Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia.
BACKGROUND
Hyponatremia [serum sodium concentration ([Na(+)]), <135 mEq/liter] is the most common fluid and electrolyte abnormality among hospitalized patients. It is frequently caused by the inappropriate release of arginine vasopressin.


OBJECTIVE
The objective of this study was to evaluate the efficacy and safety of oral conivaptan, a vasopressin V(1A)/V(2) receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia.


METHODS
The study design was a 5-d placebo-controlled, randomized, double-blind study.


METHODS
The study was performed at a hospital.


METHODS
Oral conivaptan (40 or 80 mg/d) or placebo was given in two divided doses.


METHODS
Seventy-four patients (average baseline serum [Na(+)], 115 to <130 mEq/liter) were studied.


METHODS
The main outcome measure was the change from baseline in serum [Na(+)] area under the curve.


RESULTS
The least-squares mean change from baseline in the serum [Na(+)] area under the curve with conivaptan (40 and 80 mg/d) was 2.0-fold (P = 0.03) and 2.5-fold (P < 0.001) greater, respectively, than that with placebo. The median time to achieve a confirmed increase in serum [Na(+)] of 4 mEq/liter or more from baseline was 71.7 h for placebo, 27.5 h for 40 mg/d conivaptan (P = 0.044), and 12.1 h for 80 mg/d conivaptan (P = 0.002). The mean total times during which patients had a serum [Na(+)] level of 4 mEq/liter or more above baseline were 46.5, 69.8, and 88.8 h (P = 0.001), respectively. The least-squares mean change in serum [Na(+)] from baseline to end of treatment was 3.4 mEq/liter for placebo, 6.4 mEq/liter for 40 mg/d conivaptan, and 8.2 mEq/liter for 80 mg/d conivaptan (P = 0.002). A confirmed normal serum [Na(+)] (>/=135 mEq/liter) or increase of 6 mEq/liter or more was observed in 48% of patients given placebo, 71% given 40 mg/d conivaptan, and 82% given 80 mg/d conivaptan (P = 0.014). Headache, hypotension, nausea, constipation, and postural hypotension were the most common adverse events.


CONCLUSIONS
Oral conivaptan (40 and 80 mg/d) was well tolerated and efficacious in correcting serum [Na(+)] in hyponatremia.
Ghali
Jalal K
JK
Division of Cardiology, Wayne State University, 4201 St. Antoine, Detroit, Michigan 48201, USA. jghali@med.wayne.edu
Koren
Michael J
MJ
Taylor
James R
JR
Brooks-Asplund
Esther
E
Fan
Kaisheng
K
Long
Walker A
WA
Smith
Neila
N
D000284:Administration, Oral; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000097:blood; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007010:Hyponatremia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D012964:Sodium / Q000097:blood
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D065607:Cytochrome P-450 Enzyme Inhibitors; C106389:conivaptan; D001127:Arginine Vasopressin; D012964:Sodium; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human