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.

Novel Treatment Targets for Cerebral Edema

“…In several double-blind, placebo-controlled clinical trials, conivaptan has been effective in improving serum sodium concentrations [91]. Serum sodium is improved by 6.3 mmol/L with a 40 mg daily dose, and by 9.0 mmol/L with an 80 mg daily dose [92][93][94]. Importantly, despite the properties of conivaptan as a V1a-receptor antagonist, it had no effect on systolic blood pressure or pulse rate.…”

Les troubles de l’équilibre hydrosodé chez les patients hospitalisés

“…53 For the most part, these drugs have been used for hyponatremia associated with normovolemic or edematous states (i.e., SIADH, heart failure). [57][58][59][60][61][62] While preliminary data are promising that these agents may be alternatives to fluid restriction or saline administration, clinical experience is limited, particularly to support their use in managing acute severe hyponatremia. Vasopressin receptor antagonists are approved by the Food and Drug Administration for use in the United States; however, they are not yet approved for use in Canada.…”

Hyponatremia: Clinical Associations, Prognosis, and Treatment in Cirrhosis

“…82,85 Conivaptan has been assessed in randomized double-blinded placebo-controlled clinical trials, only 1 of which used IV conivaptan. 83,[86][87][88] Zeltser and associates used a small cohort of 84 patients with euvolemic or hypervolemic hyponatremia and randomly assigned them to 40 mg/d, 80 mg/d of IV conivaptan, or placebo, with outcomes measures including net increase in sodium levels and time from initial dose to ≥ 4 mEq/L increase. As compared with only 0.8 mEq/L with placebo, IV conivaptan significantly increased serum sodium levels during a 4-day treatment period, with 6.3 mEq/L and 9.4 mEq/L with 40 mg and 80 mg dosages.…”

“…However, few patients had underling cirrhosis as the cause of hyponatremia (< 9 of 29 study population. 86 Interestingly, in an openlabel multicenter trial involving 251 hospitalized patients, increases in serum sodium level from conivaptan use persisted through day 34, suggesting more long-term effects of IV conivaptan. 89 However, because conivaptan also has activity against V1R, causing vasodilatory effects in the portal and splanchnic circulation, it theoretically has an increased risk of variceal bleeding.…”