Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan - EVEREST


The goal of the trial was to evaluate the safety and efficacy of tolvaptan compared with placebo among patients hospitalized with acute decompensated heart failure (ADHF).

Study Design

Patients Enrolled: 4,133
Mean Follow Up: Median, 9.9 months
Mean Patient Age: Mean age, 66 years
Female: 26

Patient Populations:

Age ≥18 years; reduced left ventricular ejection fraction (≤40%); signs of volume expansion; NYHA class III/IV symptoms; and hospitalization for exacerbation of chronic heart failure within 48 hours


Cardiac surgery within 60 days of enrollment, cardiac mechanical support, biventricular pacemaker placement within the prior 60 days, comorbid conditions with an expected survival of <6 months,="" acute="" myocardial="" infarction="" at="" the="" time="" of="" hospitalization,="" hemodynamically="" significant="" uncorrected="" primary="" cardiac="" valvular="" disease,="" refractory="" end-stage="" heart="" failure,="" hemofiltration="" or="" dialysis,="" supine="" systolic="" arterial="" blood="" pressure=""><90 mm="" hg,="" serum="" creatinine="">3.5 mg/dl, serum potassium >5.5 mEq/L, and hemoglobin <9 g/dl="">

Primary Endpoints:

1) All-cause mortality, and 2) CV mortality or heart failure hospitalization

Secondary Endpoints:

Changes in dyspnea, body weight, and edema

Drug/Procedures Used:

Within 48 hours of hospitalization, patients were randomized in a double-blind manner to tolvaptan (30 mg/day, n = 2,072) or placebo (n = 2,061). Treatment was to continue for at least 60 days. The EVEREST program was comprised of two trials.

Principal Findings:

At baseline, mean ejection fraction was 27.5%, and 65% of patients presented with ischemic heart failure etiology. New York Heart Association (NYHA) class III was present in 60% of patients and class IV in 40%. Diabetes was present in 39% of patients; 31% of patients had mitral valve disease.

Improvement in patient-assessed dyspnea at day 1 was greater in the tolvaptan group (74.3% vs. 68.0%, p

The primary endpoint of all-cause mortality did not differ between the tolvaptan group and placebo group (25.9% vs. 26.3%, hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.87-1.11, p = 0.68 for superiority, p

The frequency of adverse events resulting in study drug discontinuation was similar in the two groups (6.5% for tolvaptan vs. 5.5% for placebo). Patients in the tolvaptan group more frequently experienced dry mouth, thirst, and hypernatremia. There was no difference in renal failure or hypotension.


Among patients hospitalized with ADHF, long-term treatment with the vasopressin V2 receptor antagonist tolvaptan was not associated with a difference in all-cause mortality or the composite of CV death or heart failure hospitalization compared with placebo at long-term follow-up.

Short-term treatment with tolvaptan was associated with improvements in early heart failure parameters of decreased body weight, reduction in edema, and improvement in patient-assessed dyspnea. However, long-term treatment with tolvaptan was not associated with improvements in clinical endpoints, suggesting that early, in-hospital therapy with tolvaptan is beneficial, but longer therapy may be unnecessary. The results of the present study are similar to those observed in the ACTIV in CHF trial, which also showed improvements in acute heart failure symptoms, but no difference in clinical endpoints with chronic therapy.


Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319-31.

Presented by Dr. Marvin A. Konstam at the American College of Cardiology Annual Scientific Session, New Orleans, LA, March 2007.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Mouth, Follow-Up Studies, Ventricular Function, Left, Body Weight, Hypotension, Edema, Dyspnea, Benzazepines, Thirst, Renal Insufficiency, Receptors, Vasopressin, Heart Failure, Stroke Volume, Confidence Intervals, Mitral Valve, Diabetes Mellitus, Hypernatremia

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