clinical Report  Tolvaptan

CLINICAL report

Effect of serum sodium concentration and tolvaptan

treatment on length of hospitalization in patients
with heart failure 
Philip L. Cyr, Katherine A. Slawsky, Natalia Olchanski, Holly B. Krasa, Thomas F. Goss,
Christopher Zimmer, and Paul J. Hauptman 

H
yponatremia is an electrolyte
disorder commonly encoun-
tered in clinical practice, espe-
cially in patients with heart failure
(HF) with comorbid conditions. 1
Although clear cut-off values for the
definition and treatment of hypona-
tremia are not firmly established, it
is often defined as a serum sodium
concentration of <136 meq/L. 1,2
Across all conditions, hyponatre-
mia represents a substantial clinical
burden. It has been estimated that
hyponatremia is present in 1–2.5%
of all hospitalized patients. This rate
increases to 15–30% in intensive care
units, where hyponatremia is associ-
ated with an increased need for me-
chanical support and a longer length
of stay (LOS).3-5
In HF, hyponatremia is character-
ized by a dilutional effect of excess
free water volume. Multiple studies
have demonstrated that hyponatre-
Purpose. The effect of serum sodium
concentration and tolvaptan treatment on
length of stay (LOS) in patients hospitalized
with heart failure (HF) was evaluated.
Methods. Data for this study were de-
rived from a large, international, Phase
III trial of patients hospitalized for HF.
Two distinct post hoc analyses were
performed, analyzing the association
between serum sodium concentration
and index hospitalization LOS in nor-
monatremic patients and hyponatremic
patients treated with placebo plus stan-
dard of care versus tolvaptan. Analysis
of covariance models were constructed
to adjust for potential variation in care
delivery and adjusted for hyponatremia
status or treatment.
Results. Patients with a baseline serum
sodium concentration of <135 meq/L who
received placebo had an adjusted mean
LOS that was 3.06 days longer than did
normonatremic patients (p < 0.001). More
severely hyponatremic patients had an
adjusted mean LOS 5.18 days longer than
did normonatremic patients (p < 0.001).
In an analysis of all hyponatremic patients,
those receiving tolvaptan had an adjusted
mean LOS that was 1.72 days shorter than
patients receiving placebo, though this
difference was not significant. In more
severely hyponatremic patients (serum
sodium concentration of <130 meq/L),
patients treated with tolvaptan had an
adjusted mean LOS 2.12 days shorter than
those receiving placebo, but this difference
was not significant.
Conclusion. A secondary analysis of a
large, international, Phase III trial of pa-
tients hospitalized for HF demonstrated
that comorbid hyponatremia was associ-
ated with a significant increase in hospital
LOS. Treatment of hyponatremia with
tolvaptan was associated with reductions
in LOS that were not significant.
Index terms: Heart failure; Hospitals;
Hyponatremia; Tolvaptan; Vasopressin
antagonists
Am J Health-Syst Pharm. 2011; 68:328-33

Philip L. Cyr, M.P.H., is Executive Director; Katherine A. Slawsky,
M.P.H., is Associate; and Natalia Olchanski, M.S., is Manager,
Health Economics and Outcomes Research, Boston Healthcare Asso-
ciates, Inc., Boston, MA. Holly B. Krasa, M.S., is Associate Director,
Global Clinical Development, Otsuka Pharmaceutical Development
and Commercialization, Rockville, MD. Thomas F. Goss, Pharm.D.,
is Vice President, Boston Healthcare Associates. Christopher
Zimmer, M.D., is Senior Director, Global Clinical Development,
Otsuka Pharmaceutical Development and Commercialization. Paul
J. Hauptman, M.D., is Professor of Medicine, School of Medicine,
Saint Louis University, St. Louis, MO, and Director, Heart Failure
Program, Saint Louis University Hospital, St. Louis.
Address correspondence to Mr. Cyr at Boston Healthcare As-
sociates, 75 Federal Street, 9th Floor, Boston, MA 02110 (pcyr@
bostonhealthcare.com). 
Mr. Cyr, Ms. Olchanski, Ms. Slawsky, and Dr. Goss received re-
search funding from Otsuka America Pharmaceutical, which markets
tolvaptan. Ms. Krasa and Dr. Zimmer are employees of Otsuka Phar-
maceutical Development and Commercialization. Dr. Hauptman is
a clinical investigator for and a consultant to Otsuka Pharmaceutical
Development and Commercialization.
Copyright © 2011, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/11/0202-0328$06.00.
DOI 10.2146/ajhp100217

328 Am J Health-Syst Pharm—Vol 68 Feb 15, 2011


mia is prevalent among individuals
hospitalized with HF.6-9 For example,
in the Acute and Chronic Thera-
peutic Impact of a Vasopressin An-
tagonist in Congestive Heart Failure
(ACTIV in CHF) trial, 21% of pa-
tients hospitalized for acute decom-
pensated HF had a baseline serum so-
dium concentration of <136 meq/L.7
In an analysis of 47,647 patients in a
registry of HF admissions across 259
academic and community hospitals,
a similar rate was observed.8
Since hyponatremia is an inde-
pendent predictor of prognosis in
HF,10,11 one goal of treatment in both
acute and chronic HF is the preven-
tion of new hyponatremia or the
worsening of established hypona-
tremia. Therapies for the treatment
of hyponatremia in HF are gener-
ally limited to fluid restriction and,
more recently, vasopressin receptor
antagonists (i.v. conivaptan and oral
tolvaptan),7,12 which inhibit the vaso-
pressin V2 receptor on principal cells
of the renal collecting duct.13
To date, no prospective studies
have assessed the effect of treatment
of hyponatremia on hospital LOS in
patients with hyponatremia. How-
ever, the Efficacy of Vasopressin An-
tagonism in Heart Failure: Outcome
Study with Tolvaptan (EVEREST)
trials provide a detailed database of
patients hospitalized with HF, per-
mitting an examination of the im-
pact of sodium status and potential
treatment on LOS.7,14,15 These trials
demonstrated that tolvaptan may
decrease acute dyspnea and lead to
weight loss, though no long-term
effects on all-cause mortality or
heart-failure-related hospitalization
were observed. However, the effect of
tolvaptan on LOS has not been previ-
ously reported. This is an important
issue, as LOS is the primary driver of
cost.16
The primary objectives of this
analysis were to (1) compare inpa-
tient LOS during an index hospital-
ization for acute decompensated HF
between normonatremic and hypo-
clinical Report  Tolvaptan
natremic patients and (2) evaluate
the effect of tolvaptan versus placebo
on LOS in hyponatremic patients
hospitalized with HF based on hypo-
natremia severity.
Methods
Data for this study were derived
from patients enrolled in EVEREST,
the design of which has been pre-
viously described. 14,15,17 Briefly,
EVEREST was a prospective, inter-
national, multicenter, randomized,
double-blind, placebo-controlled
study conducted at 359 sites between
October 2003 and February 2006
and included 4133 patients who were
hospitalized with a primary diagno-
sis of HF. Patients were eligible for
the study if they were 18 years of age
or older with reduced left ventricular
ejection fraction (≤40%), were hos-
pitalized for exacerbation of chronic
HF no more than 48 hours earlier,
and had signs of volume expansion
with New York Heart Association
(NYHA) functional class III or IV
symptoms. Exclusion criteria includ-
ed but were not limited to a serum
creatinine concentration of >3.5 mg/
dL (>309 mmol/L), a serum potas-
sium concentration of >5.5 mmol/L,
and a supine systolic arterial blood
pressure of <90 mm Hg. There were
no specific requirements with respect
to serum sodium concentration.
Institutional review board or ethics
committee approval was obtained
at each site, and all patients signed
an informed consent form. Patients
were randomly assigned to receive
oral tolvaptan 30 mg daily or match-
ing placebo. The study included both
an inpatient treatment period and a
postdischarge treatment and follow-
up period.
Data analysis. Two distinct post
hoc analyses were performed utiliz-
ing the EVEREST data. The first
analysis examined the association be-
tween serum sodium concentration
and index hospitalization LOS in
patients receiving placebo plus stan-
dard of care. The analysis compared
Am J Health-Syst Pharm—Vol 68 Feb 15, 2011
LOS in normonatremic patients
(serum sodium concentration, ≥135
meq/L) with each of two subsets of
hyponatremic patients: those with
a serum sodium concentration of
<135 meq/L and those with a se-
rum sodium concentration of <130
meq/L. Baseline serum sodium val-
ues collected within 48 hours after
hospital admission were used to de-
fine the relevant population subsets.
Unadjusted mean LOS and adjusted
mean LOS for each subgroup were
compared with mean LOS observed
in normonatremic patients. A confir-
matory analysis examining U.S. trial
patients was also performed using
the same methodology to confirm
the findings of the adjusted analysis,
as geographic variation in practice
patterns in the EVEREST population
has been previously reported.18 Due
to the small sample size in the United
States, particularly patients with a se-
rum sodium concentration of <130
meq/L, the confirmatory analysis was
limited to a comparison of patients
with normonatremia and patients
with any degree of hyponatremia
(baseline serum sodium concentra-
tion, <135 meq/L).
A second analysis was performed
to evaluate the effect of tolvaptan
versus placebo on index hospital-
ization LOS within two subsets of
hyponatremic patients (baseline
serum sodium concentrations, <135
and <130 meq/L). Specifically, the
analysis compared unadjusted and
adjusted index hospitalization LOS
of patients based on therapy. For
all analyses, LOS was defined as the
number of days from baseline to
discharge for the index hospitaliza-
tion, excluding individuals who died
during index hospitalization. In addi-
tion, patients lacking a baseline serum
sodium measurement were excluded.
Statistical analysis. Statistical
analyses were conducted using SPSS,
version 14 (SPSS software, Chicago,
IL). Student’s t test and Levene’s test
for equality of variances were used
to determine statistical significance
329
 clinical Report  Tolvaptan

for unadjusted mean LOS differ-
ences among groups. An analysis of
covariance (ANCOVA) model was
constructed to account for regional
variation in care delivery attribut-
able to the multinational design of
the trials. An ANCOVA model tests
whether certain factors have an effect
on a continuous outcome variable af-
ter removing the variance for which
quantitative predictors or covariates
account. The inclusion of covariates
can increase statistical power because
it accounts for some of the variability
observed in the outcome.19 For the
analysis comparing hyponatremic
patients with normonatremic pa-
tients, the model was adjusted for
hyponatremia status as a factor and
for both geographic region and the
interaction between hyponatremia
status and geographic region as co-
variates. An ANCOVA model was
also constructed for the multivariate
analysis of LOS comparing tolvaptan
with placebo. The model was ad-
justed for treatment as a factor and
for both geographic region and the
interaction between treatment and
geographic region as covariates. Sta-
tistical significance was assessed us-
ing a two-tailed independent sample
t test at a significance level of 0.05.
Results
Of 441 hyponatremic patients
(serum sodium concentration, <135
meq/L), 225 (51%) were randomized
to receive tolvaptan and 216 (49%)
were randomized to receive placebo
(Figure 1). Patients enrolled from
U.S. sites represented 13.5% (n =
557) of all patients in EVEREST and
15.4% (n = 68) of all hyponatremic
patients.
Association between serum so-
dium concentration and index
hospitalization LOS in patients re-
ceiving placebo. Patients with a base-
line serum sodium concentration
of <135 meq/L had a significantly
longer unadjusted mean LOS dur-
ing index hospitalization (2.11 days)
than did normonatremic patients
(p < 0.01) (Table 1). More severely
hyponatremic patients (serum so-
dium concentration of <130 meq/L
at baseline) had an unadjusted mean
LOS 2.88 days longer than did nor-
monatremic patients, but this differ-
ence was not statistically significant
(p = 0.17) (Table 1).
After adjusting for geographic re-
gion and for the interaction between
geographic region and hyponatremia
status as covariates, hyponatremic
patients had a statistically significant
longer adjusted mean LOS across
both subgroups (Figure 2). In pa-
tients with a serum sodium concen-
tration of <135 meq/L, the observed
mean LOS during index hospitaliza-
tion was 3.06 days longer compared
with that of normonatremic patients
(p < 0.001); this difference was more
pronounced in the subset of patients
with a serum sodium concentration
of <130 meq/L (5.17 days longer,
p < 0.001).
When the analysis was replicated
in U.S. trial participants only, patients
with a baseline serum sodium con-
centration of <135 meq/L (n = 68)
had a significantly longer unadjusted
mean LOS (1.39 days) during index
hospitalization than did normona-
tremic patients (n = 489) (p < 0.05).
Effect of tolvaptan versus placebo
on index hospitalization LOS in hy-
ponatremic patients. In patients with

Figure 1. Definition of analysis cohorts from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan
(EVEREST). All randomized patients received standard of care in addition to tolvaptan or placebo. Patients with a serum sodium
concentration (Na) of <130 meq/L were also included in the analysis of patients with Na of <135 meq/L.

EVEREST cohort
(n = 4133)

Placebo + standard of care Tolvaptan + standard of care

(n = 2061) (n = 2072)

Died during index Died during index

hospitalization or hospitalization or
missing baseline Na missing baseline Na
(n = 56) (n = 77)

Na ≥ 135 meq/L Na < 135 meq/L Na ≥ 135 meq/L Na < 135 meq/L
(n = 1789) (n = 216) (n = 1770) (n = 225)

Na < 130 meq/L Na < 130 meq/L

(n = 48) (n = 32)

330 Am J Health-Syst Pharm—Vol 68 Feb 15, 2011

 clinical Report  Tolvaptan

a baseline serum sodium concentra-

Table 1.
tion of <135 meq/L, the unadjusted
Comparison of Unadjusted Mean Length of Stay (LOS) Among
LOS during the index hospitalization
Hyponatremic and Normonatremic Patients With Placebo
did not differ significantly between
the tolvaptan and placebo groups Serum Sodium Unadjusted Mean LOS
(Table 2). In the small proportion of Concentration Mean LOS Differences
(meq/L) n (days) (95% CI) (days)a pa
patients with a serum sodium con-
centration of <130 meq/L, the same All Patients
lack of significant difference was   <135 216 10.86 2.11 (0.55 to 3.69) <0.01
  <130 48 11.63 2.88 (–1.28 to 7.04) 0.17
observed. After adjusting for treat-
  ≥135 1789 8.74
ment as a factor and both geographic
U.S. Patients
region and the interaction between   <135 68 6.96 1.39 (0.12 to 2.67) <0.05
treatment and geographic region as   ≥135 489 5.17
covariates, the mean LOS observed a
For comparison with patients with serum sodium concentration of ≥135 meq/L. Equal variances were not
in patients with serum sodium con- assumed. CI = confidence interval.
centrations of <135 and <130 meq/L
treated with tolvaptan was 1.72 days
and 2.12 days shorter than that ob-
served with placebo (p = 0.06 and p = Figure 2. Comparison of adjusted mean length of stay between hyponatremic and
0.58, respectively) (Figure 3). normonatremic patients after adjustment for geographic region and for the interaction
between geographic region and hyponatremia as covariates. Error bars represent the
standard error. Na = serum sodium concentration.
Discussion
Hyponatremia is associated with 15 13.55
a substantial clinical burden and is 14
p < 0.001

an independent predictor of com- 13

Adjusted Mean Days

plications and death in patients 12

11.44
p < 0.001
suffering from a number of condi-
11
tions, including HF.20 Various studies
10
have reported that hyponatremia 8.38
9
adversely affects morbidity, mortal-
ity, and inpatient direct medical 8
costs. Shea et al.21 reported that in 7
a general hospitalized population, 6
hyponatremia was a significant in- 5
Na ≥ 135 meq/L Na < 135 meq/L Na < 130 meq/L
dependent predictor of inpatient (n = 1789) (n = 216) (n = 48)
costs at both six months (76.4% in-
crease; 95% confidence interval [CI],
55.0–100.7%) and one year (95.6%
increase; 95% CI, 73.3–120.8%). In
patients with congestive HF, hypona- Table 2.
tremia has been demonstrated to be Comparison of Unadjusted Mean Length of Stay (LOS) Among
a significant predictor of worsening Hyponatremic Patients Treated With Tolvaptan or Placebo
outcomes, including morbidity and Serum Sodium Unadjusted Mean LOS
mortality.8,10,11,21-23 Concentration Mean LOS Difference
Additional evidence suggests that and Treatmenta n (days) (95% CI) (days)b pb
the normalization or improvement <135 meq/L
in serum sodium concentration   Tolvaptan 225 9.48 1.38 (–3.16 to 0.41) 0.13
may have a positive effect on health  Placebo 216 10.86
outcomes. In the ACTIV in CHF <130 meq/L
trial, a Phase II study of tolvaptan,   Tolvaptan 32 11.25 0.38 (–5.88 to 5.13) 0.89
21.6% of patients hospitalized for  Placebo 48 11.63
worsening HF had hyponatremia; at a
Tolvaptan treatment was 30 mg orally daily.
b
For comparison with placebo group. Equal variances were not assumed. CI = confidence interval.
discharge, 66.2% had improvements
in serum sodium concentrations

Am J Health-Syst Pharm—Vol 68 Feb 15, 2011 331

 clinical Report  Tolvaptan

Figure 3. Comparison of adjusted mean length of stay between patients treated with tolvaptan or placebo after adjustment for geo-
graphic region and for the interaction between geographic region and hyponatremia as covariates. Error bars represent the standard
error. Na = serum sodium concentration.

Na < 135 meq/L Na < 130 meq/L

p < 0.06 p < 0.58
15 15
14 14 13.55
13 13

Adjusted Mean Days

Adjusted Mean Days

11.44 11.43
12 12
11 9.72 11
10 10
9 9
8 8
7 7
6 6
5 5
Tolvaptan Placebo Tolvaptan Placebo
(n = 225) (n = 216) (n = 32) (n = 48)

(>2 meq/L).23 In addition, in pa-
tients with improved serum sodium
concentrations, the mortality rate at
60 days postdischarge was approxi-
mately half the comparable figure in
patients showing no improvement
(11.1% versus 21.7%, respectively),
though the study was not powered
to show a statistically significant dif-
ference for this variable. Change in
serum sodium level was a statistically
significant predictor of 60-day mor-
tality (hazard ratio, 0.74; p < 0.0185),
and patients with an improvement
in serum sodium concentration of
≥2 meq/L at discharge had a 60-day
mortality rate of 16%, compared
with 30% observed in patients
with no improvement in serum so-
dium concentration. A retrospective
analysis of data from a large registry
demonstrated that patients with a
baseline serum sodium concentra-
tion of >135 meq/L had a lower 60-
day mortality rate compared with
hyponatremic patients.8 In addition,
in the Evaluation Study of Conges-
tive Heart Failure and Pulmonary
Artery Catheterization Effectiveness
(ESCAPE), patients with persis-
tent hyponatremia (serum sodium
concentration of ≤134 meq/L) had
higher six-month mortality and
rehospitalization rates compared
with patients with corrected hypo-
natremia or normonatremia.9 Taken
together, these results suggest that
hyponatremia is an independent pre-
dictor of mortality in patients with
HF; however, whether improvement
in serum sodium levels directly leads
to lower mortality rates still requires
validation.  additional covariates given the
In our analyses, we observed that
baseline serum sodium concentra-
tions were significantly associated
with overall inpatient LOS among
patients with NYHA functional class
III or IV HF. Patients receiving treat-
ment with tolvaptan therapy did not
have a significant reduction in overall
LOS; the failure to achieve statisti-
cal significance was likely due to the
small sample size. The trial did not
have adequate statistical power for
these post hoc analyses. Another po-
tential limitation of the current anal-
ysis is that EVEREST was conducted
multinationally, and variations in
LOS were observed among geo-
graphic locations associated with
differences in clinical practice. We
attempted to adjust for this varia-
tion through the use of an ANCOVA
model; however, the adjusted mean
LOS differences observed were esti-
mations. In addition, other collinear
surrogate markers for outcomes in
patients with HF, such as ventricular
size, level of biomarkers (e.g., brain
natriuretic peptide), and frequency
of antecedent hospitalizations, were
not included as covariates, largely
because the multivariate model did
not have sufficient power to include
relatively small numbers of study
subjects.
Larger observational studies are
needed to confirm our findings.
Verification that tolvaptan can re-
duce LOS in patients with HF and
hyponatremia, as suggested by our
underpowered analysis, might have
important economic consequences
in light of data demonstrating that
LOS is the major cost driver for
hospitals.16
Conclusion
A secondary analysis of a large, in-
ternational, Phase III trial of patients
hospitalized for HF demonstrated
that comorbid hyponatremia was as-
sociated with a significant increase in
hospital LOS. Treatment of hypona-
tremia with tolvaptan was associated
with reductions in LOS that were not
significant.

332 Am J Health-Syst Pharm—Vol 68 Feb 15, 2011


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