The two largest studies to date on hyponatremia show that tolvaptan can significantly improve serum sodium levels in hyponatremia due to various diseases including heart failure and cirrhosis of the liver, according to a presentation at the annual meeting of the American Heart Association. Results of the SALT-1 and SALT-2 trials were also published in an article in the November 16 issue of the New England Journal of Medicine.

Tolvaptan is a novel, nonpeptide selective antagonist of the vasopressin V2 receptor.

SALT-1 and SALT-2 [Sodium Assessment With Increasing Levels of Tolvaptan in Hyponatremia] were phase III studies involving 205 (SALT-1) and 243 (SALT-2) patients with hyponatremia predominantly associated with heart failure, cirrhosis or syndrome of inappropriate ADH secretion.

SALT-1 was conducted in the US, and SALT-2 was conducted in the US, Canada, Belgium, Germany, Spain, Italy, Poland, Czech Republic and Hungary. The studies evaluated the efficacy and safety of tolvaptan for the treatment of euvolemic hyponatremia and hypervolemic hyponatremia of any origin.

Patients were randomized to placebo or tolvaptan 15 mg once daily. Over the first four days of treatment, doses could be titrated between 30 mg and 60 mg daily based on the observed change in serum sodium levels.

Patients received treatment for 30 days, with a follow-up visit seven days after use of study medication terminated. Primary endpoints were the change in the average daily area under the curve (AUC) for serum sodium concentration over the first four days and over 30 days of treatment.

In SALT-1, patients receiving tolvaptan had an increase in the average daily area under the curve (AUC) in serum sodium over the first four days of treatment of 3.62 plus or minus 2.68 mEq/L, compared with 0.25 plus or minus 2.08 for the placebo group.

The increase over 30 days was 6.22 plus or minus 4.10 mEq/L in the tolvaptan group and 1.66 plus or minus 3.59 in the placebo group. Normal serum sodium is between 135-145 mEq/L (or mmol/L).

In SALT-2, patients receiving tolvaptan had an increase in the average daily AUC in serum sodium over the first four days of treatment of 4.33 plus or minus 2.87 mEq/L, compared with 0.42 plus or minus 2.56 mEq/L in the placebo group. The increase in the average daily AUC in serum sodium over 30 days was 6.20 plus or minus 3.92 mEq/L in the tolvaptan group and 1.84 plus or minus 3.83 mEq/L in the placebo group.

In both studies, greater changes in serum sodium at day 4 and 30 also were observed in patients with mild (greater than or equal to 130 and less than 135 mEq/L at baseline) and severe hyponatremia (lesser than 130 mEq/L at baseline) treated with tolvaptan than in those treated with placebo. In both studies, more patients receiving tolvaptan reached normalization (i.e. greater than 135 mEq/L) of serum sodium both at day 4 and day 30. Within seven days after discontinuation of study drug, serum sodium returned to the placebo levels.

"With mounting evidence showing that hyponatremia, commonly seen in a variety of diseases, is correlated with a poor prognosis and even death, there is a stronger need for a safe and effective medication to normalize serum sodium concentrations," said Robert W. Schrier, MD, Professor of Medicine, Division of Renal Diseases and Hypertension at the University of Colorado Health Sciences Center in Denver, Colorado, and Chair of the Safety Oversight Committee of the SALT-1 and SALT-2 trials.