ECLIPSE: Tolvaptan altered hemodynamics in patients with HF

WASHINGTON — Results from the Effect of Tolvaptan on Hemodynamic Parameters in Subjects with Heart Failure trial suggested that tolvaptan had a positive effect on filling pressure reduction in patients with decompensated heart failure.

The ECLIPSE trial demonstrated that a single dose of the vasopressin receptor antagonist tolvaptan (Otsuka America Pharmaceuticals) helped reduce pulmonary capillary wedge pressure and right atrial pressure, also resulting in a dose-dependent increase in urine output. The ECLIPSE results were presented at the Heart Failure Society of America 11th Annual Scientific Meeting by James E. Udelson, MD, associate chief of cardiology at Tufts-New England Medical Center, Boston.

“The administration of tolvaptan doesn’t have a direct effect on blood vessels and results quickly in the improvement of hemodynamics and lowered filling pressures through urine output of the kidney,” Udelson told Cardiology Today. “This provides a mechanism for the reduction in dyspnea observed in the EVEREST trial.”

Reduction in filling pressures

ECLIPSE researchers randomly assigned 181 patients into a multicenter, double blind, placebo-controlled single-dose trial. For inclusion, patients were required to have symptomatic NYHA Class III and IV HF for at least three months with left ventricular systolic dysfunction and left ventricular ejection fraction of <40%. Patients were given either tolvaptan in doses of 15 mg, 30 mg, or 60 mg or placebo, and were followed for 24 hours. The primary outcome variable was pulmonary capillary wedge pressure.

All three doses of tolvaptan were shown to reduce the primary outcome variable (tolvaptan 15 mg, –6.38 mm Hg; 30 mg, –5.67 mm Hg; 60 mg, –5.71 mm Hg, placebo –4.16 mm Hg). Change vs. placebo were significant for all three doses.

Treatment-emergent adverse events – including dry mouth – were observed in 42.5% of patients. These events occurred most frequently in the 60-mg tolvaptan group.

The results of ECLIPSE bolster the findings of the Efficacy of Vasopressin Antagonism in Heart Failure trial (EVEREST). EVEREST demonstrated that patients with HF who received tolvaptan showed short-term improvements in body weight and reduction in both dyspnea and edema.

“Adverse events that were seen in this trial with only a single dose were the expected ones that have been seen in other trials, and of course we have a lot of information on adverse effects on 4,000 patients in the EVEREST trial,” Udelson said at the meeting. “The events were generally mild in severity, but were reported by patients as an adverse event. So this drug was generally very well tolerated.”

The results of ECLIPSE, when combined with the data from EVEREST, suggest that patients with decompensated HF can derive short-term benefit from tolvaptan. – by Eric Raible

Dr. Udelson does research support and consulting for Otsuka.

For more information:

• Udelson J. Acute hemodynamic effects of tolvaptan, a vasopressin V-2 receptor blocker, in patients with symptomatic heart failure and systolic dysfynction: The ECLIPSE international, multicenter, randomized placebo-controlled trial. Recent and late breaking trials. Presented at: Heart Failure Society of America Annual Scientific Meeting; Sept. 16-19, 2007; Washington.
• Konstam M, Gheorghiade M, Burnett J, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA. 2007;297:1319-1331