Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia.
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 V1A/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 > or = 4 mEq/l serum [Na+] increase, total time patients had serum [Na+] > or = 4 mEq/l higher than baseline, change in serum [Na+] from baseline to the end of treatment, and number of patients with a confirmed > or = 6 mEq/l increase in serum [Na+] or normal [Na+] (> or = 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.


CONCLUSIONS
Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na+] and was well tolerated.
Zeltser
David
D
Department of Internal Medicine D, Sourasky Medical Center, Tel Aviv, Israel. davidz@tasmc.health.gov.il
Rosansky
Steven
S
van Rensburg
Hannes
H
Verbalis
Joseph G
JG
Smith
Neila
N
D000368:Aged; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D001810:Blood Volume; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007010:Hyponatremia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D016037:Single-Blind Method; D012964:Sodium / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C106389:conivaptan; D012964:Sodium