SAN FRANCISCO — Satavaptan and conivaptan seem effective in treating dilutional hyponatremia, a frequent consequence of heart failure and of renal failure.
Data supporting the efficacy of the vasopressin receptor antagonists for this indication were presented in two posters at the annual meeting of the American Society of Nephrology. Satavaptan has not yet received Food and Drug Administration approval. Conivaptan, which was approved in 2005 for euvolemic hyponatremia, received approval in early 2007 for dilutional (hypervolemic) hyponatremia.
The conivaptan study was supported by Astellas Pharma US Inc. and the satavaptan study was supported by Sanofi Aventis. Both companies manufacture the vasopressin receptor antagonists.
Safety and efficacy in patients with heart failure (HF) are noteworthy findings because the current labeling for conivaptan says the drug is not indicated for the treatment of HF and should be used in these patients only when the expected benefit of increased serum sodium outweighs the potential adverse events.
Dr. Stephen R. Goldsmith of the University of Minnesota, Minneapolis, and his colleagues reported that conivaptan was effective at dosages of 20–40 mg/day, yielding significant increases in serum sodium concentration and in the area under the serum sodium concentration curve, compared with placebo.
The study was a retrospective analysis of two trials of conivaptan, one a randomized controlled trial and the other an open-label trial of patients with euvolemic and hypervolemic (dilutional) hyponatremia. For their presentations, they limited analysis to the 28 patients in the randomized controlled trial and the 69 patients in the open-label trial with hypervolemic hyponatremia.
The patients had serum sodium concentrations of 115–130 mEq/L and fasting blood glucose levels of less than 275 mg/dL. Their mean age was 71 years, and 62% had heart failure. They received either a 20-mg IV loading dose of conivaptan or placebo by 30-minute IV infusion followed by a continuous 4-day IV infusion.
Conivaptan infusion was associated with increases in serum sodium concentration over baseline of 4 mEq/L or more at all dosages. This increase occurred in a median of 58 hours at the lowest dosage (20 mg/day) and in a median of 24 hours at the higher dosages (40 and 80 mg/day). Most of the patients treated with conivaptan achieved at least a 6-mEq/L increase in serum sodium concentration over baseline or normal serum sodium concentrations at or above 135 mEq/L.
Significantly more serious adverse events occurred in those treated with conivaptan, compared with those on placebo. Deaths occurred at a similar frequency across all four groups. The most common adverse events were infusion-site phlebitis, infusion-site reactions, vomiting, and hypotension.
Conivaptan was as effective and as safe in patients with HF as it was in patients with other conditions. Still, the drug is intended to treat the hyponatremia that accompanies HF and not HF itself, Dr. Goldsmith emphasized in an interview. But, “since there is inevitable decongestion with a vaptan as a consequence of the free water excretion, one does, of course, 'treat' the [heart failure] to some extent.”
In the other presentation, Dr. Doron Aronson of Rambam Medical Center, Haifa, Israel, and colleagues found 50 mg/day of satavaptan was superior to placebo with respect to the sodium responder rate.
That study involved 118 patients randomized to receive either placebo or satavaptan at 25 mg/day or 50 mg/day. All of the patients had dilutional hyponatremia with serum sodium concentrations between 115 and 132 mEq/L. Heart failure was the cause of hyponatremia in 76% of the patients. The study excluded those with liver cirrhosis or the syndrome of inappropriate antidiuretic hormone secretion.
At the end of the 4-day double-blind period, 61% of the patients in the 50-mg group had a sodium response, compared with 27% in the placebo group, a significant difference. The sodium responder rate seemed higher in the 25-mg group than in the placebo group, but this figure did not quite reach statistical significance.
The median time to response was 3.3 days in the 25-mg group and 2.8 days in the 500-mg group, both significantly shorter than that for placebo, where the median time to response was more than 4 days.
Significantly more patients in the satavaptan groups than in the placebo group had overly rapid correction of serum sodium (increases of 12 mEq/L or more within 24 hours). Other adverse events in the satavaptan groups were atrial fibrillation, a prolonged QTc interval, hypotension, hypertension, and pyrexia.