Vasopressin Receptor Antagonists for the Treatment of Hyponatremia
in patients with hyponatremia and CHF or cirrhosis is problematic secondary to the poor inherent prognosis of these conditions. It is still of importance to acknowledge that the majority of patients in SALTWATER had improved serum sodium concentrations and less need for fluid restriction. This was accomplished safely and without the risk of too rapid correction of the serum sodium concentration. It is also difficult to judge if hyponatremia is the only metric that should guide the use of vaptans in chronic hyponatremia. To date there is no evidence to suggest improved survival or improved symptoms associated with treated hyponatremia.40
Tolvaptan has also been studied as a treatment for decompensated CHF irrespective of serum sodium. The rationale for this approach was to assess the potential benefit of pharmacological blockade of ADH, a hormone that is significantly and persistently elevated in patients with CHF. A small clinical trial had previously shown that tolvaptan significantly increases urinary output and decreases body weight without causing electrolyte disturbances or worsening renal function.41
tolvaptan was associated with a significant improvement in the combined endpoint of self-reported global clinical status and fluid loss, but the difference was driven entirely by a 0.7 kg difference in weight loss between the two groups during the index hospitalization. In the long-term arm, with a median follow-up period of 9.9 months, tolvaptan was not associated with improved survival, improved CHF management, or decreased need for re-hospitalization. This study does not address treatment of hyponatremia even in patients with CHF, but does provide some assurance, in a large-scale, carefully adjudicated trial, that tolvaptan is safe.34,42
Conclusion and Recommendation
The Efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) trial was designed to prove the hypothesis that tolvaptan would improve symptoms and survival in patients admitted to the hospital with acute decompensated CHF. A total of 4,133 patients hospitalized with heart failure were randomized to receive tolvaptan 30 mg orally once a day (n=2072) or placebo (n=2,061). Hyponatremia was not an inclusion criterion, and only 7.7 % of the study participants had hyponatremia as defined by serum sodium levels below 134 mmol/l. In the short-term arm,
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