Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial.
BACKGROUND
Nearly 1 million hospitalizations for chronic heart failure occur yearly in the United States, with most related to worsening systemic congestion. Diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function.


OBJECTIVE
To evaluate the short- and intermediate-term effects of tolvaptan in patients hospitalized with heart failure.


METHODS
Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial conducted at 45 centers in the United States and Argentina and enrolling 319 patients with left ventricular ejection fraction of less than 40% and hospitalized for heart failure with persistent signs and symptoms of systemic congestion despite standard therapy.


METHODS
After admission, patients were randomized to receive 30, 60, or 90 mg/d of oral tolvaptan or placebo in addition to standard therapy, including diuretics. The study drug was continued for up to 60 days.


METHODS
In-hospital outcome was change in body weight at 24 hours after randomization; outpatient outcome was worsening heart failure (defined as death, hospitalization, or unscheduled visits for heart failure) at 60 days after randomization.


RESULTS
Median (interquartile range) body weight at 24 hours after randomization decreased by -1.80 (-3.85 to -0.50), -2.10 (-3.10 to -0.85), -2.05 (-2.80 to -0.60), and -0.60 (-1.60 to 0.00) kg in the groups receiving tolvaptan 30, 60, and 90 mg/d, and placebo, respectively (P< or =.008 for all tolvaptan groups vs placebo). The decrease in body weight with tolvaptan was not associated with changes in heart rate or blood pressure, nor did it result in hypokalemia or worsening renal function. There were no differences in worsening heart failure at 60 days between the tolvaptan and placebo groups (P =.88 for trend). In post hoc analysis, 60-day mortality was lower in tolvaptan-treated patients with renal dysfunction or severe systemic congestion.


CONCLUSIONS
Tolvaptan administered in addition to standard therapy may hold promise for management of systemic congestion in patients hospitalized for heart failure.
Gheorghiade
Mihai
M
Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Ill 60611, USA. m-gheorghiade@northwestern.edu
Gattis
Wendy A
WA
O'Connor
Christopher M
CM
Adams
Kirkwood F
KF
Elkayam
Uri
U
Barbagelata
Alejandro
A
Ghali
Jalal K
JK
Benza
Raymond L
RL
McGrew
Frank A
FA
Klapholz
Marc
M
Ouyang
John
J
Orlandi
Cesare
C
D000553:Ambulatory Care; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004232:Diuretics / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077602:Tolvaptan; D018487:Ventricular Dysfunction, Left; D015431:Weight Loss
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D002317:Cardiovascular Agents; D004232:Diuretics; D000077602:Tolvaptan