remained a significant predictor of increased 60-day
mortality (hazard ratio [HR] 1.18 per 3-mEq/dL decrease,
95% CI 1.03 to 1.36, P⫽0.018). This translates into an 18%
relative increase in the probability of death within 60 days of
randomization for every 3-mEq/dL decrease in admission
sodium values (Figure 2). Other predictors of 60-day mortal-
ity were increasing age (HR⫽1.26 per 10-year increase, 95%
CI 1.06 to 1.51, P⫽0.01), lower systolic blood pressure
(HR⫽1.28 per 10-mm Hg decrease, 95% CI 1.12 to 1.46,
P⬍0.001), NYHA class IV symptoms (HR⫽1.93, 95% CI
Worsening heart failure that results in hospitalization repre-
sents a major public health problem because of the high
postdischarge mortality rate, large number of hospital read-
missions, and significant associated costs. Several recent
studies have tried to identify predictors of mortality or
rehospitalization that could potentially aid clinical decision
making in this population.9 –14 The present analysis, con-
ducted in a sample derived from a large clinical trial,
identifies a substantial risk of short- and intermediate-term
clinical events associated with decreasing serum sodium
concentration in patients hospitalized for worsening heart
failure. Lower concentrations of serum sodium on admission
remained a predictor of increased number of days hospital-
ized for cardiovascular causes and increased mortality within
60 days of discharge after adjustment was made for a variety
of baseline variables.
In heart failure, decreased stimulation of mechanoreceptors
in the left ventricle, carotid sinus, aortic arch, and renal
 2458 Circulation May 17, 2005
Figure 1. Kaplan-Meier survival curves to 60 days by serum
sodium quartiles (unadjusted analysis). Probability value ⬍0.05
for first quartile vs each of the other quartiles from Cox propor-
tional hazards model.
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afferent arterioles leads to increased sympathetic discharge,
activation of the renin-angiotensin-aldosterone system, and
nonosmotic release of vasopressin, among other neurohor-
mones.15 Increased sympathetic drive contributes to avid
sodium and water retention through renal vasoconstriction,
stimulation of the renin-angiotensin-aldosterone system, and
a direct effect on the proximal convoluted tubule.15,16 In-
creased angiotensin II and aldosterone levels in heart failure
lead to decreased sodium and water delivery to the collecting
duct, which, combined with resistance to the action of
natriuretic peptides, result in impairment of free-water excre-
tion and hyponatremia.15 Finally, the nonosmotic stimulation
of vasopressin release leads to elevated vasopressin concen-
tration, which results in an increased number of aquaporin
water channels in the collecting duct of the kidney that
promote abnormal free water retention and contribute to the
development of hyponatremia.17–19
In several studies from the early 1980s, Dzau et al20 –22
observed that patients with heart failure and low serum
sodium had higher circulating levels of catecholamines,
renin, angiotensin II, aldosterone, and vasopressin than nor-
monatremic patients. Hyponatremic patients had an impaired
Figure 2. Fourteen-day and 60-day mortality rates by serum
sodium levels (unadjusted analysis). Survival estimates are prod-
uct-limit estimates from Cox proportional hazards model.
neurohormonal response to orthostasis, lower hepatic and
renal plasma flows, elevated liver enzymes, and prerenal
azotemia compared with normonatremic patients. These stud-
ies raised the hypothesis that low serum sodium may be a
marker of neurohormonal activation, reflecting the severity of
the disease. Indeed, the degree of neurohormonal activa-
tion23–25 and the prevalence of low serum sodium (21%
versus 7%)1,26 are markedly higher in hospitalized patients
with worsening heart failure than in outpatients with stable
disease.
Low serum sodium has also been correlated with ventric-
ular ectopy,27 an increase in sudden death28 and increased
in-hospital mortality.29 A clinical risk model derived from a
retrospective review of medical records has shown a signif-
icant 50% increase in 30-day all-cause mortality in patients
with serum sodium below 136 mEq/L, risk that was also
maintained at 1 year, compared with patients with normal
serum sodium.10
Hyponatremic patients have a greater immediate improve-
ment in the cardiac index and left ventricular filling pressures
in response to ACE inhibitors,30 and although they may
initially have more symptomatic hypotension in response to
ACE inhibitors, they have significant improvement in serum
sodium and survival compared with normonatremic
patients.30 –32
Many prior reports examining the prognostic value of
serum sodium in hospitalized heart failure patients were
either small or consisted of retrospective medical records
review. The present retrospective analysis is the first to
examine this relationship using data from a prospective,
randomized clinical trial that had an extensive standardized
assessment of baseline characteristics and outcomes and a
99% complete follow-up rate. In addition, we were able to
analyze changes in serum sodium between admission and
discharge. In the present analysis, lower serum sodium on
admission was associated with more severe heart failure
(longer duration of the disease and more hospitalizations in
the previous year) but not with higher degree of congestion
(similar prevalence of rales, jugular venous pressure, and
edema across groups; Table 1). Lower serum sodium was also
associated with a lower blood pressure and higher BUN
(Table 1). Reduction in renal perfusion, renin-angiotensin-
aldosterone, and sympathetic activation lead to increased
sodium and water reabsorption that is coupled with enhanced
urea reabsorption in the proximal tubules.13 Vasopressin, on
binding to V2 receptors in the inner medullary collecting
ducts, increases urea permeability through activation of urea
transporters, which enables its reabsorption.33 The marked
activation of neurohormonal systems, particularly vasopres-
sin, may be the cause of both low serum sodium and high
BUN in patients with decompensated heart failure. Use of
neurohormonal blockade with ACE inhibitors and ␤-blockers
may blunt some of these effects and may explain why
hyponatremic patients in the OPTIME-CHF study had much
lower BUN levels than in studies done in the 1980s, in which
the use of ACE inhibitors and ␤-blockers was significantly
lower.
Although the OPTIME-CHF study excluded patients with
active ischemia, renal failure, significant arrhythmias, or
 Klein et al Hyponatremia in Hospitalized Heart Failure Patients 2459

TABLE 3. Outcomes by Serum Sodium Quartiles and Treatment Assignments

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile

Milrinone Placebo Milrinone Placebo Milrinone Placebo Milrinone Placebo

(n⫽126) (n⫽129) (n⫽102) (n⫽105) (n⫽115) (n⫽105) (n⫽129) (n⫽131) P
Primary end point, d* 7 (4–19) 9 (5–18) 6 (4–10) 6 (4–14) 6 (4–9) 6 (4–13) 6 (4–13) 6 (4–10) 0.35
Mortality, %
In hospital† 6.3 5.4 1 1 3.5 1 3.1 1.5 0.53
60 Days‡ 18.3 13.6 5.9 6.8 5.3 10.6 9.3 4.7 0.91
Rehospitalization/death at 60 days§ 39.7 42.4 26.7 34 33.3 33.7 36.4 30.8 0.59
*Continuous variables are presented as median (interquartile range). P value is of interaction of treatment and serum sodium from regression of log-transformed
response.
†P value is of interaction of treatment and serum sodium from logistic model.
‡Raw percentages of patients followed up to 60-day visit. P value is of interaction of treatment and serum sodium level from Cox model.
§Raw percentages of patients followed up to 60-day visit. P value is of interaction of treatment and serum sodium level from logistic model.

those who required inotropes,1,8 patients in the lowest serum the OPTIME-CHF study, however, do appear to have a
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sodium quartile had an event rate (death/rehospitalizations) of
41% within 60 days, which suggests that they are at partic-
ularly high risk (Table 2). Moreover, only 38% of these
patients were able to normalize their serum sodium by the
time of discharge. The 60-day mortality rate in this group was
11% compared with 17% in patients who remained persis-
tently hyponatremic at discharge; however, this difference did
not achieve statistical significance, probably owing to the
small number of end points.
Milrinone is known to improve hemodynamics in heart
failure patients,34 and it has been suggested that it might be
useful especially in patients with more severe heart fail-
ure.35,36 In the present analysis, patients in the lowest serum
sodium quartile (with more severe heart failure and presum-
ably worse hemodynamics) experienced more sustained hy-
potension while using milrinone, despite having a similar
improvement in QOL score.
It has also been suggested that heart failure patients with
hyponatremia are more susceptible to the hypotensive and
azotemic effects of ACE inhibitors, possibly because they are
more dependent on neurohormones to sustain their blood
pressure, and therefore initiation or uptitration of ACE
inhibitors is particularly difficult in these patients.30,31 Nev-
ertheless, in the present study, there were no significant
differences in the percentages of patients able to achieve
target doses of ACE inhibitors at discharge across serum
sodium quartiles.
The high short-term mortality and morbidity rates in
patients hospitalized with worsening heart failure underline
the importance of identification of modifiable risk factors. Of
the predictors of mortality in the OPTIME-CHF study (age,
NYHA class, low blood pressure, high BUN, and hyponatre-
mia), hyponatremia is potentially modifiable by an available
treatment (ie, vasopressin antagonists).37,38
The present analysis has several limitations. The study
sample is derived from a randomized, controlled trial and
consists solely of patients with impaired systolic function and
relatively preserved renal function. Whether serum sodium
concentration would be predictive of outcomes in patients
hospitalized for heart failure and more advanced renal dys-
function deserves further investigation. Patients enrolled in
clinical profile similar to that of unselected registry patients
hospitalized for heart failure who have left ventricular dys-
function: normotensive, with a high degree of congestion and
relatively preserved renal function.39 Finally, although lower
serum sodium is related to higher mortality, care must be
observed in interpreting the exact shape of the relationship
because of the relatively small number of deaths observed.
Conclusions
In this retrospective analysis, we found that in patients
hospitalized for worsening heart failure and systolic dysfunc-
tion, serum sodium on admission is an important predictor of
increased number of days hospitalized for cardiovascular
causes and increased mortality within 60 days of discharge.
The present study also raised the hypothesis that normaliza-
tion of serum sodium during hospitalization may improve
survival; however, this assumption needs to be tested further
in randomized clinical trials.
Acknowledgment
Dr Klein is supported by a National Heart, Lung, and Blood Institute
training grant (No. T32 HL069771-O1A1).
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 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
Liviu Klein, Christopher M. O'Connor, Jeffrey D. Leimberger, Wendy Gattis-Stough, Ileana L.
Piña, G. Michael Felker, Kirkwood F. Adams, Jr, Robert M. Califf and Mihai Gheorghiade
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for the OPTIME-CHF Investigators

Circulation. 2005;111:2454-2460; originally published online May 2, 2005;

doi: 10.1161/01.CIR.0000165065.82609.3D
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