Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST).
BACKGROUND
Hospitalizations for worsening heart failure due to fluid overload (congestion) are common. Agents that treat congestion without causing electrolyte abnormalities or worsening renal function are needed. Tolvaptan is an oral vasopressin (V 2 ) antagonist that decreases body weight and increases urine volume without inducing renal dysfunction or hypokalemia. The Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial is evaluating mortality, morbidity, and patient-assessed global clinical status in patients treated with tolvaptan compared with standard care.


RESULTS
Patients are eligible for inclusion if they have a reduced left ventricular ejection fraction and are hospitalized for worsening heart failure with evidence of systemic congestion. Patients are randomized 1:1 to tolvaptan 30 mg/day or matching placebo for a minimum of 60 days. Time to all-cause mortality and time to cardiovascular mortality or heart failure hospitalization are the coprimary end points. Patient-assessed global clinical status and quality of life are also evaluated. EVEREST will be continued until 1065 deaths occur. As of April 18, 2005, 2260 patients have been enrolled.


CONCLUSIONS
Tolvaptan has been shown to reduce body weight in patients with worsening heart failure without inducing renal dysfunction or causing hypokalemia. The results of EVEREST will determine whether these effects translate into improved clinical outcomes.
Gheorghiade
Mihai
M
Division of Cardiology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Orlandi
Cesare
C
Burnett
John C
JC
Demets
David
D
Grinfeld
Liliana
L
Maggioni
Aldo
A
Swedberg
Karl
K
Udelson
James E
JE
Zannad
Faiez
F
Zimmer
Christopher
C
Konstam
Marvin A
MA
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy*; D006760:Hospitalization; D006801:Humans; D007008:Hypokalemia / Q000517:prevention & control; D010919:Placebos; D011788:Quality of Life; D012107:Research Design; D013318:Stroke Volume / Q000187:drug effects; D015996:Survival Rate; D000077602:Tolvaptan; D016896:Treatment Outcome; D014554:Urination / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D010919:Placebos; D000077602:Tolvaptan