Tolvaptan does not improve long-term HF outcomes

Clinical Question

What are the effects of tolvaptan in patients hospitalized with heart failure?

Bottom Line

Tolvaptan improved symptoms of heart failure in the short-term but did not reduce long-term mortality or heart failure-related morbidity in patients hospitalized for decompensated heart failure. (LOE = 1b)


Konstam MA, Gheorghiade M, Burnett JC, et al, for the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure. The EVEREST outcome trial. JAMA 2007;297:1319-1331. Gheorghiade M, Konstam MA, Burnett JC, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure. The EVEREST clinical status trials. JAMA 2007;297:1332-1343.  [PMID:17384438]

Study Design

Randomized controlled trial (double-blinded)






Inpatient (any location)


Tolvaptan is an oral vasopressin receptor antagonist that selectively blocks the V2 receptors in the renal collecting ducts, leading to excretion of solute-free water. The EVEREST trials evaluated the effects of tolvaptan in patients hospitalized with decompensated heart failure. Two identically designed studies were conducted to evaluate the short-term effects of tolvaptan on clinical status, and an outcome study included all randomized patients to evaluate long-term clinical outcomes (mortality and hospitalization for heart failure). A total of 4133 patients (approximately 2000 each in the clinical status trials) were randomized to receive tolvaptan 30 mg daily or placebo within 48 hours of admission. All patients were managed with standard heart failure therapy, including diuretics. Treatment was continued for at least 60 days. Data were analyzed by intention to treat and outcome assessors were blinded to treatment assignment. The clinical trials found no difference in patient-assessed global clinical status at day 7. Tolvaptan resulted in significantly greater reductions in body weight at days 1 and 7 (-3.35 kg vs - 2.73 kg at 7 days; P < .001), and in improvement in patient-assessed dyspnea at day 1. Physician assessment showed improvement in dyspnea, orthopnea, fatigue, jugular venous distension, rales, and edema at days 1 through 4. There were no adverse effects on blood pressure, heart rate, or electrolyte levels. The outcome trial followed up patients for a median of 9.9 months, and found no difference in mortality or the composite of cardiovascular death or hospitalization for heart failure. The results of the EVEREST trials indicate that the main benefits of tolvaptan are limited to short-term volume removal rather than long-term benefits from neurohormonal blockade.