Tolvaptan can rapidly improve signs and symptoms of acute decompensated heart failure, but it does not reduce the risk of rehospitalization or death, according to results from a late-breaking trial presented at the scientific session of the American College of Cardiology.

In the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan)Trial, Marvin A. Konstam, MD, of Tufts - New England Medical Center, Boston, and colleagues examined tolvaptan, an oral formulation of a vasopressin receptor antagonist. The phase III EVEREST trial involved a total of 4,133 patients and represented three studies: a long-term outcomes trial evaluating patients after their discharge for a minimum of 60 days of treatment, and two identical, embedded short-term pivotal studies that examined tolvaptan compared with placebo over seven days of inpatient care or discharge, whichever came first.

Within 48 hours of hospital admission, patients randomized to oral tolvaptan, 30 mg once daily (2,072 patients) or placebo (2,061 patients) for a minimum of 60 days in addition to standard therapy.

At a median follow-up of 9.9 months, 25.9 percent of tolvaptan patients and 26.3 percent of placebo patients had died. The combined outcome of cardiovascular death or rehospitalization for heart failure occurred in 42 percent of tolvaptan patients and 40.2 percent of placebo patients.

Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight and day 7 edema. The frequency of major adverse events was similar in both patient 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 heart failure," the authors wrote. "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, 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 exhibited short-term symptomatic benefits in patients hospitalized with worsening heart failure," Konstam summarized. "In the long-term trial, tolvaptan neither statistically improved nor worsened survival relative to placebo. The EVEREST data suggest that tolvaptan may be a potential therapy for patients with heart failure."

In terms of findings that might merit study of patient subgroups, the researchers found that tolvaptan patients who enrolled with hyponatremia (serum sodium less than 134 mEq/L) exhibited significantly greater corrections in serum sodium at day seven or discharge, if earlier, and the effect was maintained through 40 weeks of treatment.

Hypernatremia occurred in 1.7 percent of tolvaptan patients compared with 0.5 percent of placebo patients. The incidence of kidney failure and low blood pressure were comparable in the two groups. Tolvaptan-treated patients showed no differences from placebo-treated patients with regard to heart rate and blood pressure. In addition, tolvaptan demonstrated no deleterious effects on renal function relative to placebo in these patients.