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CLINICAL RESEARCH: CLINICAL TRIALS

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

James E. Udelson, MD^_*,_*, Frank A. McGrew, MD, Enrique Flores, MD, Hassan Ibrahim, MD, Stewart Katz, MD^¶, Gregory Koshkarian, MD^||, Terrence O'Brien, MD^_**, Marvin W. Kronenberg, MD, Christopher Zimmer, MD, Cesare Orlandi, MD and Marvin A. Konstam, MD^_*

^_* Division of Cardiology, Tufts-New England Medical Center/Tufts University School of Medicine, Boston, Massachusetts
The Stern Cardiovascular Center, Memphis, Tennessee
Georgia Heart Specialists, Covington, Georgia
North Ohio Research Ltd., Sandusky, Ohio
^¶ Yale University School of Medicine, New Haven, Connecticut
^|| Desert Cardiology of Tucson, Tucson, Arizona
^_** Ralph H. Johnson VA Medical Center, Charleston, South Carolina
Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee
Otsuka America Pharmaceutical, Inc., Rockville, Maryland

Manuscript received October 16, 2006; revised manuscript received January 17, 2007, accepted January 22, 2007.

^_* Reprint requests and correspondence: Dr. James E. Udelson, Tufts-New England Medical Center, 750 Washington Street, Box 70, Boston, Massachusetts 02111 (Email: JUdelson{at}tufts-nemc.org).

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 ± 10.0 ml/m²). After 1 year of tolvaptan, there was a small reduction in LV volume (decrease of 1.8 ± 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 [ClinicalTrials.gov] )

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   BUN = blood urea nitrogen   EF = ejection fraction   HF = heart failure   LAO = left anterior oblique   LV = left ventricular   LVEDV = left ventricular end-diastolic volume   LVEF = left ventricular ejection fraction   LVESVi = left ventricular end-systolic volume index   RVG = radionuclide ventriculography

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