Short-term efficacy and safety of vasopressin receptor antagonists for treatment of hyponatremia

Abstract

Background: We performed a meta-analysis to systematically measure efficacy and safety of vasopressin receptor antagonists (VRAs) tested in randomized controlled trials for treatment of hyponatremia.

Methods: MEDLINE, ClinicalTrials.gov, and scientific abstracts were searched without language restriction. Two authors independently screened citations and extracted data on patient characteristics, quality of reports, and efficacy and safety endpoints.

Results: Eleven trials were identified (1094 patients). By meta-analysis, VRAs achieved a net increase in serum sodium concentration ([Na(+)](serum)) relative to placebo of 3.3 mEq/L at day 1 (95% confidence interval [CI], 2.7-3.8), and 4.2 mEq/L at day 2 (95% CI, 3.6-4.8), persisting at days 3-5. Larger net increases in [Na(+)](serum) at days 1-4 were observed in euvolemic hyponatremia and with higher doses. VRAs induced a net increase in effective water clearance relative to placebo of 1244 mL at day 1 (95% CI, 920-1567), persisting at days 2 and 4. VRAs were associated with odds ratios of 3.0 for overly rapid correction of [Na(+)](serum) (P <.001), 7.8 for development of hypernatremia (P <.001), 3.3 for thirst development (P <.001), and 2.2 for postural hypotension (P=.04).

Conclusions: Short-term use of VRAs in treating hyponatremia was successful at raising [Na(+)](serum). Additional experience is required to guide their optimal use and minimize safety concerns.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Literature search and selection.

Figure 2

Meta-analysis of randomized trials comparing the effect of vasopressin receptor antagonists (VRAs) vs. placebo on net change in serum sodium concentration ([Na+]serum) at day 1 in patients with hyponatremia.

Figure 3

Meta-analysis of randomized trials comparing the effect of vasopressin receptor antagonists (VRAs) vs. placebo on net change in serum sodium concentration ([Na+]serum) at days 1-5 and day 30 in patients with hyponatremia.

Figure 4

Subgroup meta-analyses of randomized trials comparing the effect of vasopressin receptor antagonists (VRAs) vs. placebo on net change in serum sodium concentration ([Na+]serum) at days 1-5, stratified by (4A) hyponatremia type (euvolemic vs. hypervolemic vs. mixed), (4B) low- vs. high-dose VRA, and (4C) Jadad score. Where indicated, P values refer to Student t-tests comparing trials of euvolemic/hypervolemic vs. hypervolemic patients (*), euvolemic/hypervolemic vs. euvolemic (†) patients, and hypervolemic vs. euvolemic (**) patients. High-dose VRA was defined as follows: conivaptan >40 mg/day; tolvaptan >30 mg/day; satavaptan >25 mg/day; and lixivaptan >125 mg/day.

Figure 5

Meta-analysis of randomized trials comparing the effect of vasopressin receptor antagonists (VRAs) vs. placebo on net change in effective water clearance (EWC) at day 1 in patients with hyponatremia.