New Drugs and Technologies

Arginine Vasopressin Antagonists for the Treatment of

Heart Failure and Hyponatremia
John J. Finley IV, MD; Marvin A. Konstam, MD; James E. Udelson, MD

A rginine vasopressin has attracted attention as a poten-

tially important neurohormonal mediator of the heart
failure (HF) syndrome and hyponatremic states in humans1
and adrenal medulla (Table 1).5,8 V1a and V1b receptors are
linked to the phosphatidylinositol and 1,2-diacylglycerol
signaling pathway (Figure 1). Activation of the V1 receptors
because vasopressin influences renal handling of free water, causes influx of extracellular calcium by an unknown mech-
vasoconstriction, and myocyte biology.2,3 Several vasopressin anism. Protein kinase C and calcium/calmodulin-activated
antagonists are under development,4 and one of these agents, protein kinases phosphorylate cell type–specific proteins, lead-
conivaptan, recently received US Food and Drug Adminis- ing to a range of cellular responses, including vasoconstriction,
tration approval for short-term intravenous treatment in pa- glycogenolysis, platelet aggregation, adrenocorticotrophic hor-
tients with euvolemic or hypervolemic hyponatremia. mone release, and growth of vascular smooth muscle cells.5
V2 (renal) receptors, expressed on the basolateral mem-
The Role of Vasopressin in HF brane of the renal collecting ducts, mediate the antidiuretic
and Hyponatremia effects of vasopressin. The intracellular effects of this recep-
A neurohypophysial hormone, vasopressin (also called antidi- tor subtype are mediated by the adenylate cyclase signaling
uretic hormone [ADH]), affects free water reabsorption by pathway (Figure 2). Intracellular events triggered by binding
the kidney, body fluid osmolality, blood volume, vasocon- of vasopressin to the V2 receptor include increased de novo
striction, and myocardial contractile function.2,3 Vasopressin synthesis and “shuttling” of aquaporin 2 water channels
is synthesized by neurosecretory cells located predominantly (AQP-2) from cytoplasmic vesicles to the luminal surface of
in the supraoptic and paraventricular hypothalamic nuclei. the renal collecting duct cells, where they are inserted into the
These neurons have axons terminating in the neural lobe of cell membrane and facilitate water transport across the
the posterior pituitary (neurohypophysis) that release vaso- collecting duct cells (Figure 2).9,10
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pressin and oxytocin.5

Evidence for Elevated Vasopressin Levels in HF
Physiology of Regulation of Vasopressin Release and/or LV Dysfunction
Normally, the dominant stimulant for vasopressin release is a In addition to plasma osmolality, nonosmotic factors such as
change in plasma tonicity, plasma volume depletion, or blood intracardiac pressures, intraarterial pressures, angiotensin II,
pressure, the last 2 mediated by arterial baroreceptors. Os- pain, and adrenergic (␣2) central nervous stimuli potentially
moreceptors in the anterior hypothalamus sense the increase influence vasopressin secretion. In normal homeostasis, these
in serum osmolality and stimulate secretion of vasopressin nonosmotic mechanisms are thought to play only a minor
from the posterior pituitary. In an attempt to normalize role. However, in edematous states, there appears to be a shift
plasma osmolality, vasopressin acts on the V2 renal recep- in regulation toward relatively greater influence of the non-
tors, increasing free water reabsorption by insertion of protein osmotic mechanisms.11 The response to osmotic changes
water channels, aquaporins, in the luminal membranes of the appears to occur at lower plasma osmolality levels in edematous
principal cells of the renal collecting ducts.6 states and is more pronounced, as demonstrated by a greater
increment of vasopressin levels in patients with HF compared
Receptor/Effector Mechanisms with non-HF subjects after an osmotic load of mannitol.11
The 3 vasopressin receptor subtypes belong to a family of Several studies have shown a significant elevation in mean
rhodopsin-like G-protein– coupled receptors.7 V1a (vascular) values of plasma vasopressin in populations of patients with
receptors are located on several cell types, including vascular HF and/or LV dysfunction.4,12–14 In the Studies of Left
smooth muscle cells and cardiomyocytes (Table 1), with Ventricular Dysfunction (SOLVD),14 patients with asymp-
effects on the maintenance and regulation of vascular tone tomatic left ventricular (LV) dysfunction had higher mean
and possibly myocardial function.3 vasopressin levels compared with a control group. Patients
V1b (pituitary) receptors are expressed on the surfaces of with mild to moderate symptomatic HF had even higher mean
corticotrophic cells in the anterior pituitary and the pancreas levels than their asymptomatic counterparts. Wide variability

From the Division of Cardiology and Department of Medicine, Tufts Medical Center, Boston, Mass.
Correspondence to James E. Udelson, MD, Box 70, Tufts Medical Center Division of Cardiology, 50 Washington St, Boston, MA 02111. E-mail
[email protected]
(Circulation. 2008;118:410-421.)
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.108.765289

410
 Finley et al AVP Antagonists in Heart Failure and Hyponatremia 411

Table 1. Vasopressin Receptors: Location and Function5,8

V1a V1b V2

Location Mediates Location Mediates Location Mediates

Vascular smooth Vasoconstriction, Corticotroph cells of ACTH release Basolateral membrane of renal Free water resorption (insertion
muscle myocardial hypertrophy anterior pituitary collecting tubule of AQP-2 water channels into
apical membrane; induction of
AQP-2 synthesis)
Platelets Aggregation 䡠䡠䡠 䡠䡠䡠 Vascular endothelium Releases von Willebrand factor
and factor VIII
Myometrium Uterine contraction 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠
ACTH indicates adrenalcorticotropin hormone.

in vasopressin levels exists among individual patients and Evidence supporting the concept that vasopressin mediates
across studies, and not all HF patients in these studies some degree of hemodynamically unfavorable effects in the
demonstrate elevated levels compared with normal referents. setting of HF comes from data using selective V1a receptor
However, these “normal” vasopressin levels may be inappro- antagonists in vivo,15 where significant improvements in
priately elevated in HF relative to the state of expanded systemic vascular resistance and cardiac output were ob-
plasma volume or diminished plasma osmolality, although served in humans after vasopressin antagonism but only when
studies are not often analyzed as such.15 Table 2 summarizes vasopressin levels were elevated. Similar findings have been
the extant published literature reporting vasopressin levels in reported in animal models.27,28
patients with HF and/or LV dysfunction.11–23
Vasopressin Effects on Myocyte Biology
Hemodynamic Effects of Vasopressin In neonatal rat myocardial cells, cellular hypertrophy by
The vasoconstrictive effects of vasopressin are not thought to means of enhanced protein synthesis has been observed as
be associated with appreciable changes in arterial blood a result of vasopressin receptor stimulation.29,30 By means
pressure at plasma levels within physiological range.24 How- of exposure to V1a receptor antagonists, the observed
ever, in patients with HF, infusion of vasopressin increases hypertrophy was significantly inhibited.29,30 Myocardial
systemic vascular resistance and pulmonary capillary wedge V1a receptor agonism results in an increase in intracellular
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pressure increase, whereas stroke volume and cardiac output

calcium concentration, causing activation of mitogen-acti-
decrease with dose-dependent increases in vasopressin infu-
vated protein kinase and protein kinase C,29 –31 thought to
sion.25 These hemodynamic effects are thought to be medi-
be central in mediating the observed hypertrophic myocar-
ated primarily by activation of V1a receptors.16,26

Figure 1. Vasopressin V1 receptor activation. The binding of Figure 2. Vasopressin V2 receptor activation. The binding of
arginine vasopressin (AVP) to its V1 receptor (V1R) stimulates arginine vasopressin (AVP) to the V2 vasopressin receptor (V2R)
membrane-bound phospholipase (PLCB) via stimulation of a stimulates a Gs-coupled protein that activates adenylyl cyclase,
G-coupled protein (Gq), which in turn results in inositol triphos- in turn causing production of cAMP to activate protein kinase A
phate (IP3) formation and mobilization of intracellular Ca2⫹ (PKA). This pathway increases the exocytosis of aquaporin
(icCa2⫹). A separate phosphorylation cascade occurs via diacyl- water channel– containing vesicles (AQMCV) and inhibits endo-
glycerol (DAG) and protein kinase C (PKC), which has down- cytosis of the vesicles, both resulting in increases in aquaporin
stream effects, including vascular smooth muscle (VSM) vaso- 2 (AQ2) channel formation and apical membrane insertion. This
constriction, cell growth, adrenocorticotrophic hormone (ACTH) allows an increase in the permeability of water from the collect-
release, and platelet aggregation. ing duct (CD).
 412 Circulation July 22, 2008

Table 2. Vasopressin Levels by Radioimmunosorbent Assay in Vasopressin Role in Water Balance

HF and Other Populations and Hyponatremia
Study Patients, n Mean AVP Levels, pg/mL Vasopressin directly alters sodium concentration and water
balance by stimulating the renal V2 receptors through in-
Creager et al16 HF, 10 2.4⫾0.6
creased expression of AQP-2 inserted into the cell mem-
Normal 1.1⫾0.2
branes of the principal cells of the renal collecting ducts,
Nicod et al17 HF, 10 2.3⫾0.8 facilitating free water absorption and a subsequent decrease
Pruszczynski et al18 HF, 14 4.6⫾0.3 in sodium serum levels.
HTN, 8 2.9⫾0.1 Elevated plasma vasopressin concentrations appear to be
CAD, 11 3.4⫾0.2 associated with impaired solute-free water excretion in the
Goldsmith et al12 HF, 31 9.5⫾0.9 setting of HF.9,10 Rats with an elevated LV end-diastolic
Normal, 51 4.7⫾0.7
pressure and reduced plasma sodium had significantly in-
19
creased expression of AQP-2 mRNA compared with rats with
Goldsmith et al HF, 15 11.6⫾5.5
compensated HF.32
Normal, 9 5.3⫾2.3
In this regard, specific antagonism of the vasopressin V2
Szatalowicz et al13 HF, 9 4.6⫾2.1 receptor results in a potent aquaresis in dogs and rats.33 In
Kramer et al15 HF, 20 humans, V2 receptor antagonism results in a dose-related
“High AVP” for Posm 14.5⫾8.8 increase in solute-free water excretion and elevation of serum
“Low AVP” for Posm 3.9⫾1.0 sodium concentration and serum osmolality in patients with
Rouleau et al20 Asx LVD, 534 1.8⫾6.7 HF.22,34,35 In 1 study, an observed reduction in urinary AQP-2
Gavras et al21 Normal, 12 1.1⫾0.2 protein levels suggested that aquaresis was associated with a
14 reduction in AQP-2 expression at the level of the renal
Francis et al HF, 80 3.5
collecting duct.36
Asx LVD, 147 2.6
Moreover, as discussed further below, vasopressin antag-
Normal, 54 2.9 onism at the level of the V2 receptor has been consistently
Uretsky et al11 HF, 42 3.0⫾2.5 associated with an improvement in serum sodium levels
Normal, 10 1.0⫾0.4 among patients with hyponatremia of multiple causes.37– 40
Udelson et al22 HF, 142 Median levels 2.1–2.9
Udelson et al23 HF randomized to 1.7⫾1.9 Vasopressin Antagonists in Development
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TLV, 120 Several vasopressin antagonists are in various stages of

HF randomized to 2.0⫾1.8 clinical trials for treating hyponatremia and/or HF. These
PLC, 120 agents differ on the basis of their degree of specificity for the
AVP indicates arginine vasopressin; HTN, hypertension; CAD, coronary artery V1a and V2 receptors (Table 3).4,41– 43
disease; Posm, plasma osmolality; Asx LVD, asymptomatic LV dysfunction; TLV, Conivaptan is a nonpeptide vasopressin antagonist with a
tolvaptan; and PLC, placebo. high affinity for both V1a and V2 receptors. Conivaptan has
been administered by oral and intravenous routes,44 although
the clinical development and recent US Food and Drug
dial cell growth. In these experiments, vasopressin inhibi- Administration approval involve only the intravenous formu-
tion with an agent acting at both the V1a and V2 receptors lation. The effects of conivaptan on urinary parameters in rat
inhibited the activity of mitogen-activated protein kinase models have included an increase in both urine volume and
on rat cardiac myocytes. sodium concentration compared with placebo.45 Decreased

Table 3. Properties of Vasopressin Antagonists Tested in Human Trials

Vasopressin
Antagonist Tolvaptan (OPC-41061)4 Lixivaptan (VPA-985)4 Conivaptan (YM-087)4 Satavaptan (SR-121463)41 Mozavaptan (OPC-31260)42,43
Receptor V2 V2 V1a/V2 V2 V1a/V2
Selectivity 29:1 100:1 10:1 112:1 10:1
(KiV1a:KiV2)
Administration route Oral Oral Intravenous/oral Oral Intravenous/oral
Half-life, h 6–8 7–10 14–17 14–17 1–8
Metabolism Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic Hepatic (CYP3A4) Hepatic (CYP3A4)
(CYP3A4/CYPD6)
Elimination Feces Feces Feces Feces Feces
Clinical Hyponatremia, Hyponatremia, Hyponatremia, Hyponatremia, HF, Hyponatremia (only SIADH)
development decompensated HF, decompensated HF decompensated HF cirrhosis (prevention of
PCKD with hyponatremia ascites)
PCKD indicates polycystic kidney disease.
 Finley et al AVP Antagonists in Heart Failure and Hyponatremia 413

intracellular free calcium and mitogen-activated protein ki- cebo plus fluid restriction, tolvaptan appeared to be more
nase activity were observed to occur in a dose-dependent effective at correcting hyponatremia in hospitalized
manner,29,30 suggesting a reduction in intracellular protein patients.49
synthesis and possibly cardiomyocyte hypertrophy. Thus, in Lixivaptan also has been evaluated in 44 patients with
animal models, inhibition of both V1a and V2 vasopressin hyponatremia from cirrhosis, HF, or SIADH receiving doses
receptors may play a beneficial role in HF. of 25, 125, or 250 mg orally twice daily for 7 days.40 The
Tolvaptan, a selective nonpeptide V2 receptor antagonist, observed effects included an aquaretic response compared
has potent aquaretic properties in animal models.46,47 In with placebo, with dose-related increases in free water clear-
cloned human receptors, the V2:V1a receptor selectivity was ance and serum sodium and without changes in orthostatic
29:1.47 Dose-dependent responses demonstrated in rats in- blood pressure or serum creatinine. Although effective at
clude increased free water clearance, less urinary loss of lower doses, the higher dose (250 mg) resulted in significant
sodium than furosemide, and no effect on serum creatinine.46 volume depletion requiring withholding of doses in 50% of
Compared with furosemide, serum sodium increased in a patients.
dose-dependent fashion in animals given tolvaptan.46 Unlike Conivaptan has been studied for short-term intravenous
the administration of loop diuretics, antagonism of V2 recep- treatment of euvolemic and hypervolemic hyponatremia and
tors appeared not to increase activation of the renin-angio- has recently achieved US Food and Drug Administration
tensin-aldosterone system.46 approval for this indication. The data that formed the basis for
Lixivaptan is a nonpeptide, highly specific antagonist of approval were published by Zeltser et al,39 who randomized
the V2 receptor. The binding affinity of lixivaptan for V2 84 hospitalized patients with either euvolemic or hypervole-
receptors is ⬇100 times greater than for V1 receptors.2 mic hyponatremia (defined by serum sodium concentrations
Dose-dependent increases in urine output and solute-free between 115 and 130 mEq/L) to receive a 20-mg loading
water clearance and increased serum sodium concentration dose of conivaptan over 30 minutes followed by a 4-day
have been demonstrated in preliminary human studies of infusion at either 40 or 80 mg/d or to receive placebo loading
single doses of lixivaptan administered to patients with New and infusion. Conivaptan resulted in a significant increase in
York Heart Association class II and III HF.34 serum sodium of 6.3⫾0.7 mEq/L in the 40-mg/d group and
Satavaptan is highly specific for the V2 receptor, has a long an increase of 9.4 mEq/L in the 80-mg/d group.39 The rate of
half-life, and is under development for the treatment of correction of serum sodium was within safe limits without
hyponatremia in the syndrome of inappropriate secretion of evidence of excessive hypernatremia or feared complications
ADH (SIADH) and cirrhosis.41 of central pontine myelinolysis from too-rapid correction of
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serum sodium. Compared with placebo, the incidence of

Clinical Trials of Vasopressin death, serious side effects, and discontinuations of treatment
Receptor Antagonists for any reason were not in excess compared with placebo.
However, an increased incidence of adverse effects in dose-
Trials in Hyponatremia related infusion-site reactions was present among patients
Hyponatremia is challenging to treat, with current approaches receiving conivaptan versus those receiving placebo.39
having significant limitations. Antagonism of vasopressin Satavaptan is highly specific for the V2 receptor and has
action at its receptor is attractive as an approach that directly the longest half-life (14 to 17 hours) of the agents studied so
addresses the pathophysiology. Table 4 summarizes the trials far. A trial of 34 patients with SIADH showed significant
that have investigated the use of vasopressin antagonists in correction of hyponatremia after doses of either 25 or 50 mg
patients with hyponatremia of multiple origins.37,39,40,41,48 versus placebo.41 In the long-term open-label extension of the
Two recently completed trials, Study of Ascending Levels trial, satavaptan demonstrated safety without adverse events
of Tolvaptan in Hyponatremia (SALT)-1 and SALT-2, inves- over a 12-month period.
tigated the effects of tolvaptan on serum sodium levels in A larger trial in 110 cirrhotics with ascites and hyponatre-
patients with euvolemic or hypervolemic hyponatremia asso- mia demonstrated improvement in serum sodium levels and
ciated with HF, cirrhosis, or SIADH. This double-blind ascites control.48 This multicenter, double-blind, randomized
multicenter trial randomized 223 patients to placebo and 225 controlled trial compared 3 oral doses (5, 12.5, or 25 mg once
patients to tolvaptan at an initial dose of 15 mg daily. Dosing daily) compared with placebo, in addition to spironolactone
of tolvaptan (or matching placebo) was increased to 30 mg 100 mg daily for 14 days. A dose-dependent improvement in
and then to 60 mg daily if sodium levels were not responding. ascites was found with satavaptan, as indicated by a reduction
Patients receiving tolvaptan had highly significant increases in body weight and abdominal girth, as well as an improve-
in serum sodium concentration at days 4 and 30. In the week ment in serum sodium.48
after discontinuation of tolvaptan at day 30, hyponatremia Overall, the data surrounding tolvaptan, lixivaptan,
recurred.37 In a prespecified analysis examining a patient- conivaptan, and satavaptan have been consistent in demon-
reported health status measure, tolvaptan had a favorable strating favorable effects on serum sodium among patients
effect compared with placebo on the Mental Component with hyponatremia of various causes but not in demonstrating
Summary of the Short Form-12 Health Survey, particularly in effects on overall or disease-specific mortality. An effect in
patients with more severe hyponatremia.37 the tolvaptan trials has been seen on symptoms as reflected by
Of note, patients in the SALT trials were not fluid the Mental Component Summary of the Short Form-12
restricted; however, in 1 smaller study compared with pla- Health Survey.37
 414 Circulation July 22, 2008

Table 4. Vasopressin Receptor Antagonists in Hyponatremia: Clinical Trials

Clinical Trial n Design Drug Inclusion Criteria End Points Results
SALT-1/SALT-237 448 Multicenter, placebo Tolvaptan Euvolemic or hypervolemic Change in the average Serum sodium
controlled, double hyponatremia daily AUC for serum concentrations
blind, multidose (HF, cirrhosis, SIADH) sodium from baseline increased more in the
(15 mg/d and then (Na ⬍135 mEq/L) to day 4 and the tolvaptan group than
increased to either change from baseline in the placebo group
30 or 60 mg/d, to day 30 during the first 4 d
depending on (P⬍0.001) and after
sodium 30 d of therapy
concentrations) (P⬍0.001)
Wong et al40 44 Multicenter, placebo Lixivaptan Hyponatremic patients Free water clearance Increase in serum
controlled, double (HF, cirrhosis, SIADH) and serum sodium sodium; increased
blind, multidose aquaretic response
(25 mg, 125 mg, or without significant
250 mg orally twice changes in orthostatic
daily for 7 d) blood pressure or
serum creatinine
levels; higher dose
(250 mg) led to
dehydration
Zeltser et al39 84 Multicenter, placebo Conivaptan Euvolemic or hypervolemic Change in the AUC for Dose-dependent
controlled, double hyponatremia (Na 115 to serum sodium during increase in serum
blind (96-hour ⬍130 mEq/L) the infusion sodium
infusion of either
40 or 80 mg/d)
Ghali et al70 74 Multicenter, placebo- Conivaptan Euvolemic or hypervolemic Change in the AUC for Dose-dependent
controlled, double- hyponatremia (Na 115 to serum sodium increase in serum
blinded, multidose ⬍130 mEq/L) sodium
(40 mg, 80 mg orally
daily for up to 5 days)
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Soupart et al41 34 Multicenter, placebo Satavaptan SIADH Percent normalization Dose-dependent

controlled, double or increase of correction in serum
blind, multidose ⱖ5 mmol/L sodium sodium (second,
(25 mg, 50 mg long-term arm
orally daily for up to showed safety)
5 d and then 23 d
of open-label dose
adjustment)
Gines et al48 110 Multicenter, placebo Satavaptan Hyponatremic cirrhotics Ascites control Improved control of
controlled, double with ascites (abdominal girth and ascites; increased
blind, multidose weight); change in serum sodium
(5, 12.5, or 25 mg serum sodium on day
orally daily for 14 d 5 from baseline
in addition to
spironlactone 100
mg PO daily)
AUC indicates area under the curve; heart failure.

HF With Hyponatremia Evaluation Study of Congestive Heart Failure and Pulmonary

The presence of hyponatremia in the setting of volume Artery Catheterization Effectiveness [ESCAPE]) have dem-
overload and HF creates substantial management challenges. onstrated.50 –52 Because such patients are thought to have
Treatment of the volume-overload state with loop diuretics vasopressin excess contributing to the pathophysiology, the
can exacerbate the free water excess and result in maintaining potential use of vasopressin antagonists in this setting is
or even worsening of the magnitude of hyponatremia. The attractive.
presence of hyponatremia in patients admitted for HF exac- In a double-blind study conducted in 254 stable chronic HF
erbation regardless of systolic dysfunction, even mild hypo- patients (regardless of LV ejection fraction), 3 oral doses of
natremia, portends a worse prognosis, as many trial registries tolvaptan (30, 45, or 60 mg) given daily for 25 days were
(Outcomes of a Prospective Trial of Intravenous Milrinone compared with placebo administration.38 Throughout the full
for Exacerbations of Heart Failure [OPTIMIZE-HF], Out- course of therapy, a significant decrease in body weight and
comes of a Prospective Trial of Intravenous Milrinone for edema was observed, as was an increased urinary volume.
Exacerbations of Chronic Heart Failure [OPTIME-CHF], Seventy of the 254 patients (28%) had hyponatremia at
 Finley et al AVP Antagonists in Heart Failure and Hyponatremia 415

Table 5. Vasopressin Receptor Antagonists in Heart Failure With Hyponatremia: Clinical Trials
Clinical Trial Design Drug Inclusion/Exclusion Criteria Endpoints Results
Gheorghiade et al Placebo controlled, double Tolvaptan HF patients regardless of Body weight Normalization of mean
(subgroup blind, multidose (30, 45, LVEF serum sodium by day
analysis)38 or 60 mg orally daily 1 and maintained
for 25 d)
Subgroup of 28% (of 254 䡠䡠䡠 䡠䡠䡠 Urine volume (day 1), Decrease in body
total) with hyponatremia edema, serum sodium weight and edema;
(Na⫹ ⬍136 mEq/L) at increased urinary
baseline volume
ACTIV in HF Multicenter, placebo Tolvaptan Decompensated HF with LVEF Secondary end point: In subgroup with
(subgroup controlled, double blind ⱕ40% and 2 clinical signs of sodium levels hyponatremia, sodium
analysis)53 (30, 60, or 90 mg orally volume overload levels increased and
daily up to 60 d) often normalized
Subgroup: 16% (of 319 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠
total) with hyponatremia
(Na ⬍136 mEq/L)
EVEREST Multicenter, placebo Tolvaptan Decompensated HF patients All-cause mortality In subgroup with
(subgroup controlled, double blind, with LVEF ⱕ40% hyponatremia, no
analysis)54 single dose (30 mg orally effect on mortality or
daily for up to 60 d) HF morbidity
Subgroup: 28% (of 4133 䡠䡠䡠 䡠䡠䡠 First occurrence of Significant increase in
total) with hyponatremia cardiovascular mortality or mean serum sodium
(Na ⬍137 mEq/L) heart failure hospitalization
BALANCE55 Multicenter, placebo Lixivaptan Decompensated HF with 䡠䡠䡠 Pending
controlled, double-blind hyponatremia
LVEF indicates LV ejection fraction; BALANCE, Treatment of Hyponatremia Based on Lixivaptan in New York Heart Association Class III/IV Cardiac Patient Evaluation.

baseline, defined in this study as serum sodium ⬍136 mEq/L. The published trials38,53–55 (Table 5) demonstrate the ben-
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In these patients, tolvaptan at all doses was associated with efit of vasopressin antagonists in terms of raising or normal-
normalization of the mean serum sodium levels in the treated izing sodium levels in hyponatremic HF patients, most per-
patients for the entire duration of the study period in the formed even without fluid restriction. In 1 trial that compared
absence of fluid restriction, although in this study the effect of fluid restriction and tolvaptan, a significant improvement in
tolvaptan on hyponatremia was not a primary study objective. hyponatremia with tolvaptan was demonstrated.49
Normalization of hyponatremia occurred in 82% of the The use of vasopressin antagonists, addressing both the
treated patients even on day 1 compared with only 40% of pathophysiological state of hyponatremia and the volume-
placebo-treated patients, with similar findings observed on overload state simultaneously, could become an important
day 25.38 approach in this clinical setting for this challenging group of
In the Acute and Chronic Therapeutic Impact of a Vaso- patients.
pressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure
(ACTIV in CHF) trial, which evaluated decompensated HF Decompensated HF
patients, 68 patients (21%) had hyponatremia (again defined In the ACTIV in CHF trial, 3 oral, once-daily doses of
as sodium level ⬍136 mEq/L) at randomization. Serum tolvaptan (30, 60, or 90 mg) or placebo were administered to
sodium concentrations were observed to rise and often patients hospitalized with acute decompensated HF.53 Body
normalize in this cohort.53 Of interest, among these patients weight decreased significantly from baseline in all tolvaptan-
admitted to hospital with decompensated HF, those with treated groups on day 1 after admission (a primary end point)
hyponatremia had a very high mortality rate at 60 days. compared with placebo and decreased further during the
In a subgroup analysis of the Efficacy of Vasopressin course of hospitalization. This effect was not dose dependent.
Antagonism in Heart Failure Outcome Study With Tolvaptan Similarly, urine volume on day 1 was significantly higher in
(EVEREST) trial, ⬇8% of enrolled patients with decompen- all groups treated with tolvaptan than in those treated with
sated HF had significant hyponatremia, defined as serum placebo.
sodium ⬍134 mEq/L. In these hyponatremic patients, serum No significant differences were observed in rates of rehos-
sodium increased 5.5 mEq/L in the tolvaptan-treated patients pitalization over the 60-day follow-up period, although a
compared with an increase of 1.8 mEq/L in the placebo- trend toward greater survival was found in the tolvaptan
treated patients, and the improvement in the tolvaptan-treated groups compared with placebo. In posthoc subgroup analy-
patients was maintained throughout the long-term course of ses, patients with elevated blood urea nitrogen and those with
therapy.54 However, as with the larger cohort, no mortality multiple signs of congestion who were treated with tolvaptan
outcome benefit in this subgroup and no association of experienced lower mortality rates out to 60 days. Although
improved hyponatremia with better outcomes were seen. this study was not sufficiently powered nor designed to assess
 416 Circulation July 22, 2008

mortality, the results were provocative and supported the normalizing serum sodium concentration in hyponatremic
performance of a fully powered trial to assess these findings patients.
prospectively. The intravenous form of conivaptan as a several-day
The EVEREST program evaluated short- and long-term infusion also has undergone investigation for potential use in
end points among patients being admitted for acute decom- acute decompensated HF. A dose-ranging pilot study assess-
pensated HF, randomized to treatment with tolvaptan 30 mg ing the efficacy and safety of intravenous conivaptan in
daily in addition to routine standard care (including diuretics) patients with acute decompensated HF found that conivaptan
or to placebo plus standard care,56 and followed up on significantly increased urine output, was hemodynamically
continuing treatment with an assigned study drug after well tolerated, and had minimal excess adverse effects.
hospital discharge.54 The trial was structured so that the main However, no apparent significant change in respiratory symp-
trial incorporated 2 short-term trials of symptom assessment toms or body weight was found.58
for the hospitalization period, whereas long-term morbidity Data on the use of vasopressin antagonism in the setting of
and mortality outcome end points were assessed in the acute decompensated HF (see Table 6)53,54,58 suggest that the
well-powered main trial over the longer follow-up period.57 reductions in body weight, increases in urine output incre-
The trial population sample size (ultimately 4133 patients) mental to that resulting from standard therapy, and potentially
and duration of follow-up were event driven. more rapid improvement in symptoms can be achieved safely.
In the short-term trials, the primary end point was a The trials in this area, particularly EVEREST, also highlight
composite of patient-assessed global clinical status (assessed the challenges inherent in studying this syndrome. This trial
as a visual analog score) and body weight reduction, both was designed as a “one size fits all” approach with a
assessed at day 7 after randomization or at the time of fixed-dose protocol, although in clinical practice such an
discharge if earlier. This primary end point was positive in agent would likely be titrated on the basis of clinical effects.
favor of treatment with tolvaptan, driven by the reductions in Moreover, a new treatment strategy must be compared with
body weight beyond that achieved with standard therapy “standard therapy,” ie, intravenous loop diuretics and other
alone and not by changes in global clinical status because the therapies, which are generally effective, so end points must
scores were almost identical between the groups.
be measured against a clinical background that is dynamic
Numerous other secondary end points such as change in
and usually improving with standard therapy, as seen in the
patient-assessed dyspnea at multiple time points were posi-
placebo groups in trials such as Vasodilation in the Manage-
tively affected during tolvaptan treatment.56 On day 1, dys-
ment of Acute Congestive Heart Failure (VMAC) and again
pnea improvement was reported, with the tolvaptan group
in EVEREST.54,59 Symptom-based end points such as dys-
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improving 77% compared with 71% in the placebo in trial A

pnea are highly subjective and incorporate substantial vari-
and 72% versus 65% in trial B. Although these differences
ability in their measurement scales. In designing trials in this
are modest, it is important to note that the changes were seen
area, researchers must account for this variability and the
with study drug given in addition to all standard therapy.
effects of standard therapy when designing the analysis and
The long-term follow-up trial was powered to assess
calculating sample sizes.
coprimary end points of all-cause mortality (for either supe-
riority or noninferiority) and cardiovascular death or HF A sign such as change in body weight, although accepted
hospitalization (for superiority). Over a median of 9.9 months by clinicians, is not yet on solid regulatory footing by itself as
of follow-up, no effect (neither favorable nor unfavorable) of a basis for approval of a new agent for this syndrome. Thus,
tolvaptan was found compared with placebo on either of the in EVEREST, change in body weight was a component of a
main trial end points despite effective short-term reductions composite, along with a patient-assessed symptom end point.
in postdischarge body weight and improved serum sodium Significant lessons have been learned from trials in this area,
levels in hyponatremic patients.54 No excess adverse effects including EVEREST, to inform the design of future studies.
on renal function, heart rate, blood pressure, and serum
potassium were reported. Hemodynamics and Remodeling in Chronic HF
Both groups were on optimal medical therapy for HF, yet In a study of 142 patients with advanced HF with systolic
some benefit was observed in signs and symptoms of HF dysfunction, conivaptan was administered as a single intra-
without the increased risks that can occur with some treat- venous dose (10, 20, or 40 mg) and compared with placebo.22
ments for acute HF. Thus, although not ultimately affecting Pulmonary capillary wedge pressure was reduced, although
natural history after admission for decompensated HF in a modestly, and right atrial pressure was significantly reduced
favorable way, the long-term EVEREST follow-up has pro- after drug administration in the 20- and 40-mg conivaptan
vided substantial safety information to guide clinicians’ groups compared with placebo without a significant change
potential treatment strategy for use in improving in cardiac index, pulmonary artery pressures, systemic or
symptomatology. pulmonary vascular resistance, systemic arterial pressure, or
Hence, the EVEREST data suggest that vasopressin antag- heart rate. Urine output in the conivaptan-treated group
onism in the setting of decompensated HF has potential demonstrated a dose-dependent increase that peaked 2 to 3
benefit, including decreasing body weight by increasing urine hours after dosing. Urine osmolality was significantly re-
output associated with improvement in dyspnea, without duced by all doses of conivaptan. Of interest, no correlation
fostering abnormalities in electrolytes or renal function (as could be established between conivaptan effects and baseline
can be seen with more aggressive loop diuretic therapy) and vasopressin or serum sodium levels.
 Finley et al AVP Antagonists in Heart Failure and Hyponatremia 417

Table 6. Vasopressin Receptor Antagonists in Decompensated HF: Clinical Trials

Inclusion/Exclusion
Clinical Trial n Design Drug Criteria End Points Results
53
ACTIV in HF 319 Multicenter, placebo Tolvaptan Decompensated HF Body weight; Decrease in body weight;
controlled, double patients with LVEF urine volume increase in urine volume;
blind (30, 60, or 90 ⱕ40% and 2 (day 1) no change in BUN, Cr, K
mg orally daily up clinical signs of
to 60 d) volume overload
EVEREST54 4133 Multicenter, placebo Tolvaptan Decompensated HF Short-term trials: Favorable effect on
controlled, double patients with composite of composite, driven by
blind, single dose LVEF ⱕ40% GCS and change body weight change
(30 mg orally daily in body weight
for a minimum at day 7 or
of 60 d) discharge
Long-term trial Secondary: improvement
coprimary: ACM, in symptoms of dyspnea,
first occurrence weight (day 1), edema
of CV mortality, (day 7); long-term: no
or HF effect on mortality or HF
hospitalization morbidity; noninferior to
placebo for ACM
Goldsmith et al58 162 Placebo controlled, Conivaptan Decompensated HF Urine volume, Increase in urine volume;
double blind (20 mg body weight, decrease in body weight;
IV loading dose visual analog no change in clinical
followed by 40, 80, score status
or 120 mg/d for 2 d) (respiratory
symptoms)
LVEF indicates LV ejection fraction; BUN, serum urea nitrogen levels; Cr, creatinine; GCS, global clinical score assessed by the patient; ACM, all-cause mortality;
and CV, cardiovascular.

Similar hemodynamic and urine output data have recently quantitative radionuclide ventriculography), was unchanged
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been presented in a dose-ranging, singe-dose administration over 1 year of follow-up in the tolvaptan-treated group
study of tolvaptan35 in which modest reductions in wedge compared with the placebo group. Although the results of the
pressure and dose-dependent increases in urine output were METEOR trial established that vasopressin antagonism (with
observed. This increase in aquaresis may have been facili- a V2 receptor–specific agent) had no incremental benefit on
tated by the increase in serum osmolality seen in this study. remodeling over 1 year of therapy, the data indirectly ad-
The data from these studies suggest that vasopressin dressed a potential issue with regard to long-term treatment.
receptor antagonism in patients with stable advanced HF (see It had been suggested that long-term treatment with an agent
Table 7)23,60 – 62 has favorable hemodynamic effects (with more specific for the V2 vasopressin receptor may have
initial dosing), possibly mediated via increased urine output. unfavorable effects resulting from the unopposed vasopressin
The generally similar results noted for hemodynamics and V1 receptor stimulation because vasopressin levels may rise
urine output with single-dose studies of both conivaptan and during receptor antagonist therapy.63 The absence of any
tolvaptan suggest that the predominant effect of vasopressin unfavorable effect on remodeling during long-term V2 recep-
receptor antagonism in these studies involves effects at the tor antagonism in the METEOR trial and the safety data
V2 receptor. accumulated in the EVEREST study suggest that if any such
A preliminary study of oral conivaptan treatment for unfavorable effects exist, that they are not easily measurable.
several months that examined the effects on exercise toler- In patients with stable chronic HF, highly specific V2
ance and functional capacity in stable HF patients demon- receptor antagonism with lixivaptan has been studied in a
strated neutral results.60 Thus, the role of these agents in dose-ranging trial. Dose-dependent increases in urine output,
affecting clinical symptoms in patients with initially stable solute-free water clearance, and serum sodium concentration
HF is uncertain at this time. have been demonstrated in a preliminary study of single
The effect of vasopressin receptor antagonism with doses of 10, 30, 75, 150, 250, and 400 mg lixivaptan
tolvaptan on LV remodeling was evaluated in the Multicenter administered to patients with New York Heart Association
Evaluation of Tolvaptan Effect on Remodeling (METEOR) class II and III HF.34 End points were measured after 4 hours
trial in 240 patients with chronic HF and systolic dysfunction of fluid restriction followed by another 20 hours of liberal
and signs of volume excess.23 In this patient sample with very fluid intake. Significant dose-related increases in urinary flow
high use of evidence-based background HF therapies (⬎90% were observed after 4 hours for all doses of lixivaptan ⬎10
use of both angiotensin-converting enzyme inhibitors or mg compared with placebo. Clinical data on chronic HF
angiotensin receptor blockers, as well as ␤-blockers), the management are limited to this small study for lixivaptan, and
primary end point, mean LV end-diastolic volume index (by data from trials using conivaptan have not been published.
 418 Circulation July 22, 2008

Table 7. Vasopressin Receptor Antagonists in Stable HF: Clinical Trials

Inclusion/Exclusion
Clinical Trial n Design Drug Criteria End Points Results
60
Russell et al 343 Multicenter, placebo controlled, Conivaptan (oral) Class III HF patients Exercise tolerance No improvement in
double-blind, multidose and functional overall functional
(10, 20, or 40 mg orally capacity capacity, exercise
twice daily) tolerance, or
quality of life
Udelson et al61 83 Placebo controlled, double Tolvaptan Class II/III HF patients Body weight; urine Decrease in body
blind, single-dose tolvaptan volume weight; increase in
monotherapy (30 mg orally urine volume;
daily), furosemide 80 mg orally change in Na
daily, or combination for 7 d within normal
range; no change
in K
Costello-Boerrigter et al62 14 Placebo controlled, crossover, Tolvaptan Class II/III HF patients Parameters of renal Tolvaptan induced
single dose (30 mg orally daily) function diuresis similar to
until day 3, and then crossover furosemide;
for 5 d total; at day 5, all furosemide
patients received furosemide decreased renal
80 mg orally daily blood flow,
tolvaptan did not
METEOR23 240 Multicenter, placebo controlled, Tolvaptan Class II/III HF patients Change from baseline No beneficial or
double blind, single dose with LVEF ⱕ30% in LV end-diastolic adverse effects on
(30 mg orally daily for up to 1 y) volume index at remodeling or
week 54 LVEF
LVEF indicates LV ejection fraction.

Given the consistent increases in urine output seen with all therapy is associated with unfavorable outcomes, as is wors-
agents in this class, it could be postulated that the adminis- ening renal function during the course of therapy.64,65
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tration of vasopressin receptor antagonists might allow “spar- One possible explanation for why the neurohormonal axis
ing” of loop diuretic dose. This concept was evaluated in a is apparently activated less23,61 with V2 receptor antagonists
preliminary study in which patients with chronic HF and than loop diuretics despite the same volume of urine losses is
signs of congestion were withdrawn from background diuret- that extracellular fluid is depleted less. With V2 receptor
ic therapy, salt restricted, and randomized to short-term antagonists, solute-free urinary losses come from intracellular
treatment with tolvaptan as monotherapy (30 mg/d), furo- fluid (two thirds) and extracellular fluid (one third), whereas
semide monotherapy (80 mg/d), or a combination for 7 sodium loss from furosemide is exclusively via extracellular
days.61 Tolvaptan-treated patients demonstrated a significant fluid. Thus, the impact on extracellular fluid is significantly
decline in body weight and increase in urine output compared greater with loop diuretic use, which in turn has greater
with furosemide alone without altering serum potassium. potential effects on the renin-angiotensin-aldosterone system.
Results of studies such as this must be interpreted keeping in In an open-label, randomized, placebo-controlled, single-
dose crossover study in patients with mild to moderate
mind that furosemide lasts only ⬇6 hours; thus, once-daily
chronic HF designed to assess the effects of tolvaptan and
diuretic dosing leaves ⬇18 hours per day of compensation for
furosemide on renal function and renal hemodynamics,62
sodium and water loss in the first 6 hours. However, these
tolvaptan was found to increase urine output and renal blood
preliminary data suggest that vasopressin receptor antago-
flow. In comparison, furosemide increased urine output to a
nism in HF patients who are stable on once-daily furosemide
comparable degree but at the expense of electrolyte excretion
dosing may allow reduction or even discontinuation of loop (urinary sodium and potassium) and renal blood flow.
diuretics in some cases, a finding that should be evaluated in Tolvaptan, furosemide, and placebo did not differ in respect
future studies. to mean arterial pressure, glomerular filtration rate, or serum
sodium and potassium.62 In EVEREST, at day 7 or day of
Effects on Renal Function discharge, a very slight but significantly higher serum creat-
In contrast to the administration of loop diuretics, antagonism inine level but a lower serum urea nitrogen level was found in
of vasopressin receptors appears not to increase activation of the tolvaptan compared with the placebo group. This differ-
the renin-angiotensin-aldosterone system, and the increase in ence was observed at many long-term follow-up points
urine output without changes in systemic vascular resistance through 56 weeks after discharge.54
and cardiac output observed in the short-term studies suggests In published studies to date,54,56 no significant adverse
that volume reduction may be achieved with less effect on effects on renal function or electrolyte status have been noted.
renal function than seen with loop diuretics. In many studies All of these results support the possibility that vasopressin
of patients with decompensated HF, higher-dose loop diuretic receptor antagonism may be associated with preserved renal
 Finley et al AVP Antagonists in Heart Failure and Hyponatremia 419

function in HF patients while promoting volume loss and treatment of hyponatremia, for decompensated HF, and for
relief of congestion. HF complicated by hyponatremia. Improvement in serum
sodium in patients with hyponatremia of several causes has
Adverse Effects consistently been documented with an acceptable safety
Vasopressin antagonists used in the published trials have profile. At the time of this writing, intravenous conivaptan
generally been well tolerated. An increase in thirst and dry has been approved by the US Food and Drug Administration
mouth has consistently been reported in patients treated with for the short-term treatment of euvolemic or hypovolemic
vasopressin antagonists compared with placebo. In EVEREST, hyponatremia. In HF, consistent increases in urine output, a
no difference was observed in major adverse events between reduction in body weight, and an improvement in many signs
the 2 randomized groups.54 Among numerous side effects and and symptoms have been seen without unfavorable changes
safety parameters examined in EVEREST, the largest data- in blood pressure, heart rate, electrolytes, or renal function.
base, a small but significant apparent increase in the risk of Pivotal trials of oral tolvaptan in the setting of decompensated
reported stroke was found, plus a small but significant HF and hyponatremia have been completed, and pivotal trials
reduction in the risk of reported myocardial infarction of of lixivaptan for hyponatremia of multiple causes and HF
similar magnitude.56 Hypotension has not occurred in excess complicated by hyponatremia are underway. Treatment of
relative to placebo. Hypokalemia was seen during long-term polycystic kidney disease also is being evaluated.
treatment in 8% of patients in EVEREST treated with Thus far, therapeutic use of vasopressin antagonists has
tolvaptan and in 9.8% of placebo-treated patients, whereas safely and effectively been shown to reduce body weight in
hypernatremia occurred in 1.7% of tolvaptan-treated patients decompensated HF and to normalize sodium levels in hy-
compared with 0.5% of placebo-treated patients. It has been ponatremic patients. In HF, an ideal agent would improve
a general finding in the vasopressin antagonist studies that both symptoms and long-term outcomes, and from this
serum sodium in normonatremic patients may rise ⬇3 mEq/L perspective, the neutral long-term outcome effects of
during initial therapy and then return to baseline after several tolvaptan can be thought of as disappointing. Nevertheless,
days.38 the data from EVEREST, SALT-1, and SALT-2 plus the
Thus, substantial published data, especially with V2 recep- conivaptan data suggest that vasopressin antagonism may
tor antagonism as reported in EVEREST, have established a
become a useful tool for clinicians in specific situations such
safety profile for this treatment approach.
as decompensated HF with volume overload and is poten-
tially an important therapy in setting of HF with hyponatre-
Future Directions mia and for hyponatremia of any cause when improvement in
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Other potential clinical uses for vasopressin antagonists are

serum sodium is a clinical goal.
currently being explored, one of which is treatment for
patients with polycystic kidney disease because vasopressin
V2 receptors have been implicated in the pathogenesis of cyst Disclosures
formation and enlargement in polycystic kidney disease. Drs Konstam and Udelson have received consulting income and
Tolvaptan is being evaluated in a multicenter trial in patients research support from Otsuka Pharmaceutical Development and
with autosomal-dominant polycystic kidney disease that is Commercialization Inc and from Cardiokine Inc. Dr Udelson has
received consulting income from Astellas. Dr Finley reports no
examining the rate of renal volume change.66 conflicts.
Many unanswered questions remain on the potential use of
vasopressin antagonists with regard to HF. Such questions
include the potential efficacy of longer-term treatment with References
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Abstract. KEY WORDS: heart failure 䡲 hormones 䡲 kidney 䡲 receptors