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.
OBJECTIVE
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).
Udelson
James E
JE
Division of Cardiology, Tufts-New England Medical Center/Tufts University School of Medicine, Boston, Massachusetts 02111, USA. JUdelson@tufts-nemc.org
McGrew
Frank A
FA
Flores
Enrique
E
Ibrahim
Hassan
H
Katz
Stewart
S
Koshkarian
Gregory
G
O'Brien
Terrence
T
Kronenberg
Marvin W
MW
Zimmer
Christopher
C
Orlandi
Cesare
C
Konstam
Marvin A
MA
D000284:Administration, Oral; D000368:Aged; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004108:Dilatation, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017483:Receptors, Vasopressin / Q000502:physiology; D013599:Systole / Q000187:drug effects / Q000502:physiology; D000077602:Tolvaptan; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D017483:Receptors, Vasopressin; D000077602:Tolvaptan