Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials.
BACKGROUND
Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V2-receptor antagonist, shows promise in this condition.


OBJECTIVE
To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure.


METHODS
Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied.


METHODS
Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission.


METHODS
Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge).


RESULTS
Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension.


CONCLUSIONS
In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events.


BACKGROUND
clinicaltrials.gov Identifier: NCT00071331
Gheorghiade
Mihai
M
Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Ill 60611, USA. m-gheorghiade@northwestern.edu
Konstam
Marvin A
MA
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; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000627:therapeutic use*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D004232:Diuretics / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005665:Furosemide / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy*; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077602:Tolvaptan
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D002317:Cardiovascular Agents; D004232:Diuretics; D000077602:Tolvaptan; D005665:Furosemide