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Study of Ascending Levels of Tolvaptan in Hyponatremia - SALT 1 and 2 – Presented at AHA 2006
Description:
The goal of the trials was to evaluate treatment with tolvaptan, a selective oral vasopressin V2-receptor antagonist, compared with placebo among patients with euvolemic or hypervolemic hyponatremia.
Study Design
Study Design:
Patients Screened: 548
Patients Enrolled: 448
Mean Follow Up: 37 days
Mean Patient Age: Mean age, 62 years
Female: 42
Patient Populations:
Age ≥18 years with hypervolemic hyponatremia, defined as a nonartifactual serum sodium concentration <135 mmol/L; chronic heart failure, cirrhosis, or SIADH in association with the hyponatremia
Exclusions:
Psychogenic polydipsia, head trauma, postoperative conditions, uncontrolled hypothyroidism or adrenal insufficiency, or any hyponatremic condition associated with the use of medications that could have been safely withdrawn
Primary Endpoints:
Change in average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30
Secondary Endpoints:
Change in the AUC for the serum sodium concentration in patients with marked hyponatremia, the absolute serum sodium concentration at each visit, the time to normalization of the serum sodium concentration, the percentages of patients with serum sodium concentrations that had normalized at day 4 and day 30, and the categorical serum sodium concentration on day 4 and day 30 for patients with mild or marked hyponatremia at baseline
Drug/Procedures Used:
Patients were randomized in the two trials in a double-blind manner to oral tolvaptan (15 mg/day, with adjustment to 30 mg or 60 mg if needed; n = 225) or placebo (n = 223) for up to 30 days.
Principal Findings:
Cause of hyponatremia was chronic heart failure in 31% of patients, cirrhosis in 27%, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or other causes in 42% of patients. Degree of hyponatremia at baseline was mild in 50% and marked in 50%. Mean serum sodium concentration was 129 mmol/L at study entry. Baseline characteristics were similar between treatment groups in each trial.
The primary endpoint of increase in serum sodium concentration was greater in the tolvaptan group compared with the placebo group at day 4 (3.62 vs. 0.25 mmol/L in SALT-1; 4.33 vs. 0.42 mmol/L in SALT-2, p < 0.001 for each) and through day 30 (6.22 vs. 1.66 mmol/L in SALT-1; 6.20 vs. 1.84 mmol/L in SALT-2, p < 0.001 for each). Results were consistent in patients with mild and marked hyponatremia at baseline. More patients in the tolvaptan group had normal sodium concentrations compared with the placebo group at day 4 (40% vs. 13% in SALT-1; 55% vs. 11% in SALT-2, p < 0.001 for each) and at day 30 (53% vs. 25% in SALT-1; 58% vs. 25% in SALT-2, p < 0.001 for each). In the week after the 30-day study drug treatment period, serum sodium concentrations were similar in the tolvaptan and placebo groups.
Adverse events leading to study drug discontinuation occurred in eight patients in the tolvaptan group and eight in the placebo group. The most common reported adverse events in the tolvaptan group were dry mouth (13%) and thirst (14%). Excesses in desirable rates of sodium correction during the first 24 hours were reported in 1.8% (n = 4) of patients in the tolvaptan group. There were 14 deaths in the tolvaptan group and 13 in the placebo group.
Interpretation:
Among patients with euvolemic or hypervolemic hyponatremia from etiologies of heart failure, cirrhosis, or SIADH, treatment with tolvaptan, a selective oral vasopressin V2-receptor antagonist, was associated with larger increases in serum sodium concentration by day 4 and day 30 compared with placebo.
The prior ACTIV CHF study with tolvaptan in the setting of heart failure patients demonstrated decreased body weight within 24 hours with tolvaptan, but no change in the clinical endpoint of worsening heart failure by 60 days. Hyponatremia, a frequent serum electrolyte abnormality, has been shown to be associated with an increase in complications and mortality in observational studies. Larger trials are needed to evaluate whether the reduction in hyponatremia with tolvaptan will be associated with improvements in clinical outcomes.
References:
Schrier RW, et al. Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. N Engl J Med 2006;355:2099-112.
Presented by Dr. Mihai Gheorghiade and Dr. Cesare Orlandi at the American Heart Association Annual Scientific Sessions, Chicago, IL, November 2006.
Keywords: Electrolytes, Thirst, Receptors, Vasopressin, Hyponatremia, Vasopressins, Weight Loss, Heart Failure, Inappropriate ADH Syndrome, Liver Cirrhosis, Benzazepines
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