Efficacy and safety of tolvaptan in acute decompensated heart failure

Congestive heart failure is one ofthe common causes for hospitalization in the developing and developedcountries. Patients with congestive heart failure develop symptoms of congestiondue to elevated filling pressure in the left or right heart. A study showedthat the 60 day mortality among patients presenting with congestion symptomssuch as dyspnea, edema and jugular vein distention. The current modalities oftherapy include diuretics, ionotropic agents and vasodilators. Although thesedrugs have been in the market for several years, their usage has also beenshown to increase mortality. Additionally furosemide is associated withhyponatremia and hypokalemia. The new drugs such as nesiritide and levosimendanhave also lost repute on account of disturbing adverse effects. Tezosentan, anendothelin receptor antagonist also showed disappointing results with noimprovement in clinical outcomes or symptomatic improvement.

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

Tolvaptan is aselective vasopressin 2 antagonist that has an affinity for V2 receptor than V1receptor. Tolvaptan reduces urine osmolality by causing excess free waterclearance and thus increases serum sodium concentration. It is available instrengths of 15 and 30 mg oral tablet. The drug has an oral bioavailability of40% and reaches maximal plasma concentration by 2 to 4 hours. The plasma halflife of tolvaptan is 12 hours.  In theSALT-1 and SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia)studies, 448 patients with with euvolemic or hypervolemic hyponatremia wererandomized using a double-blinded, placebo-controlled study design.  The increase in the average daily area underthe curve (AUC) for the Na+ concentration was significantly higher in thetolvaptan group than in the placebo group from baseline to study day 4, and day30 (P <0.001). Within 8 hours after the first administration of tolvaptan,the serum Na+ concentrations were significantly higher in the tolvaptan groupthan in the placebo group for both the total patient population and thesubgroups 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 significantlygreater in the tolvaptan groups in both studies (P < 0.001). The most commonadverse events were thirst and dry mouth, and other adverse events includeddizziness, hypotension, acute renal failure, sepsis, and ascites.

The EVEREST (Efficacyof Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) studyis the largest study performed to date with tolvaptan in chronic heart failurepatients. The study included 4133 patients with New York Heart Associationclass III and IV having an ejection fraction of less than 40 % and randomizedthem to receive tolvaptan or placebo in addition to conventional medical therapy.Data from the study showed that addition of tolvaptan 30 mg/d produced earlyand sustained decrease in body weight during hospitalization and afterdischarge as compared to placebo along with a marginal improvement in dyspneaand edema, improved hyponatremia reduced blood urea nitrogen. There was noeffect on global clinical status at day 7. Post discharge mortality rates andreshospitalization rates were not affected by tolvaptan.

Tolvaptan was approved by the USFDA in 2009 for the treatment of hypervolemic or euvolemic hyponatremia inassociation with cirrhosis, cardiac failure and SIADH. The drug has beenapproved in India in August 2012. However there are no studies performed tilldate that have examined the safety and efficacy of tolvaptan in the Indianpopulation. The study aims to explore the efficacy and safety of tolvaptan inthe treatment of acute decompensated heart failure when added to conventionaltherapy over five days.