Introduction Management of patients with acute decompensated heart failure (HF) and hyponatremia is challenging. Indeed, loop diuretics, the mainstay therapy in acute HF, achieve the necessary luid removal, but are also known for their side efects and to lead to further electrolyte imbalances. 1 Deined as a serum sodium concentration of <135 mEq/L, hyponatremia is seen in more than 20% of patients hospitalized with heart failure. 2 In these patients, hyponatremia is an independent and signiicant predictor of mortality and HF-related morbidity as well as hospital readmission. 2–4 An analysis of data from 48,612 heart failure patients enrolled in the OPTIMIZE-HF registry demonstrated that for each 3-mmol/L decrease in serum sodium concentration below 140 mmol/L, the risk of in-hospital mortality increased by 19.5% among all patients. 2 Although the association between hyponatremia and poor clinical outcomes is well documented, a causal link has not been established. Cognitive impairment frequently observed as clouded mental state, impaired mental status, confusion, lethargy, and fatigue is also common in patients with hyponatremia. However, it is unknown whether hyponatremia is associated with cognitive dysfunction in patients with heart failure and whether improvements in sodium concentrations would also result in improved cognition. 5 The hyponatremia and fluid retention seen in patients with acute and chronic heart failure is due at least in part to elevated levels of arginine vasopressin (AVP). 6–9 AVP secretion is induced by changes in serum osmolality and by nonosmotic factors, including low cardiac output and low systemic blood pressure. 10,11 Vasopressin promotes water retention by binding to vasopressin V 2 receptors located in the distal tubules of the nephron, which induces free water reabsorption by increasing the number of available aquaporin-2 water channels in the apical membrane of renal collecting duct cells. 12,13 hus, it is not surprising that a group of vasopressin receptor antagonists including conivaptan, lixivaptan, satavaptan, and tolvaptan have all demonstrated the ability to increase serum sodium levels in patients with hyponatremia. 14 he V 2 -selective vasopressin antagonist tolvaptan has been evaluated in a series of clinical trials and is approved by the Food and Drug Administration for the treatment of hyponatremia. However, studies designed to assess the efects of tolvaptan in patients with hyponatremia included only 14 heart failure patients in a study by Gheorghiade et al. 15 and 68 and 70 patients in the Salt 1 and Salt 2 studies, respectively. 16 Investigators assessed the efects of three diferent doses of tolvaptan on change in body weight in 254 patients with let ventricular; however, only 70 of the patients had hyponatremia. 17 More recently, in the Eicacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) 4113 hospitalized with heart failure were randomized to 30 mg of tolvaptan or placebo—but only 318 patients had a serum sodium less than 134 mEq/L. 18,19 hus, there is considerable equipoise Rationale and Design of the Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (THE BALANCE) Study William T. Abraham, M.D. 1 , Juan M. Aranda, M.D. 2 , John P. Boehmer, M.D. 3 , Uri Elkayam, M.D. 4 , Edward M. Gilbert, M.D. 5 , Stephen S. Gottlieb, M.D. 6 , Gerd Hasenfuß, M.D. 7 , Marrick Kukin, M.D. 8 , Brian D. Lowes, M.D. 9 , John B. O’Connell, M.D. 10 , Luigi Tavazzi, M.D. 11 , Arthur M. Feldman, M.D., Ph.D. 12 , Barry Ticho, M.D., Ph.D. 13 , and Cesare Orlandi, M.D. 14 Clinical Trial Design 1 Division of Cardiovascular Medicine, The Ohio State University Heart Center, Columbus, Ohio, USA; 2 Division of Cardiovascular Medicine, University of Florida Medical Center, Gainesville, Florida, USA; 3 Penn State Heart & Vascular Institute, Penn State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA; 4 Keck School of Medicine, University of Southern California Medical Center, Los Angeles, California, USA; 5 Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA; 6 Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland, USA; 7 Department of Cardiology and Pneumology, Heart Center, Georg-August University Göttingen, Göttingen, Germany; 8 Division of Cardiology, St. Luke’s–Roosevelt Hospital Center, New York, New York, USA; 9 Cardiac and Vascular Center, University of Colorado at Denver Health Sciences Center, Denver, Colorado, USA; 10 Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; 11 GVM Hospitals of Care and Research, Cotignola, Italy; 12 Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA, 13 Biogen Idec, Inc., Cambridge, Massachusetts, USA; 14 Cardiokine, Inc., Philadelphia, Pennsylvania, USA. Dr. Andre Terzic served as the guest Editor in Chief on this manuscript. Correspondence: WT Abraham (william.abraham@osumc.edu) DOI: 10.1111/j.1752-8062.2010.00217.x WWW.CTSJOURNAL.COM 249 VOLUME 3 • ISSUE 5 Abstract Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V 2 -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evalu- ation (BALANCE) study is a randomized, double-blind, placebo-controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N = 650), signs of congestion and serum sodium con- centrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital-free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30-day safety follow-up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure. Clin Trans Sci 2010; Volume 3: 249–253 Keywords: hyponatremia, arginine vasopressin, heart failure