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 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."