Tolvaptan, hyponatremia, and heart failure.

Tolvaptan is the first FDA-approved oral V(2) receptor antagonist for the treatment of euvolemic and hypervolemic hyponatremia, in patients with conditions associated with free water excess such as heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. Tolvaptan inhibits the binding of arginine vasopressin to the V(2) receptors on the collecting ducts of the kidneys resulting in aquaresis, the electrolytes sparing excretion of water. This article reviews the accumulated experience with tolvaptan and all the major clinical trials that were conducted to study its safety and efficacy and concludes by summarizing clinicians' views of its current application in clinical practice.

The potential role for lixivaptan in heart failure and in hyponatremia.

INTRODUCTION: Hypervolemia and hyponatremia are common features in heart failure and have been associated with increased morbidity and mortality. Stimulation of arginine vasopressin (AVP) plays an important role in the development of both hypervolemia and hyponatremia. Lixivaptan is a selective vasopressin type 2 (V(2)) receptor antagonist that has been demonstrated to have the ability to induce aquaresis, the electrolyte sparing excretion of water, resulting in fluid removal as well as correction of hyponatremia. AREAS COVERED: This article describes the prevalence, pathophysiology and current treatment limitations of hyponatremia, highlights the importance of arginine vasopressin and the potential role of arginine vasopressin antagonists and reviews all available literature on lixivaptan, a selective V(2) receptor antagonist. EXPERT OPINION: The available experience of lixivaptan in heart failure, although limited, is encouraging. Its aquaretic effect provides the basis for its use to correct hypervolemia and hyponatremia in patients with heart failure, and the absence of neurhormonal stimulation provides positive signal for the exploration of its potential in improving outcomes.

Red cell distribution width and mortality in predominantly African-American population with decompensated heart failure.

INTRODUCTION: Red-cell distribution width (RDW) has been identified as a novel prognostic marker in heart failure patients. However, evidence is limited for its predictive value in the setting of patients hospitalized with decompensated heart failure (DHF) and no data are available for African Americans (AA). METHODS AND RESULTS: Data that included baseline characteristics, laboratory findings, and discharge medications were collected retrospectively on a total of 789 patients with DHF (mean age 62.7 ± 15.1 years, 50% males and 80% AA), admitted to an urban medical center between January 2007 and August 2007, 145 (18.38%) died during median follow-up of 573 days. Unadjusted and adjusted Cox-proportional hazard models were used to analyze predictive value of discharge RDW on mortality. There was a significant negative association between RDW and statin use, blood hemoglobin levels and mean corpuscular volume (MCV); whereas serum creatinine and blood urea nitrogen (BUN) increased with increasing RDW. A statistically significant graded increase in all-cause mortality with higher RDW quartiles (lowest vs highest quartile), independent of hemoglobin and creatinine levels, was found for all patients (adjusted hazard ratio [HR] 3.21; 95% confidence interval [CI]: 1.77-5.83, P < .05) for AAs (adjusted HR 2.92; 95% CI: 1.50-5.71, P < .05) and for non-AAs (adjusted HR-1.27, 95% CI: 1.03-1.55, P = 0.019; RDW evaluated as continuous variable). CONCLUSION: Discharge RDW is an independent predictor of all-cause mortality in predominantly AA patients hospitalized with DHF. Further research is warranted to delineate underlying pathophysiological mechanisms including the association between statin use and RDW.

Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia.

Lixivaptan (VPA-985), being developed by Biogen Idec and Cardiokine, under license from Wyeth (now part of Pfizer), is a non-peptide, selective vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia associated with heart failure. Arginine vasopressin, the native V2 receptor ligand, stimulates water reabsorption via activation of V2 receptors that are expressed in the collecting ducts of the kidney. In preclinical studies, lixivaptan displayed competitive antagonist activity at V2 receptors in vitro, and increased urine volume and decreased urine osmolality in rats and dogs. The therapeutic benefits of lixivaptan are being evaluated in patients with conditions that are associated with water excess and hyponatremia. Phase II clinical trials in patients with congestive heart failure, liver cirrhosis with ascites or syndrome of inappropriate antidiuretic hormone have demonstrated that, unlike traditional diuretics, lixivaptan increases water clearance without affecting renal sodium excretion or activating the neurohormonal system. Administration of lixivaptan in combination with the diuretic furosemide has been tested in rats as well as in trials in healthy volunteers, in which the two agents were well tolerated. Ongoing phase III trials will determine the role of lixivaptan in the management of hyponatremia, especially when associated with heart failure.

Conivaptan and its role in the treatment of hyponatremia.

Hyponatremia is the most common electrolyte abnormality in hospitalized patients and is associated with increased morbidity and mortality. The recognition of the central role that arginin vasopressin plays in the pathogenesis of hyponatremia and the discovery that its actions are mediated by stimulation of V(1A) and V(2) receptors have led to the development of a new class of drugs, the arginin vasopressin antagonists. Conivaptan is a nonselective V(1A) and V(2) receptors antagonist that was the first of this class to be approved by the FDA for the management of euvolemic and hypervolemic hyponatremia. Its short-term safety and efficacy for the correction of hyponatremia have been established by multiple double-blind, randomized, controlled studies. Blocking the effects of arginin vasopressin on V(2) receptors produces aquaresis--the electrolyte-sparing excretion of water--an ideal approach to correct hypervolemic hyponatremia. The nonselectivity of conivaptan offers a theoretical advantage for its use in heart failure that may merit further exploration.