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Gheorghiade M, Gattis WA, O'Connor CM, et al. Effects of Tolvaptan, a Vasopressin Antagonist, in Patients Hospitalized With Worsening Heart Failure: A Randomized Controlled Trial. JAMA. 2004;291(16):1963–1971. doi:10.1001/jama.291.16.1963
Author Affiliations: Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Ill (Dr Gheorghiade); Duke Clinical Research Institute, Durham, NC (Drs Gattis and O'Connor); Division of Cardiology, University of North Carolina, Chapel Hill (Dr Adams); Division of Cardiology, University of Southern California, Los Angeles (Dr Elkayam); Division of Cardiology, Italian Hospital, Buenos Aires, Argentina (Dr Barbagelata); Division of Cardiology, Cardiac Centers of Louisiana, Shreveport (Dr Ghali); Division of Cardiology, University of Alabama, Birmingham (Dr Benza); Division of Cardiology, Stern Cardiovascular Center, Memphis, Tenn (Dr McGrew); Division of Cardiology, St Vincent's Hospital, New York, NY (Dr Klapholz); Otsuka Maryland Research Institute, Rockville (Drs Orlandi and Ouyang).
Context 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.
Design, Setting, and Participants 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.
Intervention 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.
Main Outcome Measures 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≤.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.
Conclusion Tolvaptan administered in addition to standard therapy may hold promise
for management of systemic congestion in patients hospitalized for heart failure.
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