Investigational drug tolvaptan treats hyponatremia

Nov 14 2006

Results of the two largest studies on hyponatremia, SALT-1 and SALT-2, presented Nov. 14 at the American Heart Association's Scientific Sessions in Chicago, found that the investigational drug tolvaptan treated hyponatremia -- water intoxication -- faster and more effectively than available treatments.

"These studies proved for the first time that hyponatremia, which is associated with poor outcomes, can be treated effectively with an oral drug that has no significant side effects," said Mihai Gheorghiade, M.D., professor of medicine at Northwestern University's Feinberg School of Medicine, who presented the results of the studies at the AHA meeting.

Hyponatremia is a relatively common electrolyte disorder. It affects a wide spectrum of patients including those with liver problems, heart failure and the elderly. It also may affect marathon runners.

Occurring in 15 to 20 percent of hospitalized patients with heart failure, hyponatremia is the opposite of dehydration. Known as "water intoxication," the condition occurs when serum sodium concentration in the blood falls to dangerously low levels causing cells in the body to stop excreting water. Normal serum sodium levels are between 135 and 145 millimoles per liter (mmol/L). Hyponatremia occurs when serum concentration drops to less than 135 mmol/L. In severe cases, it can lead to cerebral edema and even death.

Yet current therapies for hyponatremia are often ineffective and poorly tolerated. The two SALT studies will be published in the November 16 issue of the New England Journal of Medicine and presented at the AHA meeting offer promising information.

Robert Schrier, M.D., professor of medicine of the University of Colorado, Denver, and Gheorghiade and their colleagues at other institutions, found that tolvaptan, a V2-receptor antagonist developed by Otsuka Pharmaceutical Co., Ltd. and Otsuka Maryland Research Institute, Inc., began to improve patients' serum sodium levels almost immediately.

"This easy-to-administer oral drug begins to normalize serum sodium within hours. The normalization is sustained during long-term therapy," Dr. Gheorghiade said. "It is also important to note that tolvaptan was associated with an improvement in mental performance. This is important since cognition can decrease as a result of low serum sodium."

The SALT-1 and SALT-2 studies (Sodium Assessment with Increasing Levels of Tolvaptan) looked at 443 patients in the U.S. and several international sites. During the trial, about half the patients were put on the tolvaptan regimen, the other half on placebo. In both studies, patients assigned to tolvaptan had higher serum sodium concentrations at day 4 and day 30 than those in the placebo group. During the week after discontinuing the tolvaptan, hyponatremia recurred in patients.

SALT-1 and SALT-2 were identical prospective, multicenter, randomized, double-blind placebo-controlled efficacy studies. SALT-1 was conducted at 42 sites in the U.S., SALT-2 at 50 international sites.