Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial

Marvin A. Konstam, Mihai Gheorghiade, John C. Burnett, Liliana Grinfeld, Aldo P. Maggioni, Karl Swedberg, James E. Udelson, Faiez Zannad, Thomas Cook, John Ouyang, Christopher Zimmer, Cesare Orlandi

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1165 Scopus citations


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, doubleblind, 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.

Original languageEnglish (US)
Pages (from-to)1319-1331
Number of pages13
Issue number12
StatePublished - Mar 28 2007

ASJC Scopus subject areas

  • Medicine(all)


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