ECLIPSE trial data suggest that the vasopressin receptor antagonist tolvaptan can improve hemodynamics associated with increased urine output in patients with advanced heart failure with as little as a single dose, according to a presentation at the annual meeting of the Heart Failure Society of America.

"These ECLIPSE data are the first to clarify the hemodynamic effects of orally dosed tolvaptan in patients with advanced heart failure due to systolic dysfunction. Such details of the mechanism of action of tolvaptan help us further understand its clinical effects," said investigator James Udelson MD, associate chief of the Division of Cardiology at the Tufts-New England Medical Center.

In the international EffeCt of ToLvaptan on HemodynamIc Parameters in Subjects with HEart failure (ECLIPSE) study,180 patients with symptomatic heart failure (New York Heart Association class III and IV) were randomized to double-blind treatment with tolvaptan at a single oral dose of 15, 30, 60 mg or to placebo.

All three doses of tolvaptan significantly changed the primary outcome variable, pulmonary capillary wedge pressure compared with placebo treatment (tolvaptan 15 mg -6.38 + 0.62 mmHg, tolvaptan 30 mg - 5.67 + 0.70 mmHg, tolvaptan 60 mg -5.71 + 0.65 mmHg, placebo -4.16 + 0.67 mmHg). The primary statistical analysis comparing effects across the placebo group and two higher doses of tolvaptan approached statistical significance.

Compared with placebo, each dose of tolvaptan significantly increased urine volume at three hours after the dose was given. Also, during the three- to eight-hour interval after tolvaptan administration, mean reductions in pulmonary artery pressure, a secondary endpoint, were observed and were statistically greater in all tolvaptan groups than in the placebo group.

Over the same time period, mean reductions in pressure within the right atrium were also observed, and those were statistically greater in the tolvaptan 15 mg and 30 mg groups than in the placebo group. None of the other secondary outcome measures, including cardiac output, cardiac index, systemic vascular resistance, heart rate, and blood pressure showed significantly different changes between tolvaptan and placebo.

Overall, 77 (42.5 percent) subjects experienced at least one treatment-emergent adverse event during the trial. The incidence of these events was highest in the tolvaptan 60 mg group (54.3 percent) and lowest in the placebo group (33.3 percent). Most common adverse events (greater than 3 percent and more frequent than placebo) associated with tolvaptan were dry mouth, thirst, back pain, headache, anxiety, and hematuria.

No treatment-emergent adverse event occurred in more than 10 percent of patients in any of group. No deaths occurred during study drug administration. Two patients died during the seven-day follow-up period (originally assigned to tolvaptan 30 mg and 60 mg, respectively). Both patients died from complications resulting from worsening of underlying disease.

ECLIPSE was an international, multicenter, randomized, placebo-controlled single-dose trial conducted at 48 trials sites in United States, Romania and Bulgaria between 2005 and 2006. Investigators enrolled patients with Class III or IV heart failure of at least three months’ duration due to left ventricular systolic dysfunction and who had a left ventricular ejection fraction of 40 percent or less.
Investigators assessed patients' inclusion criteria for up to two weeks prior to randomization. Suitable candidates underwent insertion of a balloon- floatation pulmonary artery catheter to assess final eligibility criteria. Final doses of cardiac concomitant medications were administered at least two hours prior to catheter insertion.

Following catheter insertion, patients entered into a 2- to 20-hour stabilization period. Researchers completed hemodynamic assessments periodically to determine final subject eligibility. Potential participants then entered a two-hour baseline period. If a participant met all criteria during the baseline period, he or she was randomized to one of four groups and received a single once-daily oral tablet of placebo or of 15, 30 or 60 mg tolvaptan. Investigators followed participants for up to 24 hours for assessments.