PRINCETON, N.J., Sept. 19, 2007 -- A single dose of Otsukas investigational oral medication tolvaptan, a vasopressin receptor antagonist, resulted in favorable changes in hemodynamics associated with a significant increase in urine output in patients with advanced heart failure (ADHF) who participated in the international trial the EffeCt of ToLvaptan on HemodynamIc Parameters in Subjects with HEart failure (ECLIPSE), presented at the late breaking trials symposium of the Heart Failure Society of Americas Annual Scientific Meeting (HFSA).
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 M.D., associate chief of the Division of Cardiology at the Tufts-New England Medical Center and associate professor of medicine at Tufts University School of Medicine.
In the 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 placebo. All three doses of tolvaptan examined in ECLIPSE significantly changed the primary outcome variable, pulmonary capillary wedge pressure (PCWP), compared to 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; p vs. placebo less than 0.05 for each tolvaptan group). The primary statistical analysis comparing the effects across the placebo group and two higher doses of tolvaptan approach statistical significance (p=0.0563). PCWP provides information about two aspects of lung and heart function: an estimate of the lung capillary pressure, which is the fluid pressure that plays a role in pulmonary edema, and an estimate of the filling pressures of the left side of the heart.
Compared with placebo, each dose of tolvaptan significantly increased urine volume at 3 hours after dose was given (p<0.0001). Also, during the three to eight hour interval after tolvaptan administration, mean reductions of the pressure in the pulmonary artery that carries venous blood from the right ventricle of the heart to the lungs, a secondary endpoint, were observed and were statistically greater (p<0.05) in all tolvaptan groups than in the placebo group. Over the same time period, mean reductions in pressure within the hearts 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 (the amount of blood the hearts left ventricle ejects into the circulation in one minute), cardiac index (cardiac output indexed to a patient's body size), systemic vascular resistance (the resistance to blood flow by all of the blood vessels, excluding those in the lungs), heart rate, and blood pressure, showed significantly different changes in the tolvaptan and placebo groups.
Overall, 77 (42.5%) 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%) and lowest in the placebo group (33.3%). Most common adverse events (greater than 3% and more frequent than placebo) associated with tolvaptan were dry mouth, thirst, back pain, headache, anxiety, and haematuria. No treatment-emergent adverse event occurred in more than 10% of the patients in any of the groups. No deaths occurred during study drug administration. Two patients died during the 7-day follow-up period (originally assigned to tolvaptan 30 mg and 60 mg, respectively). Both of those patients died from complications resulting from worsening of underlying disease.
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