Context Nearly 1 million hospitalizations for chronic heart failure occur yearly
in the United States, with most related to worsening systemic congestion.
Diuretic use, the mainstay therapy for congestion, is associated with electrolyte
abnormalities and worsening renal function. In contrast to diuretics, the
vasopressin antagonist tolvaptan may increase net volume loss in heart failure
without adversely affecting electrolytes and renal function.
Objective To evaluate the short- and intermediate-term effects of tolvaptan in
patients hospitalized with heart failure.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging,
phase 2 trial conducted at 45 centers in the United States and Argentina and
enrolling 319 patients with left ventricular ejection fraction of less than
40% and hospitalized for heart failure with persistent signs and symptoms
of systemic congestion despite standard therapy.
Intervention After admission, patients were randomized to receive 30, 60, or 90 mg/d
of oral tolvaptan or placebo in addition to standard therapy, including diuretics.
The study drug was continued for up to 60 days.
Main Outcome Measures In-hospital outcome was change in body weight at 24 hours after randomization;
outpatient outcome was worsening heart failure (defined as death, hospitalization,
or unscheduled visits for heart failure) at 60 days after randomization.
Results Median (interquartile range) body weight at 24 hours after randomization
decreased by −1.80 (−3.85 to −0.50), −2.10 (−3.10
to −0.85), −2.05 (−2.80 to −0.60), and −0.60
(−1.60 to 0.00) kg in the groups receiving tolvaptan 30, 60, and 90
mg/d, and placebo, respectively (P≤.008 for all
tolvaptan groups vs placebo). The decrease in body weight with tolvaptan was
not associated with changes in heart rate or blood pressure, nor did it result
in hypokalemia or worsening renal function. There were no differences in worsening
heart failure at 60 days between the tolvaptan and placebo groups (P = .88 for trend). In post hoc analysis, 60-day mortality was lower
in tolvaptan-treated patients with renal dysfunction or severe systemic congestion.
Conclusion Tolvaptan administered in addition to standard therapy may hold promise
for management of systemic congestion in patients hospitalized for heart failure.
Hospitalizations for heart failure are common in the United States.
The most recent data from the National Hospital Discharge Survey indicate
995 000 discharges for heart failure in 2001, at a rate of 35.1 per 10 000
patients.1 These patients commonly have a history
of progressive volume retention manifested by an increase in body weight,
leading to worsening symptoms requiring hospitalization.2,3 Pharmacological
management of systemic congestion in heart failure is often inadequate; in
spite of a transient symptomatic improvement, the 6-month postdischarge readmission
rates are as high as 50%.4,5 Although
non–potassium-sparing diuretics are the mainstay therapy for congestion,
their use is often associated with hypotension, electrolyte abnormalities,
worsening renal function, and possibly increased mortality.6-9
Arginine-vasopressin (AVP) levels are elevated in heart failure and
may result in myocardial fibrosis/hypertrophy and vasoconstriction by activating
V1a receptors, as well as in water retention and hyponatremia by
activating V2 receptors.10 In
heart failure, vasopressin antagonists may not only prevent progression of
left ventricular dysfunction but, in contrast to angiotensin-converting enzyme
inhibitors and β-blockers, may also produce an acute improvement in congestion
and hyponatremia.
Tolvaptan is an oral, once-daily, nonpeptide vasopressin V2 receptor
antagonist without intrinsic agonist properties.11,12 In
mild heart failure, tolvaptan added to standard therapy including non–potassium-sparing
diuretics resulted in a significant decrease in body weight without causing
hypokalemia or worsening renal function.13 The
Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive
Heart Failure (ACTIV in CHF) trial was conducted to evaluate the clinical
effects of tolvaptan in patients hospitalized for heart failure.
The ACTIV in CHF trial was a multicenter, randomized, double-blind,
placebo-controlled, parallel-group, dose-ranging, phase 2 feasibility trial
that compared the use of 3 oral, once-daily doses of tolvaptan (30 mg, 60
mg, 90 mg) with placebo. Detailed information about the study design rationale
has been published elsewhere.14 Eligible patients
receiving standard therapy for heart failure were enrolled at 34 centers in
the United States and 11 centers in Argentina. The study received approval
from the institutional review board of each site, and written informed consent
was obtained from all patients.
Patients 18 years and older admitted for worsening heart failure were
included if they had a left ventricular ejection fraction of less than 40%
within 1 year of admission and systemic congestion as evidenced by jugular
venous distention (JVD), rales, or peripheral edema after initial in-hospital
therapy for heart failure.14
Patients with any of the following characteristics were excluded: women
of childbearing age; cardiac surgery within 60 days; myocardial infarction,
sustained ventricular tachycardia, or ventricular fibrillation within 30 days;
angina at rest; primary valvular disease; hypertrophic cardiomyopathy; stroke
within the last 6 months; significant hepatic, renal, or hematologic dysfunction;
systolic arterial blood pressure less than 110 mm Hg; use of drugs known to
inhibit cytochrome P 3A4 enzyme within 7 days of randomization, except for
amiodarone, which should not have been taken within 10 weeks of randomization;
use of nonsteroidal anti-inflammatory agents or of aspirin at a dose of more
than 700 mg/d; substance or alcohol abuse; uncontrolled diabetes mellitus;
urinary tract obstruction; morbid obesity; or malignancy or other terminal
illness.14
Study Design and Organization
The study consisted of a screening day and an inpatient period of up
to 10 days, followed by a 7-week (49-51 days) outpatient period. Patients
received the study drug in both inpatient and outpatient settings. All patients
were randomized if they continued to have signs and symptoms of congestion
at the time of randomization in spite of standard therapy including diuretics
(Table 1).
Eligible patients were randomized to receive 30, 60, or 90 mg/d of tolvaptan
or placebo in a 1:1:1:1 ratio, using an interactive voice recognition system
programmed with a computer-generated randomization scheme. Randomization was
stratified by study center in blocks of 4.
Patients were screened within 72 hours and randomized within 96 hours
of admission. Randomization occurred between 8 and 9 AM; the
study drug was administered at 9 AM and was to be administered
at that time on all study days. Patients hospitalized for more than 10 days
after the first dose of study drug were withdrawn from the study per protocol
in order to limit irrelevant data associated with comorbid conditions occurring
with prolonged hospitalization. After hospital discharge, office visits were
scheduled for outpatient weeks 1, 3, 5, and 7. A safety follow-up telephone
contact was made at least 30 days after administration of the last dose of
study drug. Body weight, urine volume, urine levels of sodium and creatinine,
and results of other laboratory tests were recorded. Physician-assessed heart
failure scores15 and patient-assessed visual
analog scale scores16 to assess global and
respiratory status were obtained at discharge and outpatient visits.
Outcomes and Measurements
The study had 2 primary end points designed to assess the acute (in-hospital)
and the intermediate-term (outpatient, after hospital discharge) effects of
the study drug. The in-hospital end point was change in body weight at 24
hours after the administration of the first dose of study drug. Body weight
was measured using a standardized scale at 9:00 AM, postvoid,
prior to administration of the medication dose.
The outpatient end point was worsening heart failure at 60 days after
randomization, defined as hospitalization for heart failure, unscheduled visit
for heart failure to an emergency department or outpatient clinic associated
with need for either increased therapy or new therapy for heart failure, or
death.
Secondary end points included changes in dyspnea, JVD, rales, edema,
body weight (at discharge and in the outpatient setting), urine output (inpatient),
serum electrolyte levels, length of hospital stay after randomization, use
of diuretics, and patient- and physician-assessed symptom scales.
The clinical event committee based at the Duke Clinical Research Institute
adjudicated all serious adverse events, cause of hospitalization, and mode
of death, blinded to treatment assignment. The safety of tolvaptan was assessed
by a blinded, independent data and safety monitoring board after the first
110 patients had completed follow-up. There were no predefined stopping rules
for the data and safety monitoring board.
The ACTIV in CHF study was designed to enroll 320 patients (80 patients
per treatment group). This estimated sample size would provide an 80% power
to detect a difference of 1.5 kg in mean body weight change from baseline
to 24 hours between any tolvaptan-treated group and placebo.
The estimated sample size would also provide an 80% power to detect
a 22% difference by the log-rank test (with a 2-sided α of .05) in the
incidence of worsening heart failure up to 7 weeks after discharge.
Since this was a phase 2 study, no adjustments in α level were
made for the multiple comparisons in the primary analysis. The primary efficacy
analysis was based on the intent-to-treat population that consisted of all
randomized patients. For safety analyses, the population consisted of all
randomized patients who received at least 1 dose of study medication. The
primary efficacy variable for the inpatient portion of the study was change
in body weight from baseline at 24 hours. The primary comparisons of interest
were tolvaptan 30 mg vs placebo, tolvaptan 60 mg vs placebo, and tolvaptan
90 mg vs placebo. Each of these comparisons was tested (at a 2-tailed P = .05 level) by fitting an analysis of covariance model
to the change in body weight from baseline data, with the baseline body weight
as covariate and study center and treatment as factors.
The primary efficacy variable for the outpatient part of the study was
a time-to-event variable, worsening heart failure, defined as time to the
first to occur of the following: death, hospitalization for heart failure,
or unscheduled visit due to heart failure requiring an increase in drug therapy
for heart failure and/or a new therapy. The time origin for this time-to-event
variable was the randomization date.
Patients were followed up for up to 7 weeks after discharge. The log-rank
test was used to assess differences for comparison of tolvaptan 30 mg vs placebo,
tolvaptan 60 mg vs placebo, and tolvaptan 90 mg vs placebo. A nominal significance
level of .05 (2-tailed) was used for each comparison. Patients lost to follow-up
due to reasons other than the primary outcome events and patients surviving
event-free at the end of 7 weeks were treated as providing censored observations
in this analysis.
Inferential analysis was also performed on the change from baseline
values by analysis of covariance with baseline value as covariate for changes
in body weight at discharge, daily serum electrolyte levels, and part of the
patient-assessed symptom score; on absolute value by analysis of variance
for urine output, length of stay after randomization, and use of diuretics;
and on change from baseline values by the Cochran-Mantel-Haenszel mean score
test for dyspnea, orthopnea, changes in body weight at discharge, JVD, rales,
and part of the physician-assessed symptom score. Data analysis was performed
using SAS version 6.12 (SAS Institute Inc, Cary, NC).
A total of 319 patients were enrolled and analyzed (Figure 1). There were no significant differences between groups
at randomization, except for PCI/CABG (P = .02) and
sex (P = .04) (Table 1). During hospitalization all patients continued to receive
standard therapy for heart failure, including diuretics. Abnormal baseline
creatinine levels (>1.3 mg/dL [114.9 µmol/L] and 1.2 mg/dL [106.1 µmol/L]
in men and women, respectively) were present in 38%, 40%, 36%, and 44% of
patients in the tolvaptan 30, 60, and 90 mg and the placebo groups, respectively;
abnormal baseline levels of blood urea nitrogen (BUN) (>29 mg/dL) were present
in 53%, 46%, 54% and 61% of patients in the tolvaptan 30, 60, and 90 mg and
the placebo groups, respectively.
Body weight at baseline was similar in the tolvaptan and placebo groups
(Table 1). Decreases in body weight
from baseline were observed on the first day of treatment in all groups. A
significantly greater median (interquartile range) reduction in body weight
was observed in patients treated with tolvaptan when compared with those receiving
placebo, and this effect did not appear to be dose dependent (−1.80
[−3.85 to −0.50], −2.10 [−3.10 to −0.85], −2.05
[−2.80 to −0.60], and −0.60 [−1.60 to 0.00] kg for
the groups receiving tolvaptan 30, 60, and 90 mg, and placebo, respectively; P = .002, .002, and .009 for the 3 tolvaptan groups compared
with the placebo group) (Figure 2).
Body weight further decreased in all groups during hospitalization. The median
(interquartile range) body weight reductions from baseline to discharge were
greater in the tolvaptan groups compared with the placebo group (−3.30
[−7.30 to −1.35], −2.80 [−5.90 to −1.80], −3.20
[−5.80 to −1.60], and −1.90 [−4.20 to −0.50]
kg in the groups receiving tolvaptan 30, 60, and 90 mg, and placebo, respectively; P = .006, .002, and .06 for the 3 tolvaptan groups compared
with placebo).
Urine volume on day 1 was significantly higher for all tolvaptan groups
when compared with the placebo group, and this effect was maintained throughout
the period of hospitalization (Figure 3).
The mean (SD) urine output at 24 hours was 4056.2 (2310.2), 4175.2 (2695.4),
4127.3 (2050.8), and 2296.5 (1134.1) mL for the tolvaptan 30, 60, and 90 mg,
and placebo groups, respectively (P = .02, P<.001, and P<.001 for the
3 tolvaptan groups compared with the placebo group).
Signs and symptoms of heart failure improved in all patients during
the period of hospitalization. By the time of discharge, fewer tolvaptan-treated
patients reported dyspnea, JVD, and peripheral edema compared with those receiving
placebo; however, the differences were not significant except for dyspnea
(P = .04)
(Figure 4). Global assessment scales did not show a significant improvement
over placebo. The median length of time between randomization and discharge
was 4 (range, 1-10) days in both treatment groups.
There was no significant difference in worsening heart failure between
the tolvaptan groups and the placebo group (Table 2). Diuretic use decreased in all patients after discharge.
In the outpatient setting, patients receiving tolvaptan received a mean (SD)
daily dose of 79.36 (116.12) mg of furosemide equivalents (a 43-mg reduction
from the mean daily dose during the period of hospitalization), compared with
102.3 (139.05) mg of furosemide equivalents for the placebo group (a 9-mg
reduction from the mean daily dose during the period of hospitalization) (P = .17 for mean dose reduction).
One day after randomization, patients treated with tolvaptan had small
mean (SD) increases from baseline in serum sodium concentrations (2.77 [3.56],
3.38 [4.84], and 3.50 [3.63] mEq/L for the patients receiving tolvaptan 30,
60, and 90 mg, respectively), whereas a small mean decrease (−0.20 [3.12]
mEq/L) was observed in patients receiving placebo. Table 3 shows the changes in sodium concentrations in the tolvaptan
and placebo groups throughout the study.
Sixty-eight patients (21.3%) had hyponatremia (sodium level <136
mEq/L) at randomization. This was observed in 15 (19.2%), 22 (26.2%), 15 (19.5%),
and 16 (20.0%) patients in the groups receiving tolvaptan 30, 60, and 90 mg,
and placebo, respectively. These patients showed a rapid increase, and often
normalization, in serum sodium levels that was sustained throughout the study.
While no differences were observed in the rate of rehospitalization
or unscheduled visits for heart failure, event-free survival tended to be
longer for the tolvaptan groups combined when compared with placebo (Table 2). In post hoc analysis, total mortality
was lower in the tolvaptan groups combined compared with placebo in patients
with elevated BUN levels (>29 mg/dL [10.35 mmol/L]) and severe systemic congestion
at randomization (defined as presence of dyspnea, JVD, and edema). Seven of
31 patients (22.5%) with high BUN levels in the placebo group died during
the study, compared with 10 of 100 patients (10%) in the tolvaptan groups
(P = .07). Five of 28 patients (17.8%) with severe
congestion in the placebo group died during the study, compared with 6 of
108 patients (5.6%) in the tolvaptan groups (P =
.03).
Adverse events were present in 85% of patients, with thirst being more
frequently encountered in the tolvaptan groups (Table 4). Tolvaptan did not appear to cause hypotension, tachycardia,
worsening renal function, or abnormalities in serum potassium levels (Table 3). One hundred thirty patients discontinued
therapy prior to completing the 7-week outpatient treatment period (Figure 1).
In patients hospitalized for heart failure, the administration of tolvaptan,
an oral vasopressin antagonist, in addition to standard therapy including
non–potassium-sparing diuretics, resulted in a greater, non–dose-dependent,
net volume loss compared with placebo and standard therapy including diuretics.
This was not associated with hypotension, increase in heart rate, hypokalemia,
or worsening renal function. Tolvaptan produced a rapid and sustained increase
of serum sodium levels in patients with hyponatremia.
There was no significant reduction in the risk of worsening heart failure
at 60 days in the patients receiving tolvaptan compared with those receiving
placebo. Although the study was underpowered and not prospectively designed
to evaluate mortality alone, in retrospect there was a trend toward lower
mortality in the tolvaptan groups combined when compared with placebo. This
decrease in mortality reached statistical significance in patients with high
BUN levels or severe systemic congestion. This post hoc analysis is hypothesis-generating
and requires confirmation by a larger study.
Pulmonary and/or systemic congestion is the major cause of hospitalization
and rehospitalization in patients with heart failure.17,18 Congestion
is usually related to increased intravascular volume that is associated with
increased left ventricular diastolic pressure.17 This
increase may cause subendocardial ischemia and/or necrosis, changes in ventricular
shape and volume resulting in secondary mitral insufficiency,19 and
arrhythmias,20 and may also contribute to progression
of heart failure. Congestion in heart failure may be an important target not
only for symptomatic improvement, but also for prevention of hospitalization
and mortality.18,21 Clinical outcomes
may be improved if congestion can be treated more effectively during and after
hospitalization.
Non–potassium-sparing diuretics are the mainstay of therapy for
systemic congestion in heart failure, but their use is associated with frequent
and important adverse effects, including hypotension; electrolyte abnormalities
such as hyponatremia, hypokalemia, and hypomagnesemia; and worsening renal
function. They also may cause hyperglycemia, hyperuricemia, and increased
sensitivity to digoxin.5-7 A
recent post hoc analysis from the Studies of Left Ventricular Dysfunction
(SOLVD) raised the hypothesis that use of non-potassium-sparing diuretics
might be associated with increased mortality.8,9 In
our study, since all patients received similar doses of diuretics as part
of their standard therapy, we were unable to assess the safety profile of
tolvaptan compared with non–potassium-sparing diuretics. In addition,
non–potassium-sparing diuretics may not always reduce congestion since
they are known to decrease plasma osmolarity and renal blood flow, resulting
in prerenal azotemia even in patients who continue to experience fluid overload.22 Hospitalized patients with worsening heart failure
and systemic congestion often have hyponatremia, elevated BUN levels, and
low systolic blood pressure, which are major predictors of poor prognosis.23 Those abnormalities can be exacerbated by use of
non–potassium-sparing diuretics.
In patients with systolic dysfunction, levels of AVP are elevated even
in those who are asymptomatic.24-27 Increased
AVP levels may have deleterious effects not only as a result of myocardial
fibrosis and vasoconstriction, but also as a result of water retention and
hyponatremia.24-27
The potential benefits of AVP receptor blockade in heart failure have
been hampered until recently by the lack of orally active, effective, and
well-tolerated agents.28 Newly developed compounds
targeting the V1a (vascular) and V2 (renal) vasopressin
receptors may represent the next generation of neurohormonal modulators to
have a beneficial effect in heart failure.10
Tolvaptan is a novel vasopressin receptor blocker. The compound binds
predominantly to the V2 receptor in the kidney, resulting in major
increased production of dilute urine. Tolvaptan appears to reduce body weight
and improve signs of heart failure in outpatients with mild chronic disease.11 Unlike furosemide, tolvaptan also appears to increase
renal blood flow, decrease renal vascular resistance, and improve glomerular
filtration rate in patients with heart failure.29 In
patients with heart failure and signs of volume overload, tolvaptan without
concomitant therapy using loop diuretics reduced body weight and edema when
compared with placebo, without adverse changes in serum electrolyte levels.30 Increases and normalization of serum sodium levels
have also been observed after tolvaptan treatment in patients with hyponatremia
due to heart failure, liver cirrhosis, or syndrome of inappropriate antidiuretic
hormone secretion.31
Neurohormonal abnormalities of the renin-angiotensin-aldosterone system,
sympathetic nervous system, and AVP systems have been identified as contributors
to the pathophysiology of heart failure.3,6 Angiotensin-converting
enzyme (ACE) inhibitors, angiotensin II receptor blockers, aldosterone antagonists
of the mineralcorticoid receptor (eg, spironolactone, eplerenone), and β-blockers
are known to improve the neurohormonal profile and have been shown to significantly
reduce mortality and morbidity in heart failure.32 These
life-saving therapies may prevent systemic congestion by decreasing the progression
of heart failure; however, they do not rapidly and effectively reduce congestion
once it develops. In addition, the available therapies do not effectively
block vasopressin, which may contribute to the progression of heart failure.
Traditionally, studies of patients with heart failure have been conducted
by examining the acute effects of drugs in hospitalized patients3,33 or
their chronic effects in outpatients.32 This
approach has been related not only to the pattern of approval of heart failure
drugs by the US Food and Drug Administration, but also to the difficulty of
conducting clinical trials in patients with heart failure requiring hospitalization.
As evidence, the first randomized trials in patients hospitalized for decompensated
heart failure were published only in 2002.3,33 Although
these trials were critical in establishing the feasibility of placebo-controlled
studies in patients hospitalized with heart failure, they had limitations.
Both studies focused on acute interventions, with treatment durations of 48
hours. Most treatments for decompensated heart failure are short-term intravenous
therapies with minimal potential for chronic maintenance therapy.4 The design of the ACTIV in CHF study was unique in
that it was the first trial to examine an oral therapy not only for its acute
effect during hospitalization for heart failure but also for its chronic outpatient
effects after discharge.
In terms of clinical outcomes, the data from the ACTIV in CHF study
should be interpreted with caution. This was a phase 2, hypothesis-generating,
feasibility study. However, these early results are encouraging for a new
class of neurohormonal modulators that addresses systemic congestion, an important
target for therapy. A substantial number of patients did not complete the
7-week postdischarge follow-up. This may have been related to the medication
changes required in the management of heart failure in hospitalized patients
and to the inexperience with a new class of compounds. Despite a relatively
high withdrawal rate from the active drug, the study demonstrated that tolvaptan
had an advantage over placebo in decreasing body weight without significant
adverse effects.
Tolvaptan in addition to standard therapy including diuretics increased
net fluid loss resulting in decreased body weight more effectively than standard
therapy alone in patients hospitalized for heart failure. This desirable effect
was achieved without adversely affecting blood pressure, heart rate, electrolyte
levels, or renal function. Tolvaptan also improved serum sodium levels in
patients with hyponatremia. Although tolvaptan did not reduce the rate of
worsening heart failure after discharge, post hoc analysis suggested that
mortality might be reduced in high-risk patients treated with tolvaptan. This
hypothesis-generating finding is presently being tested in a large international
mortality trial of patients hospitalized with heart failure.
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