A medication used to treat heart failure, tolvaptan, appears to improve some symptoms and signs of heart failure during hospitalization, but does not reduce the risk of re-hospitalization or death, according to two articles in the March 28 issue of JAMA. The study is being released early to coincide with its presentation at the American College of Cardiology's annual conference.
During the past 2 decades, there have been substantial advances in drug therapy for chronic heart failure (HF), but the number of annual hospitalizations for HF continues to increase, and the risk of death remains high among patients hospitalized with HF, according to background information in the first article. "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."
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 (n = 2,072), or placebo (n = 2,061) for a minimum of 60 days, in addition to standard therapy.
The researchers found that 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 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."
(JAMA. 2007;297:1319-1331. Available pre-embargo to the media at www.jamamedia.org)
Editor's Note: Otsuka Inc. funded the EVEREST trial 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.
Tolvaptan Provides Some Short-Term Symptom Relief in Patients with Heart Failure
Use of tolvaptan in addition to standard therapy improves some symptoms and signs of heart failure including congestion and breathing difficulty without major side effects, according to an article which examined the short-term (i.e., up to seven days) effects of tolvaptan.
"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," the authors write. 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 from sites in North America, Europe and South America, 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.
(JAMA. 2007;297:1332-1343. Available pre-embargo to the media at www.jamamedia.org)
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.
Editorial: Climbing the Mountain of Acute Decompensated Heart Failure - The EVEREST Trials
In an accompanying editorial, Clyde W. Yancy, M.D., of the Baylor University Medical Center, Dallas, examines the findings of the EVEREST trial.
"In the context of acute decompensated heart failure (ADHF), these are noteworthy findings. 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."
(JAMA. 2007;297:1374-1376. Available pre-embargo to the media at www.jamamedia.org)
Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc.
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