CLINICAL RESEARCH: HEART FAILURE
Aquaretic Effect of Lixivaptan, an Oral, Non-Peptide, Selective V2 Receptor Vasopressin Antagonist, in New York Heart Association Functional Class II and III Chronic Heart Failure Patients
William T. Abraham, MD*,*,
Alireza A. Shamshirsaz, MD ,
Kim McFann, MD,
Ron M. Oren, MD and
Robert W. Schrier, MD
* The Ohio State University Heart Center, Columbus, Ohio
University of Colorado, Health Sciences Center, Denver, Colorado
University of Iowa Hospitals and Clinics, Iowa City, Iowa
Manuscript received January 11, 2005;
revised manuscript received November 20, 2005,
accepted November 28, 2005.
* Reprint requests and correspondence: Dr. William T. Abraham, The Ohio State University Heart Center, Division of Cardiovascular Medicine, 473 West 12th Avenue, Room 110P DHLRI, Columbus, Ohio 43210-1252 (Email: abraham-1{at}medctr.osu.edu).
OBJECTIVES: The purpose of this study was to examine the renal effects of a V2 receptor arginine vasopressin (AVP) antagonist in heart failure.
BACKGROUND: Arginine vasopressin has been implicated in the renal water retention and dilutional hyponatremia associated with chronic heart failure.
METHODS: We examined the effects of the oral, non-peptide, selective V2 receptor antagonist lixivaptan in 42 diuretic-requiring patients with mild-to-moderate heart failure in a randomized, double-blind, placebo-controlled, ascending single-dose study. After overnight fluid deprivation, patients received single-blind placebo on day –1 (baseline) and double-blind study medication (placebo [n = 12] or lixivaptan 10, 30, 75, 150, 250, or 400 mg [n = 5 per dose group]) on day 1, followed by 4 h of continued fluid restriction and additional 20 h with ad libitum fluid intake.
RESULTS: At all but the 10-mg dose, lixivaptan produced a significant and dose-related increase in urine volume over 4 h, compared with placebo. During 24 h, increases in urine volume ranged from 1.8 l with placebo to 3.9 l after the 400-mg lixivaptan dose (p < 0.01). These increases in urine volumes were accompanied by significant increases in solute-free water excretion. At higher doses, serum sodium was significantly increased; AVP antagonism was well tolerated in these patients.
CONCLUSIONS: These observations confirm a role for AVP in the renal water retention associated with heart failure and suggest that the V2 receptor antagonist lixivaptan may be a promising therapeutic agent for the treatment of heart failure.
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Abbreviations and Acronyms
| | AQP-2 = aquaporin-2 | | AVP = arginine vasopressin | | CHF = chronic heart failure | | CNS = central nervous system | | ECF = extracellular fluid | | GCRC = General Clinic Research Center | | NYHA = New York Heart Association |
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