Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.
BACKGROUND
Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure.


OBJECTIVE
To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure.


METHODS
The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study. The outcome trial comprised 4133 patients within 2 short-term clinical status studies, who were hospitalized with heart failure, randomized at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006, and followed up during long-term treatment.


METHODS
Within 48 hours of admission, patients were randomly assigned to receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for a minimum of 60 days, in addition to standard therapy.


METHODS
Dual primary end points were all-cause mortality (superiority and noninferiority) and cardiovascular death or hospitalization for heart failure (superiority only). Secondary end points included changes in dyspnea, body weight, and edema.


RESULTS
During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and day 7 edema. In patients with hyponatremia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups.


CONCLUSIONS
Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity.


BACKGROUND
clinicaltrials.gov Identifier: NCT00071331
Konstam
Marvin A
MA
Division of Cardiology, Tufts-New England Medical Center, Boston, Mass, USA. mkonstam@tufts-nemc.org
Gheorghiade
Mihai
M
Burnett
John C
JC
Grinfeld
Liliana
L
Maggioni
Aldo P
AP
Swedberg
Karl
K
Udelson
James E
JE
Zannad
Faiez
F
Cook
Thomas
T
Ouyang
John
J
Zimmer
Christopher
C
Orlandi
Cesare
C
D000284:Administration, Oral; D000368:Aged; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D006760:Hospitalization; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012964:Sodium / Q000097:blood; D000077602:Tolvaptan
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D002317:Cardiovascular Agents; D000077602:Tolvaptan; D012964:Sodium; D003404:Creatinine