Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: a clinical review

Carrie Nemerovski, David J Hutchinson
Clinical Therapeutics 2010, 32 (6): 1015-32

BACKGROUND: Tolvaptan is an oral nonpeptide selective vasopressin V(2)-receptor antagonist indicated for the treatment of clinically relevant hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or syndrome of inappropriate antidiuretic hormone.

OBJECTIVE: The objective of this article was to review the pharmacology, efficacy, and tolerability of tolvaptan in the treatment of hypervolemic or euvolemic hyponatremia, heart failure, and autosomal dominant polycystic kidney disease (ADPKD).

METHODS: Articles were identified using MEDLINE (1966-February 28, 2010) and EMBASE (1947-February 28, 2010). Abstracts and proceedings from the annual meetings (2007-2009) of the American Heart Association, the European Society of Cardiology, and the American Society of Nephrology were searched to identify additional relevant publications. Searches were conducted using the terms tolvaptan, vasopressin antagonist, heart failure, polycystic kidney disease, hyponatremia, drug interaction, pharmacokinetics, and pharmacology. The reference lists of the identified publications were reviewed for additional references. All clinical trials that assessed the use of tolvaptan in the management of hypervolemic/euvolemic hyponatremia or heart failure in humans were included, regardless of study design.

RESULTS: A total of 9 trials were identified. For the treatment of hyponatremia, tolvaptan was associated with significantly increased serum sodium concentrations compared with placebo on treatment days 4 (3.62 [2.68] vs 0.25 [2.08] mmol/L, respectively; P < 0.001) and 30 (6.22 [4.10] vs 1.66 [3.59] mmol/L; P < 0.001). In the clinical trials in patients with heart failure, tolvaptan at doses of 30, 60, and 90 mg/d was associated with mean weight changes of -1.80, -2.10, and -2.05 kg, respectively, versus -0.60 kg with placebo (P = 0.002, P = 0.002, and P = 0.009). Trials of tolvaptan in humans with ADPKD are ongoing. Overall, mortality rates were not significantly altered with tolvaptan compared with placebo (25.9% vs 26.3%). The most commonly reported adverse events associated with tolvaptan in clinical trials were dry mouth (4.2%-23.0%), thirst (7.7%-40.3%), and polyuria (0.6%-31.7%), all consistent with the mechanism of action of the drug.

CONCLUSION: Based on findings from clinical trials to date, tolvaptan is effective for the correction of hyponatremia but has not been associated with significant improvements in mortality in patients with heart failure compared with placebo, and its utility in the treatment of ADPKD in humans remains to be determined.

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