Heart Fail Rev (2012) 17:1726
DOI 10.1007/s10741-010-9193-3
Significance of hyponatremia in heart failure
Luca Bettari Mona Fiuzat Gary M. Felker
Christopher M. OConnor
Published online: 14 September 2010
Springer Science+Business Media, LLC 2010
Abstract Heart failure is one of the most common,
costly, disabling and growing diseases (McMurray and
Pfeffer in Lancet 365(9474):18771889, 2005). Hypona-
tremia, conventionally defined as a serum-sodium con-
centration equal or less than 135 mmol/l (American Heart
Association in Heart disease and stroke statistics2007
update. American Heart Association, Dallas, 2007; Stewart
et al. in Eur J Heart Fail 4:361371, 2002), is a common
phenomenon in patients with heart failure, with an inci-
dence of 2025% (Krumholz et al. in Arch Intern Med
157:e99e104, 1997; Rosamond et al. in Circulation
117(4):e25e146, 2008; Adrogue and Madias in N Engl J
Med 342:15811589, 2000) and seems to be of prognostic
importance in patients with heart failure (Luca et al. in Am
J Cardiol 96:19L23L, 2005; Gheorghiade et al. in Eur
Heart J 28:980988, 2007; Gheorghiade et al. in Arch
Intern Med 167:19982005, 2007). So far treatment strat-
egies have been limited and burdened by side effects. The
development of hyponatremia in the setting of heart failure
is related to the arginine vasopressin (AVP) dysregulation.
Thus, AVP receptor antagonists are a promising approach
to treatment. However, several questions remain: whether
there is a cause-and-effect mechanism, if the correction of
hyponatremia improves outcomes, and defining the specific
cut-off level of serum-sodium that should be used to define
hyponatremia. In this review, we aim to summarize the
literature on hyponatremia in patients with heart failure
L. Bettari (&)
University of the Studies of Brescia, Piazzale Spedali Civili 1,
Brescia, Italy
e-mail: luca_bettari@yahoo.it
M. Fiuzat
G. M. Felker
C. M. OConnor
Duke University Medical Center, Duke Clinical Research
Institute, 2400 Pratt street, Durham, NC, USA
within several aspects: incidence in clinical trials and
registries, prognostic value, underlying mechanisms, ther-
apeutic options, and possible future perspectives.
Keywords Heart failure
Hyponatremia
Clinical trials

Outcomes
Arginine vasopressin antagonists
Introduction
Heart failure (HF) is one of the most common, costly,
disabling and growing diseases [1]. About 5 millions of
Americans are affected by HF, and more than 5,00,000 new
cases are diagnosed each year [2]. HF mortality rate still
high, over 60% within 5 years of diagnosis [3], and within
6 months of discharge 50% of patients require readmission
[4]. The estimated costs in the United States amount to
more than $35 billion [5].
Hyponatremia (conventionally defined as a serum-
sodium concentration [Na] B135 mmol/l) [6, 7], is a
common phenomenon in HF patients, with an incidence of
2025% [810], and it is known to be associated with
increased morbidity and mortality in these patients
[1113]. So far treatment strategies have been limited and
burdened by side effects. The development of hyponatremia
in the setting of HF is related to the arginine vasopressin
(AVP) dysregulation. Thus, AVP receptor antagonists are a
promising approach to treatment.
Hyponatremia seems to be of prognostic importance in
HF patients. However, several questions remain: whether
there is a cause-and-effect mechanism, whether the cor-
rection of hyponatremia improves outcomes, and defining
the specific cut-off level of serum-sodium ([Na]) that
should be used to define hyponatremia. In this review,
we aim to summarize the literature on hyponatremia in HF
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patients within several aspects: incidence in clinical trials
and registries, prognostic value, underlying mechanisms,
therapeutic options, and possible future perspectives.
Scope of the problem
Published estimates of the prevalence of hyponatremia in
HF patients vary according to the [Na] value used in the
different studies [14]. Moreover, the incidence and out-
comes vary according to the severity of HF [11].
In the Acute Decompensated HEart failure REgistry
(ADHERE) of 1,58,168 HF patients, hyponatremia ([Na]
\130 mmol/l) was found on admission in only 5% of the
patients and was considered to be a risk factor for mortality
and morbidity [15, 16].
In the Outcomes of a Prospective Trial of Intravenous
Milrinone for Exacerbation of Chronic Heart Failure
(OPTIME-CHF) Study of 949 patients hospitalized for
worsening HF, hyponatremia ([Na] \135 mmol/l) was
present on admission in 27% of the patients, and it was an
important predictor of increased number of days of hos-
pitalization for cardiovascular causes and mortality within
60 days of discharge (P = 0.018) [10].
Likewise in the Acute and Chronic Therapeutic Impact of
a Vasopressin Antagonist in Congestive Heart Failure
(ACTIVinCHF) trial of 319 patients with left ventricular
ejection fraction (LVEF)\40% and hospitalized for HF with
persistent signs and symptoms of systemic congestion
despite standard therapy, hyponatremia ([Na]\136 mmol/l)
was found on admission in 21% of patients. However, no
differences in worsening HF at 60 days between the groups
were observed [17].
In the Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Effectiveness (ESCAPE) trial of 433 HF
patients (NYHA IV, LVEF \30%), 23.8% of patients had
hyponatremia on admission ([Na] B134 mmol/l). Notably,
68.9% of these patients had persistent hyponatremia, which
was found to be an independent predictor of mortality, HF
hospitalization, and death or rehospitalization at 6 months
(P = 0.01) [9].
In the Organized Program to Initiate Lifesaving Treat-
ment in Hospitalized Patients with Heart Failure (OPTI-
MIZE-HF) registry, which included 48,162 HF patients,
19.7% of these patients had hyponatremia on admission
([Na] \135 mmol/l). It was associated with longer hospital
stays and higher in-hospital and early (6090 days) post-
discharge mortality (P \ 0.0001); however, no difference
was found in the readmission rates. Notably, the risk of
mortality significantly increased with [Na]\138 mmol/l [8].
In a subgroup analysis of the Efficacy of Vasopressin
Antagonism in Heart Failure Outcome Study With Tol-
vaptan (EVEREST) trial of 4,133 HF patients (NYHA III/
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Heart Fail Rev (2012) 17:1726
IV, LVEF B40%), 8% of the patients had hyponatremia at
admission ([Na] \134 mEq/l). No mortality outcome
benefit was seen with treatment in this subgroup, and there
was no association of improved hyponatremia with better
outcomes [18].
The secondary analyses of RCTs evaluating hyponatre-
mia in HF are summarized in Table 1.
Hyponatremia in prognostic models
Risk assessment based on any single factor has limited
accuracy and reproducibility. By combining individual
clinical characteristics into a multivariable predictive
index, frequently discordant implications of univariable
analyses may be made meaningful. Prognostic models are
important tools that can be used to estimate outcomes,
enhance compliance and increase the use of life-saving
medications and devices.
Hyponatremia has been found to be an important pre-
dictor of survival in several risk models in HF patients.
These models have been developed in different HF cohorts:
ambulatory patients, hospitalized patients, and cardiac
transplant patients, and have been used to predict both
short-term and long-term outcomes.
The Heart Failure Survival Score (HFSS) is the first
predictive model in HF developed (1997) [19]. It was
developed in a prospective study for pretransplant risk
stratification in ambulatory patients (age B70 years) with
advanced HF (LVEF B40%) referred for cardiac transplant
evaluation. A predictive model based on 268 patients
(derivation sample) was generated, obtaining 7 significant
variables after stabilization with maximal medical therapy:
ischemic cardiomyopathy, resting heart rate (HR), LVEF,
QRS duration C0.12 s, mean resting blood pressure (BP),
peak VO2, and [Na] (for patients with vs. patients without
the characteristic for dichotomous variables or per unit
increase for continuous variables). Between the variables,
the ischemic etiology of HF was found to be the strongest
predictor (HR 2.00, 95% CI 1.352.97), while [Na] was the
weakest, associated with a 5% increased mortality risk (per
1U decrease) (HR 0.95, 95% CI 0.921.00).
The EFFECT model is another clinical model that was
developed to identify predictors of mortality using infor-
mation available at hospital presentation. In this retrospec-
tive study of 4,031 patients presenting to the hospital with
HF, the main outcome measures were all-cause 30-day and
1-year mortality. The multivariable predictors of mortality
at both 30 days and 1 year were found to be: older age (per
10U increase), lower systolic BP (per 10U decrease), higher
respiratory rate (per 5U increase), higher blood urea nitrogen
levels (per 10U increase), and baseline hyponatremia.
Hyponatremia was defined as [Na] \136 mEq/l, and it was
Heart Fail Rev (2012) 17:1726 19

Table 1 Secondary analyses of randomized clinical trials evaluating hyponatremia in heart failure
RCTs Number Hyponatremia on admission Results
of patients

OPTIME-CHF [10]
(exacerbation of HF,
LVEF \40%, not
requiring iv inotrope
support)
ACTIVinCHF [17]
(persistent HF, LVEF
\40%)
ESCAPE [9] (persistent HF,
LVEF \30%, NYHA IV)
949 [Na] \135 mmol/l (27% of the Lowest [Na] quartile associated with more
patients) days hospitalized for CV causes
(P \ 0.015) ? trend toward higher
mortality/rehospitalization
Lower [Na] associated with higher in-
hospital and 60-day mortality (P \ 0.015,
P = 0.002, respectively)
Baseline [Na] predicted increased 60-day
mortality (for 3 mEq/l decrease, HR 1.18)
319 [Na] \136 mmol/l (21.6% of the Baseline hyponatremia: significant predictor
patients) of 60-day mortality (P = 0.0016)
Change in [Na]: significant predictor of
60-day mortality (for 1 mmol/l increase,
HR 0.736, P = 0.018)
433 [Na] B134 mmol/l (23.8% of the Hyponatremia associated with higher
patients) 6-month mortality (for each 3 mEq/l
decrease, HR 1.23, P = 0.01)
Persistent hyponatremia (68.9% of Persistent hyponatremia associated with
the patients) increased risk of all-cause mortality, HF
rehospitalization, and death/
rehospitalization (HR 1.82, 1.52, 1.54;
P = 0.04, 0.03, 0.01 respectively)

significantly associated with increased risk of 30-day mor-
tality (HR 1.53, 95% CI 1.142.05) and 1-year mortality
(HR 1.46, 95% CI 1.191.80) [20].
Subsequently, a prognostic index for long-term mortal-
ity (over a 5-year period) in patients with mild to moderate
chronic HF (CHF) was developed (Area Under the Curve
[AUC] 0.74, 95% CI 0.700.78) [21]. Five hundred and
fifty-three HF outpatients from the UK-HEART study were
enrolled. Eight non-invasive prognostic measurements
were identified to be significantly associated with long-
term mortality: baseline hyponatremia ([Na] B140 mmol/
l), serum-creatinine, cardiothoracic ratio, standard devia-
tion of normal-to-normal RR intervals, maximum corrected
QT, QRS dispersion, presence of non-sustained ventricular
tachycardia (NSVT) and voltage criteria for LV hypertro-
phy on 12-lead ECG. In this model, baseline hyponatremia
was associated with an increased mortality risk of 13%
(HR 1.13, 95% CI 1.051.19).
The Seattle Heart Failure Model was derived in a cohort
of 1,125 HF patients and validated in 5 additional cohorts
totaling 9,942 HF patients. Eleven prognostic variables were
identified as predictors of increased mortality: the calculated
daily diuretic dose per kg of body weight (BW), NYHA
class, ischemic etiology, 1/x transformation of EF, choles-
terol, hemoglobin (\ or [16 g/dl), lymphocytes ([47%),
uric acid (\3.4 mg/dl), systolic BP ([160 mmHg), statin
use, and baseline [Na]. There was increased mortality risk
associated with [Na] \138 mEq/l (HR 1.050, 95% CI
1.0051.097). Subsequently, 3 other variables were forced
into the model: age and gender as important demographic
variables, and potassium-sparing diuretics [22].
A model to predict outcomes in patients with decom-
pensated HF was developed from the OPTIME-
CHF study. The variables at admission that predicted death
at 60 days were found to be increasing age (per 10U
increase), lower systolic BP (per 10U decrease), NYHA
class IV symptoms, elevated BUN (per 5U increase) and
lower [Na], which resulted to be associated with a 25%
increase in mortality risk each 5U decrease (HR 0.75, 95%
CI 0.600.95) [23].
The MUSIC model was developed to predict mortality
in an independent, non-clinical trial, outpatient CHF pop-
ulation easily assessable in clinical practice. The MUerte
Subita en Insuficiencia Cardiaca (MUSIC) study was a
prospective, multicentre, longitudinal study designed to
assess risk predictors of cardiac mortality and sudden
cardiac death (SCD) in either systolic dysfunction (75%) or
preserved EF (25%) ambulatory HF patients. Four final
models (total mortality, cardiac mortality, pump failure
death (PFD), SCD (c-indices of 0.76, 0.78, 0.80, and 0.77
respectively) were developed including several combina-
tions of the same discovered 10 independent predictors:
prior atherosclerotic vascular event, left atrial size
([26 mm/m2), EF (B35%), AF, left bundle branch block

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(LBBB) or intraventricular conduction delay, NSVT and
frequent ventricular premature beats, estimated glomerular
filtration rate (eGFR \60 ml/min/1.73 m2), hyponatremia
([Na] B138 mEq/l), NT-proBNP ([1,000 ng/l), and
positive troponin (values greater than the 99th reference
percentile). On the basis of Cox models, the MUSIC Risk
scores were calculated. A cardiac mortality score [20
points identified a high-risk subgroup with a fourfold
increased cardiac mortality risk. Hyponatremia was not
associated with SCD mortality, but significantly associ-
ated with total mortality (3 points), cardiac mortality (3
pointsHR 1.38, 95% CI 1.031.77) and particularly
PFD mortality (4 pointsHR 1.60, 95% CI 1.122.29)
[24].
At last, the ESCAPE risk model and discharge score was
derived from the namesake study, which examined the
efficacy of pulmonary artery catheter (PAC)-guided ther-
apy versus clinical assessment on the resolution of symp-
toms and signs of congestion, with days alive out of the
hospital during the first 6 months as primary endpoint. In
this study, the patients discharged with complete data
(n = 423) had 6-month mortality and combined death and
rehospitalization rates of 18.7 and 64%, respectively.
Discharge risk factors significantly associated with mor-
tality were found to be BNP per doubling, cardiopulmonary
resuscitation or mechanical ventilation during hospitaliza-
tion, BUN per 20U increase, serum-sodium per 1U
increase, age [70 years, daily loop diuretic furosemide
equivalents[240 mg, lack of beta-blocker, and 6-min walk
per 100-foot increase. The c-index for the model was 0.76.
Discharge serum-sodium was found to be an independent
predictor of mortality, associated with a 7% decreased risk
(per 1U increase) of all-cause death (HR 0.93, 95% CI
0.870.99). Baseline [Na] was significantly different
between those who died or survived (P = 0.001). A Sim-
plified Discharge Score Model of Mortality was developed
(c-index 0.739), and in this model hyponatremia at dis-
charge ([Na] \130 mEq/l) was found to be the 4th most
important predictor out of 8 variables. The simplified dis-
charge score discriminated mortality risk from 5% (lowest
score) to 94% (highest score). This discharge risk model
allows for risk assessment after in-hospital therapy for
advanced decompensated systolic HF [25].
Thus, hyponatremia has been demonstrated to be an
important prognostic predictor of mortality in HF patients,
ranging from hospitalized patients to ambulatory patients
and from short to long-term mortality. However, there is
no consistency between these models on the value of
serum-sodium level to use, or the incremental value of
hyponatremia as a predictor compared to other prognostic
markers.
The HF prognostic models in which hyponatremia is
included are summarized in Table 2.
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Heart Fail Rev (2012) 17:1726
Classification and pathophysiology
Hyponatremia results from an excess of body water com-
pared to serum-sodium. It can be classified into 3 categories:
hypertonic, in which osmotically active non-electrolyte
solutes accumulate (e.g., glucose); isotonic, due to labora-
tory artifact (e.g., hyperproteinemia, hyperlipidemia,
hyperglycemia); hypotonic, which can either be hypovole-
mic caused by the depletion of water and sodium (e.g.,
diarrhea, diuretics) or euvolemic caused by water retention
(e.g., syndrome of inappropriate secretion of antidiuretic
hormone [SIADH]) [26]; hypervolemic, in which the
increase in body water overtakes that of sodium (e.g., HF,
cirrhosis) [6].
The pathogenesis of hyponatremia in HF is multifacto-
rial: the reduction of cardiac output (CO) decreases renal
perfusion and GFR and enhances the reabsorption of
sodium and water compromising their delivery to the distal
diluting segment of the nephron [11]. The increase in AVP
binding to the vasopressin-2 receptor (V2R) increases the
number of aquaporin-2 water channels, enhancing free-
water retention [27, 28]. Increased sympathetic nervous
system (SNS) activity [29] causes renal vasoconstriction,
decreasing GFR [30] and stimulates the reninangiotensin
aldosterone system (RAAS), increasing sodium and water
retention, thirst center activity and release of AVP [31, 32].
Hyponatremia may also result from diuretic therapy [11,
14] with thiazides due to increased sodium and potassium
excretion in a setting of AVP-enhanced water reabsorption,
resulting in the excretion of hypertonic urine. Loop
diuretics induce isotonic diuresis with salt loss, which in
turn can worsen hyponatremia [14, 33].
The mechanisms leading to hypotonic hypervolemic
hyponatremia in HF are summarized in Table 3.
AVP: role in HF
AVP dysregulation is the most common cause of hypotonic
hypervolemic hyponatremia [34]. AVP is a non-peptide
hormone synthesized and regulated by 2 mechanisms:
osmotical (increase in serum osmolality increases AVP
release) and non-osmotical (decrease in plasma circulating
volume increases AVP release). In HF patients, AVP pro-
duction is increased, and AVP levels do not fall to the
expected levels but often remain elevated despite the
presence of volume overload, atrial distension, hyponatre-
mia, and low plasma osmolality [35, 36].
AVP has 3 different receptor subtypes. V1A receptors,
found on vascular smooth muscle and cardiac myocytes,
may cause vasoconstriction, positive inotropic effect, and
increase in the synthesis of contractile protein in myocytes,
potentially leading to increased afterload, left ventricular
hypertrophy and remodeling [3739]. V2 receptors, on the
 Heart Fail Rev (2012) 17:1726

Table 2 Hyponatremia in HF prognostic models

Models Number Cohort of patients Model endpoints [Na] value cutoff Significance of C-Index
of patients hyponatremia in model
(HR, 95% CI)

HFSS 268 Outpatients with systolic HF 1-year mortality [Na] per 1 mEq/l change 1.05, 1.001.08 0.74
(NYHA IIIIV) (value after medical
therapy optimization)
EFFECT 2,624 Hospitalized patients with 30-day and 1-year mortality [Na] \136 mEq/l (baseline 1.53, 1.142.05 (for 30-day 0.77
systolic and diastolic HF value) mortality) 1.46, 1.191.80
(NYHA IIIII) (for 1-year mortality)
UK-HEART 553 Outpatients with systolic HF 5-year mortality [Na] per 2 mmol/l change 1.13, 1.051.19 0.78
(NYHA IIIII) [Na] B140 mmol/l
(baseline value)
Seattle heart 1,125 Hospitalized patients with 1-, 2-, 3-year mortality [Na] \138 mEq/l (baseline 1.05, 1.0051.097 0.73
failure model systolic HF (NYHA IIIV) value)
MUSIC 992 Outpatients with systolic and 4-year mortality for total, [Na] B138 mEq/l (baseline 1.35, 1.031.77 (for cardiac 0.76
diastolic HF (NYHA IIIII) cardiac, PFD mortality value) mortality) 1.60, 1.122.29 0.78
(for PFD mortality)
0.80
ESCAPE 423 Hospitalized patients with 6-month mortality [Na] per 1U change [Na] 0.93, 0.870.99 0.74
systolic HF (NYHA IIIIV) \130 mEq/l (discharge
value)
OPTIME-CHF 949 Hospitalized patients with 60-day mortality [Na] per 5 mmol/l change 0.75, 0.600.95 0.77
systolic HF (NYHA IIIIV) (baseline value)
21

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Table 3 Mechanisms leading to hypotonic hypervolemic hyponatremia in heart failure
Direct hemodynamic effects
Reduction of CO
Reduction of GF pressure ? reduction of GFR
Reabsorption of sodium and water in the proximal
tubule ? reduction of the delivery to the distal diluting segment of diluting segment of the nephron
the nephron
Reduction of atrial-renal reflexes
The increase in left atrial pressure does not decrease anymore the
release of AVP and the renal adrenergic tone
renal collecting ducts, may cause free-water reabsorption,
which leads to increased water retention, volume expansion
and potentially hyponatremia [40]. Finally, V1B receptors,
located in the anterior pituitary gland, determine ACTH
and b-endorphin release. This subtype does not seem to be
related to HF, however, recent studies have demonstrated
that AVP is involved in the regulation of glucose homeo-
stasis through V1A and V1B receptors. Indeed V1A receptor
deficiency results in decreased insulin sensitivity, whereas
V1B receptor deficiency results in increased insulin sensi-
tivity [41].
AVP levels are increased in HF patients [4244]
and seem to correlate with severity and adverse outcome
[4547]; however, a cause-and-effect relationship between
inappropriate AVP levels and HF progression has not yet
been proven. Due to the number of different mechanisms
that may underlie the pathophysiology of hyponatremia,
blocking either or both the V1A and V2 receptors may be
useful. Evidence is needed that interfering with hormone
secretion or effect has a clinically important benefit.
Treatment and AVP antagonism
Treatment options are limited. Dietary sodium restriction
and diuretic therapy are the mainstays [48]. The purpose is
to generate a negative solute-free water balance, thus fluid
restriction to 1 l/day is recommended. However, it induces
thirst and therefore may have lack of compliance. Another
possible treatment is the use of intravenous (iv) hypertonic
saline infusion; however, this may cause worsening of
congestion symptoms. The use of demeclocycline and/or
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Heart Fail Rev (2012) 17:1726
Chronic neurohormonal activation
SNS
Peripheral and renal vasoconstriction ? decrease of renal blood flow and
GFR ? decrease of the rate of solute and water delivery to the distal
Excretion of renin
SRAA
Sodium and water reabsorption in the proximal tubule
Increase in the efferent arteriolar tone ? enhancing the
GFR ? promoting sodium and water absorption
Activation of the thirst center
Release of AVP
ANP
Renal sodium loss (direct effect ? inhibition of aldosterone release)
AVP
Increase the expression of aquaporin-2 water channels ? enhancing free-
water retention
urea is linked with toxicity making these options
unpleasant. Diuretic therapy can be associated with wors-
ening of hyponatremia. All these treatment may not be
effective in all patients and can result in significant adverse
events [6].
AVP secretion is the leading mechanism of hyponatre-
mia in HF. So far there are no therapies aimed to reduce
AVP production. The blockade of AVP receptors is a
rational therapeutic approach [49, 50]. The antagonism of
V2 receptors induces the elimination of free-water
(aquaresis) without depleting electrolytes or activating
neurohormonal systems, common side effects of diuretic
therapy [51]. Furthermore, the antagonism of V1A/V2
receptors provides aquaresis induced by the V2 receptor
stimulation and should suppress the deleterious cardiac
effects caused by the activation of the V1A receptor
[49, 52]. Experimental models and clinical trials have
shown that AVP receptor antagonists represent a promising
approach for the treatment of hyponatremia in HF [53, 54].
So far 3 vasopressin antagonists have been studied for the
treatment of hyponatremia in HF: conivaptan (V1A/V2
receptor antagonist), lixivaptan, and tolvaptan (both
selective V2 antagonists) [55]. Of these, conivaptan is
approved as intravenous formulation for the treatment of
euvolemic and hypervolemic hyponatremia (for up to
4 days) [56]; tolvaptan is approved as an oral formulation
for euvolemic and hypervolemic hyponatremia [57]; while
lixivaptan is in phase 3 evaluation [58].
Hyponatremia seems to be effectively managed by the
vasopressin receptor antagonists, but it is not yet clear
whether normalization of [Na] leads to an improved
prognosis.
Heart Fail Rev (2012) 17:1726
RCTs on AVP receptors antagonists
V1A/V2 receptor antagonism
The only V1A/V2 receptor antagonist available is
conivaptan. It has been evaluated in phase 3, double-blin-
ded, placebo-controlled, multicenter RCTs in patients with
euvolemic or hypervolemic hyponatremia.
Data from 3 RCTs [5961] were combined and analyzed
to determine the efficacy of conivaptan in the subset of
patients with hyponatremia and HF. Of the 241 enrolled
patients, 94 patients (39%) had HF (placebo31, conivap-
tan 40 mg/day25, conivaptan 80 mg/day28 patients,
respectively). Compared with placebo, [Na] increased sig-
nificantly from baseline after iv and oral administration of
conivaptan 40 and 80 mg/day. Notably, there was a slower
[Na] rate of correction in patients with HF compared to those
without HF. Adverse events were similar between groups,
indicating conivaptan was well tolerated in HF patients.
Conivaptan has been approved as intravenous adminis-
tration by the Food and Drug Administration (FDA) for the
treatment of euvolemic and hypervolemic hyponatremia.
It should be initiated with a loading dose of 20 mg/100 ml
administered over 30 min, followed by a continuous infu-
sion of 20 mg/100 ml/24 h. If [Na] is not rising at the
desired rate, conivaptan may be titrated upward to a dose of
40 mg/day. The total duration of infusion (after the loading
dose) should not exceed 4 days. Moreover, patients
receiving conivaptan must have frequent monitoring of
[Na] and volume status. An overly rapid rise in [Na]
([12 mEq/l/day) should be avoided due to possible neu-
rologic sequelae [56].
V2 receptor antagonism
There are 2 available V2 receptor antagonists, tolvaptan,
which has already been approved, and lixivaptan, which is
still under investigation.
The efficacy and safety of tolvaptan were evaluated in a
randomized, double-blinded, placebo-controlled study that
enrolled 254 HF patients (NYHA Class I to III). The patients
were randomly assigned to tolvaptan (30, 45, or 60 mg/day)
or placebo for 25 days, along with stable dose of furosemide.
Tolvaptan reduced mean BW significantly more than pla-
cebo, regardless of the dosage given (P \ 0.001). However,
there was no further reduction beyond the first day; thus, it
was largely due to fluid loss at initiation of therapy. Urine
volume was also significantly greater and urinary osmolality
significantly lower with tolvaptan than with placebo
(P \ 0.05). Urinary sodium excretion also increased sig-
nificantly during the first day of tolvaptan treatment. In 28%
of the patients who had hyponatremia ([Na]\136 mEq/l) at
baseline, [Na] normalized on day 1 of treatment in 80% of
23
patients given tolvaptan, compared with 40% of those given
placebo (P \ 0.05); a similar percentage of patients main-
tained normal [Na] throughout the study. Plasma AVP levels
tended to be higher in patients given tolvaptan, but this
finding was not significant [62].
The ACTIVinCHF trial was a phase 2, dose-ranging,
randomized, double-blinded, placebo-controlled trial
designed to evaluate the efficacy and safety of oral tolvaptan
(30, 60, or 90 mg) in 319 patients hospitalized with acute
decompensated HF (ADHF) (LVEF \40%) for no longer
than 10 days while hospitalized, and continued for up to
60 days on an outpatient basis. Treatment with tolvaptan at
all 3 doses significantly reduced median BW at 24 h com-
pared to placebo, but had no effect on HF outcomes at
60 days (P = 0.002, P = 0.002, and P = 0.009, respec-
tively). In a post hoc analysis, tolvaptan reduced 60-day
mortality in patients with renal dysfunction or severe sys-
temic congestion. 21% of the patients had hyponatremia
([Na] \136 mEq/l) at baseline. Tolvaptan produced a rapid
increase in [Na], and often a return to normal [Na], that was
maintained throughout the study (P \ 0.001). However, no
differences in worsening HF (WHF) at 60 days between the
groups were observed [17].
The EVEREST programs are multicenter, randomized,
double-blinded, placebo-controlled trials (2 short-term and 1
long-term outcome studies) that evaluated the effects of
Tolvaptan among 4,133 patients admitted for ADHF (LVEF
B40%). Patients were randomized 1:1 to tolvaptan 30 mg/
day or placebo for a minimum of 60 days. Tolvaptan
determined a statistically significant improvement com-
pared to placebo on the primary short-term endpoint (com-
posite of patient-assessed global clinical status and BW
change) at day 7 (P = 0.0004) or discharge (P \ 0.0001)
[63]. However, in the long-term follow-up (FU) trial during
a mean FU of 9.9 months, tolvaptan had no effect on all-
cause mortality or the combined endpoint of cardiovascular
mortality, or subsequent hospitalization for WHF. Adverse
events resulting in study drug discontinuation occurred in
6.5% of tolvaptan patients. Notably, those taking tolvaptan
had reductions in BW and improved [Na] with modest
improvements in signs and symptoms of HF with no excess
adverse events. In a subgroup analysis, *8% of patients had
hyponatremia ([Na] \134 mEq/l); in these patients, tol-
vaptan exerted a significant effect in increasing [Na] com-
pared to placebo. However, as in the larger cohort, there was
no associated decrease in mortality related to improvement
in [Na] [18]. Tolvaptan was well tolerated in these studies.
Tolvaptan has been approved as oral administration for
the treatment of euvolemic and hypervolemic hyponatre-
mia. The usual starting dose for tolvaptan is 15 mg/day
which can be increased to 30 mg/day, after at least 24 h, to
a maximum of 60 mg/day, if [Na] does not rise. During
initiation and titration, changes in serum electrolytes and
123
24
volume must be frequently monitored. Fluid restriction
during the first 24 h of therapy must be avoided. An overly
rapid rise in [Na] ([12 mEq/l/day) should be avoided due
to possible neurologic sequelae [57].
Lixivaptan has been evaluated in a randomized, double-
blinded, placebo-controlled, ascending single-dose (oral
lixivaptan 10, 30, 75, 150, 250, or 400 mg) trial on 42
HF patients (NYHA II/III) and hyponatremia (120\ [Na]
\140 mEq/l), all but the 10-mg dose demonstrated a sig-
nificant and dose-dependent increase in urine output (P \
0.01), solute-free water clearance (P \ 0.05), and [Na] at
higher doses (250400 mg) (P \ 0.01) compared with pla-
cebo. Lixivaptan demonstrated significant dose-dependent
decreases in urinary osmolality, but did not demonstrate any
significant effects on levels of plasma renin, norepinephrine,
aldosterone, ANP and endothelin-1 [64].
The Treatment of Hyponatremia Based on Lixivaptan in
NYHA Class III/IV Cardiac Patient Evaluation (BAL-
ANCE) Study is an ongoing double-blinded, randomized,
multicenter study aimed to evaluate the effects of titrated
oral lixivaptan in patients with hyponatremia hospitalized
for WHF. The study will include approximately 650
patients, who will receive lixivaptan or placebo with dose
titration for 60 days. The primary objective of the study is
to determine whether lixivaptan can effectively and safely
increase [Na] in HF patients with hyponatremia. Secondary
objectives are to assess all-cause mortality, cardiovascular
effects, HF hospitalization, and acute change in BW [55].
Studies have shown that V2 receptor antagonists can
increase the plasma AVP levels. The increased V1A activity
and the resulting vasoconstriction, release of coagulation
factors, and platelet aggregation would be deleterious to
patients with HF. Therefore, V1A/V2 receptors antagonists
may provide better outcomes in HF patients [65].
So far the role of AVP receptor antagonists in the therapy
of HF remains undefined. Further studies are needed to
better define their role in the setting hyponatremia in HF.
Future perspectives
Hyponatremia is a common and important comorbidity in
HF patients and is a strong independent predictor of mor-
tality in HF risk assessment models. It is primarily caused
by increased AVP levels in HF patients, which in turn may
be the determinant of the poor outcome. Moreover, hypo-
natremia seems to be an important marker of HF progres-
sion, consequential to neurohormonal systems activation
and impaired hemodynamics. These characteristics are
translated into worse short-term and long-term outcomes.
Vasopressin receptor antagonists appear promising in the
management of patients with volume overload and hypo-
natremia. However, so far only V2 receptor antagonism
(tolvaptan) has been studied in testing long-term outcomes
123
Heart Fail Rev (2012) 17:1726
with these agents, and it failed to demonstrate a benefit
despite the correction of hyponatremia in a large random-
ized clinical trial [63]. Moreover, the cost of these new
therapies, associated with the lack of positive results on
mortality and rehospitalization endpoints, makes the cost-
effectiveness controversial. Future research should focus
on a better understanding of the cause-and-effect mecha-
nism existing between HF and hyponatremia, to further
analyze whether the correction of hyponatremia improves
long-term outcomes and to determine a consistent defini-
tion of serum-sodium level that should be used to define
hyponatremia.
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