Multicenter, Randomized, Double-Blind, Placebo-Controlled Study on the Effect of Oral Tolvaptan on Left Ventricular Dilation and Function in Patients With Heart Failure and Systolic Dysfunction

Abstract

Objectives: This study sought to examine the effects of vasopressin V2 receptor antagonism with tolvaptan on the changes in left ventricular (LV) volumes over time. Background: Vasopressin levels may be increased in patients with heart failure (HF) and may be a factor driving the progression of HF. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial conducted to evaluate the effect of long-term administration of the vasopressin V2-receptor antagonist tolvaptan (30 mg/day) on reducing left ventricular end-diastolic volume (LVEDV) compared with placebo in patients with HF and reduced systolic function, using quantitative radionuclide ventriculography at baseline, repeated after 1 year of therapy, and repeated again approximately 1 week after withdrawal of study drug. Results: A total of 120 patients were randomized to tolvaptan and 120 were randomized to placebo. In the placebo group, there was no change in LVEDV over the course of follow-up (change of 0.0 (plus or minus) 10.0 ml/m2). After 1 year of tolvaptan, there was a small reduction in LV volume (decrease of 1.8 (plus or minus) 10.7 ml/m2); the between-group difference was not significant (p = 0.21). During the course of the trial, there were 6 deaths (5%) and 21 HF hospitalizations (18%) in the tolvaptan group, compared with 11 deaths (9%) and 34 HF hospitalizations (28%) in the placebo group. In a time-to-event analysis, there was a significant favorable effect of tolvaptan on the composite of mortality or heart failure hospitalization (p < 0.03 by log-rank test). Conclusions: In a well-treated population of stable HF patients, there was no significant effect of tolvaptan therapy on LV volumes observed during 1 year of therapy. Nonprespecified natural history data favored therapy with tolvaptan, with a reduction in the combined end point of mortality and heart failure hospitalization observed. (Multicenter, Randomized, Double-Blind, Placebo Controlled, Efficacy Study on the Effects of Tolvaptan on Left Ventricular Dilatation in Congestive Heart Failure Patients; http://clinicaltrials.gov/ct/show/NCT00043758?order=1; NCT00043758). (copyright) 2007 American College of Cardiology Foundation.