Congestive heart failure is one of the common causes for hospitalization in the developing and developed countries. Patients with congestive heart failure develop symptoms of congestion due to elevated filling pressure in the left or right heart. A study showed that the 60 day mortality among patients presenting with congestion symptoms such as dyspnea, edema and jugular vein distention. The current modalities of therapy include diuretics, ionotropic agents and vasodilators. Although these drugs have been in the market for several years, their usage has also been shown to increase mortality. Additionally furosemide is associated with hyponatremia and hypokalemia. The new drugs such as nesiritide and levosimendan have also lost repute on account of disturbing adverse effects. Tezosentan, an endothelin receptor antagonist also showed disappointing results with no improvement in clinical outcomes or symptomatic improvement.

Patient with chronic heart failure develop elevated concentration of arginine vasopressin (AVP). Elevated AVP is said to be a maldaptation of the pathological response in acute congestive heart failure. AVP can cause excess water retention by its action on the V2 receptors in the kidney which causes increased expression of aquaporin- 2 channels. The secretion of vasopressin is regulated by fine changes in the plasma osmolality. Decreased blood volume that is sensed in the carotid sinus and aortic arch can also trigger AVP release.

Tolvaptan is a selective vasopressin 2 antagonist that has an affinity for V2 receptor than V1 receptor. Tolvaptan reduces urine osmolality by causing excess free water clearance and thus increases serum sodium concentration. It is available in strengths of 15 and 30 mg oral tablet. The drug has an oral bioavailability of 40% and reaches maximal plasma concentration by 2 to 4 hours. The plasma half life of tolvaptan is 12 hours.  In the SALT-1 and SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia) studies, 448 patients with with euvolemic or hypervolemic hyponatremia were randomized using a double-blinded, placebo-controlled study design.  The increase in the average daily area under the curve (AUC) for the Na+ concentration was significantly higher in the tolvaptan group than in the placebo group from baseline to study day 4, and day 30 (P <0.001). Within 8 hours after the first administration of tolvaptan, the serum Na+ concentrations were significantly higher in the tolvaptan group than in the placebo group for both the total patient population and the subgroups categorized to degree of hyponatremia at baseline (all P < 0.01). Significantly more patients in the tolvaptan treated group had normal Na+ values at 30 days than placebo (P < 0.001). Urine output was significantly greater in the tolvaptan groups in both studies (P < 0.001). The most common adverse events were thirst and dry mouth, and other adverse events included dizziness, hypotension, acute renal failure, sepsis, and ascites.

The EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) study is the largest study performed to date with tolvaptan in chronic heart failure patients. The study included 4133 patients with New York Heart Association class III and IV having an ejection fraction of less than 40 % and randomized them to receive tolvaptan or placebo in addition to conventional medical therapy. Data from the study showed that addition of tolvaptan 30 mg/d produced early and sustained decrease in body weight during hospitalization and after discharge as compared to placebo along with a marginal improvement in dyspnea and edema, improved hyponatremia reduced blood urea nitrogen. There was no effect on global clinical status at day 7. Post discharge mortality rates and reshospitalization rates were not affected by tolvaptan.

Tolvaptan was approved by the US FDA in 2009 for the treatment of hypervolemic or euvolemic hyponatremia in association with cirrhosis, cardiac failure and SIADH. The drug has been approved in India in August 2012. However there are no studies performed till date that have examined the safety and efficacy of tolvaptan in the Indian population. The study aims to explore the efficacy and safety of tolvaptan in the treatment of acute decompensated heart failure when added to conventional therapy over five days.