SALT 1 and 2: Tolvaptan Shows Promise in Hyponatremia

Susan Jeffrey

November 14, 2006

November 14, 2006 — Results of 2 trials of tolvaptan (Otsuka America Pharmaceutical), a novel oral vasopressin V2-receptor antagonist, show that treatment effectively increased serum sodium concentrations vs placebo in patients with euvolemic or hypervolemic hyponatremia associated with heart failure and other conditions.

The trials, called the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT 1 and 2), are published online in advance of the November 16 issue in the New England Journal of Medicine, to coincide with their presentation here at the American Heart Association (AHA) 2006 Scientific Sessions.

"We demonstrated conclusively that it's a clean drug in the sense that you can improve hyponatremia, but you don't change renal function, heart rate, or blood pressure," Mihai Gheorghiade, MD, from the Northwestern University Feinberg School of Medicine, in Chicago, Illinois, who presented the study here at the AHA meeting, told Medscape.

"The vasopressin V2-receptor antagonists such as tolvaptan open a new therapeutic era for treating patients with hyponatremia," Robert W. Schrier, MD, from the University of Colorado in Denver and first author on the paper, told Medscape. "While correction of hyponatremia may improve cognition and gait, thereby decreasing falls, it remains to be seen if aquaretics will alter mortality in patients with advanced heart failure and cirrhosis."

SALT 1 and 2 were supported by the Otsuka Maryland Research Institute.

SALT Imbalance

Hyponatremia, defined as a serum sodium concentration of less than 135 mmol/L, is associated with increased morbidity and mortality in patients with heart, liver, and neurologic disease; even mild chronic hyponatremia has been associated with mild neurologic defects, the researchers write, including impairment of balance and attention that can lead to falls.

Diuretics used to reduce congestion tend also to produce electrolyte abnormalities and may adversely affect renal function. Tolvaptan, a still-investigational vasopressin V2-receptor antagonist, induces the excretion of electrolyte-free water without changing the total level of electrolyte secretion, they explain.

The ACTIVE in CHF trial (Gheorghiade M et al. JAMA. 2004;291:1963-1971), for example, showed that tolvaptan on top of diuretics was associated with significant weight reduction related to fluid loss and with improved serum sodium levels in patients hospitalized for heart failure. This was accomplished without electrolyte imbalance or worsening renal function.

Identical Trials

SALT 1 and 2 were identical trials carried out in the United States and Europe, respectively. Both were randomized, double-blind, placebo-controlled studies looking at tolvaptan in patients with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone secretion (SIADH), all conditions where hyponatremia is common.

Patients with either hypervolemic or euvolemic hyponatremia were eligible. They could have mild or severe hyponatremia, but at least 50% of patients were required to have severe hyponatremia in both cohorts. Patients were randomized to receive placebo or tolvaptan at a dose of 15 mg per day, which could be increased to 30 or 60 mg per day if necessary on the basis of serum sodium concentrations. SALT 1 randomized 102 patients to tolvaptan and 103 to placebo; SALT 2 randomized 123 to tolvaptan and 120 to placebo.

The 2 primary end points for all patients was the change in the average daily area underthe curve for serum sodium concentration from baseline to day 4 and from baseline to day 30. Patients were also monitored for 7 days following withdrawal of the study drug.

Dr. Gheorghiade reported that serum sodium concentrations increased significantly more with tolvaptan than placebo both at the 4-day ( P < .001) and 30-day ( P < .001) time points. This significant improvement applied both to patients with mild and severe hyponatremia, he noted.

Serum sodium levels in treated patients rapidly fell to levels similar to the placebo group within 7 days after withdrawal of tolvaptan, No changes were seen in serum creatinine levels, BUN, or other electrolyte levels, including potassium and magnesium, between groups, he said.

The most common adverse events with treatment were thirst, dry mouth, and increased urination. Serious adverse events occurred in 8 patients on tolvaptan, including hypotension, dizziness, and syncope.

Interestingly, a planned analysis combining patient self-assessment data from both studies on the Medical Outcomes Study 12-item Short Form General Health Survey showed significant improvement from baseline to day 30 in the tolvaptan group on the mental, although not on the physical, component of that survey.

The SALT trials were not powered to look at clinical end points, he added, but death occurred in similar numbers of patients in both tolvaptan and placebo groups.

Dr. Gheorghiade told Medscape that submission for regulatory approval of tolvaptan would await final results of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, now ongoing. The trial has randomized patients hospitalized for worsening heart failure to tolvaptan 30 mg/day or placebo for a minimum of 60 days. Co–primary end points are time to all-cause mortality and time to cardiovascular mortality or heart failure hospitalization.

EVEREST investigators expect to report results in April 2007 at the American College of Cardiology meeting, he added.

"Careful Oversight" Required

In an editorial accompanying the NEJM paper, Richard M. Hays, MD, from the Albert Einstein College of Medicine, Bronx, New York, calls the SALT trial findings "encouraging in terms of the efficacy of tolvaptan as a V2-receptor antagonist and its use, at least during a limited period, in the outpatient setting.

"At the same time," he adds, "it is clear that careful oversight of the use of this agent is required, not only by means of frequent clinic visits and measurement of serum sodium, but also through daily measurements of body weight by patients."

Dr. Schrier reports having served as a consultant to Otsuka, Astellas, Bayer, and Amgen. Dr. Gheorghiade has served as a consultant to Otsuka, PDL, Sigma Tau, Medtronic, and GlaxoSmithKline, and reports having received honoraria from Medtronic, AstraZeneca, Scios, GlaxoSmithKline, Otsuka, PDL, Abbott, and Sigma Tau. Other coauthor disclosures appear in the paper.

N Engl J Med . 2006;355: 2099-2112, 2146-2148.


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