Tolvaptan: any evidence of efficacy in SIADH?

The cornerstone of treatment for syndrome of inappropriate antidiuretic hormone secretion (SIADH) is fluid restriction. Demeclocycline is sometimes used but its efficacy is based solely on laboratory endpoints. This drug also has the adverse effects shared by all tetracyclines. Tolvaptan antagonises receptors for arginine vasopressin, a hormone that regulates blood sodium levels by stimulating renal water resabsorption. Tolvaptan is now authorised in the European Union for the treatment of hyponatraemia due to SIADH. Clinical evaluation of tolvaptan in this setting is based on two comparative double-blind placebo-controlled trials including a total of 448 patients with SIADH or hyponatraemia from various other causes. The two trials were combined for analysis. However, because of major methodological flaws, no firm conclusions can be drawn concerning the efficacy in SIADH patients. It remains to be shown that tolvaptan improves symptoms of hyponatraemia (especially neuropsychiatric disorders) or even that it corrects hyponatraemia in these patients. The adverse effects observed in clinical trials were predictable, given the mechanism of action, and included thirst and dry mouth (respectively 16% and 8.4% of patients), hypernatraemia (1.7%), pollakiuria and polyuria. Tolvaptan is metabolised by the cytochrome P450 isoenzyme CYP 3A4, hence a high risk of pharmacokinetic interactions. In summary, there is no reason to use tolvaptan to treat the syndrome of inappropriate antidiuretic hormone secretion: its efficacy on symptoms or even on sodium levels has not been demonstrated, and its adverse effect profile is poorly documented. It is better to concentrate on non-drug management.