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The EVEREST Outcome Trial

Marvin A. Konstam, MD; Mihai Gheorghiade, MD; John C. Burnett, Jr, MD; Liliana Grinfeld, MD; Aldo P. Maggioni, MD; Karl Swedberg, MD; James E. Udelson, MD; Faiez Zannad, MD; Thomas Cook, PhD; John Ouyang, PhD; Christopher Zimmer, MD; Cesare Orlandi, MD; for the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators

JAMA. 2007;297:1319-1331. Published online March 25, 2007 (doi:10.1001/jama.297.12.1319).

Context  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.

Design, Setting, and Participants  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.

Intervention  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.

Main Outcome Measures  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.

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

Trial Registration  clinicaltrials.gov Identifier: NCT00071331

Author Affiliations: Tufts–New England Medical Center, Boston, Mass (Drs Konstam and Udelson); Northwestern University Feinberg School of Medicine, Chicago, Ill (Dr Gheorghiade); Mayo Clinic, Rochester, Minn (Dr Burnett); Hospital Italiano, Buenos Aires, Argentina (Dr Grinfeld); Associazione Nazionale Medici Cardioligi Ospedalieri Research Center, Florence, Italy (Dr Maggioni); Sahlgrenska University Hospital/Östra, Gothenburg, Sweden (Dr Swedberg); Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigations Cliniques, Nancy, France (Dr Zannad); University of Wisconsin, Madison (Dr Cook); and Otsuka Maryland Research Institute, Rockville (Drs Ouyang, Zimmer, and Orlandi).

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