Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

Abstract

Background: Most cases of hyponatremia – serum sodium concentration ([Na⁺]) <135 mEq/l (<135 mM) – are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V_1A/V₂-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. Methods: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na⁺] 115 to <130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na⁺], measured by the baseline-adjusted area under the [Na⁺]-time curve. The secondary measures included time from first dose to a confirmed ≧4 mEq/l serum [Na⁺] increase, total time patients had serum [Na⁺] ≧4 mEq/l higher than baseline, change in serum [Na⁺] from baseline to the end of treatment, and number of patients with a confirmed ≧6 mEq/l increase in serum [Na⁺] or normal [Na⁺] (≧135 mEq/l). Results: Both conivaptan doses increased area under the [Na⁺]-time curve during the 4-day treatment (p < 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean ± standard error serum [Na⁺] increase associated with placebo was 0.8 ± 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 ± 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 ± 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p < 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. Conclusion: Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na⁺] and was well tolerated.