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Senior Citizen Health & Medicine
Heart Failure Drug Provides Relief, Fails to Reduce
Risk Of Re-Hospitalization or Death
Tolvaptan does help patients feel better quickly
 March 26, 2007-Two evaluations of a study of a
medication used to treat heart failure, tolvaptan, conclude that
although it helps patients struggling with heart failure to feel better
quickly, it does not help in the long-run to reduce the risk of
re-hospitalization or death. Despite advances in drug therapy for
chronic heart failure (HF), which primarily strikes senior citizens,
hospitalizations continue to increase each year and the risk of death
remains high.
The study is being presented at the American
College of Cardiologys annual conference and will appear in the March
28 issue of the Journal of the American Medical Association.
To date, no treatment initiated at the time of
hospitalization for acute decompensated [characterized by severe
symptoms and signs] HF has been found to improve clinical outcomes. In
fact, in randomized controlled trials of such treatments, the observed
clinical benefits have been marginal at best, and concern has been
raised about the adverse effect of these treatments on long-term
clinical outcomes, according to the first article in JAMA.
Marvin A. Konstam, M.D., of Tufts - New England
Medical Center, Boston, and colleagues with the Efficacy of Vasopressin
Antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST)
trial, examined the long-term clinical outcomes of the heart failure
medication tolvaptan.
The trial, comprised of two short-term clinical
status studies, included 4,133 patients hospitalized with heart failure
at 359 North American, South American, and European sites between
October 2003 and February 2006, and followed up during long-term
treatment. Within 48 hours of hospital admission, the patients were
randomly assigned to receive oral tolvaptan, 30 mg once per day, or
placebo for a minimum of 60 days, in addition to standard therapy.
The researchers found:
● During a median (midpoint) follow-up of 9.9 months, 25.9 percent of
patients in the tolvaptan group and 26.3 percent in the placebo group
died.
● The combined outcome of cardiovascular death or
hospitalization for heart failure occurred in 42 percent of the
tolvaptan patients and 40.2 percent of the placebo group patients.
● The secondary end points of the combined
outcome of cardiovascular death or cardiovascular hospitalization, the
incidence of cardiovascular death and clinical worsening of HF did not
differ between the 2 treatment groups.
● Tolvaptan did, however, significantly improved
secondary end points of day 1 patient-assessed dyspnea (difficulty in
breathing), day 1 body weight and day 7 edema (swelling from excessive
accumulation of fluid in tissue).
● The frequency of major adverse events were
similar in the 2 groups.
Long-term tolvaptan treatment had no effect,
either favorable or unfavorable, on all-cause mortality or the combined
end point of cardiovascular mortality or subsequent hospitalization for
worsening HF, the authors write.
Our long-term clinical outcome findings do not
justify continuation of tolvaptan treatment beyond the time of
improvement in fluid balance and clinical status.
However, our
findings of sustained reduction in body weight, without worsening of
renal function and with sustained normalization of serum sodium levels
in patients with baseline hyponatremia [abnormally low concentration of
sodium in the blood], suggest a role for either longer-term or
intermittent tolvaptan treatment, at least in patients in whom
abnormalities in fluid and electrolyte balance and/or renal function are
difficult to manage by other means.
Tolvaptan provides some short-term symptom
relief no major side effects
In the second article, which examined the
short-term (up to seven days) effects of tolvaptan, the researchers
found that when used with standard therapy it improves some symptoms and
signs of heart failure including congestion and breathing difficulty
without major side effects
Heart failure is a major international public
health problem presenting significant medical and economic challenges.
In the United States, HF has high prevalence (greater than 5 million
individuals), high incidence (550,000 new cases yearly), increasing
hospitalization rates (400,000 in 1979 to greater than 1 million in
2004), and exorbitant cost (estimated to exceed $33 billion in 2007). A
considerable share of the burden of HF is accounted for by the acute HF
syndromes (AHFS), defined as conditions with gradual or rapid changes in
the signs and symptoms of HF that require urgent therapy. Patients
hospitalized with AHFS have poor overall prognosis, according to Mihai
Gheorghiade, M.D., and colleagues. Given the negative results in terms
of efficacy and safety of drugs tested so far in this setting, an unmet
need exists for more effective and safe strategies to treat AHFS.
Mihai Gheorghiade, M.D., of Northwestern
University, Feinberg School of Medicine, Chicago, and colleagues with
the EVEREST trial, evaluated whether treatment of heart failure with
tolvaptan, in addition to standard therapy including diuretics, would
result in clinical improvements during the inpatient period. Two trials
were conducted during the inpatient period of EVEREST. A total of 2,048
(trial A) and 2,085 (trial B) patients hospitalized with heart failure
and congestion were studied. Patients received either tolvaptan (30
mg/d) or matching placebo, within 48 hours of admission.
● Analysis of the primary outcome (combined
changes in clinical status and body weight) showed significantly greater
improvement in the tolvaptan groups than in the placebo groups.
● Average body weight reduction was greater with
tolvaptan on day 1 and day 7 or discharge, whereas improvements in
global clinical status were not different between groups.
● In both trials, more patients in the tolvaptan
groups reported an improvement in dyspnea when compared with the placebo
groups.
● Edema at day 7 or discharge improved
significantly with tolvaptan in trial B but did not reach significance
in trial A.
● Serious adverse event frequencies were similar
between groups, without excess in kidney failure or hypotension
(abnormally low blood pressure).
These 2 trials demonstrate in a reproducible
manner that tolvaptan, when added to standard therapy including
diuretics, improves many, though not all, of the signs and symptoms of
HF, as assessed by both patients and physicians, and reduces body weight
throughout hospitalization. These positive effects were achieved without
adversely affecting heart rate, blood pressure, or serum electrolytes,
the authors write.
Editorial: Climbing the mountain of acute
decompensated heart failure
In the context of acute decompensated heart
failure (ADHF), these are noteworthy findings," writes Clyde W. Yancy,
M.D., of the Baylor University Medical Center, Dallas, in an editorial
in JAMA
"To date, no other therapeutic intervention has
been demonstrated in large-scale randomized, placebo-controlled studies
to positively influence symptoms in ADHF without generating a question
of harm, he writes.
Taken together, these findings would suggest some
short-term benefit of tolvaptan on certain acute symptoms of ADHF
without evidence of harm and represent an important contribution for
understanding the management of patients with ADHF.
However, use of tolvaptan must be carefully
considered, as evidence of long-term benefit is lacking. Moreover, given
the characteristics of the patient cohort in EVEREST, the use of
tolvaptan should not be extrapolated to patients who are dissimilar,
Dr. Yancy writes.
As additional reports from EVEREST and from new
clinical trials with both medical and device therapies become available,
the hope is that progress toward reaching additional evidence-based
therapies on the mountain of ADHF will continue.
Editor's Note: This study was funded by Otsuka Inc.
under the guidance of the EVEREST steering committee. Please see the
article for additional information, including other authors, author
contributions and affiliations, financial disclosures, funding and
support, etc.
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