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Hyponatremia, Heart Failure, and the role of Tolvaptan (Samsca) Slide 2 Authors: John B. OConnell, MD and Addis Alemayehu, PharmD Funding: Heart Failure Consultants, Sunset, SC and Otsuka America Pharmaceutical, Inc., Rockville, MD Journal: Postgraduate Medicine Slide 3 Otsuka funded this study and is the manufacturer of Tolvaptan Otsuka manufactures Tolvaptan and there is currently only one other drug in its class: Conivaptan (Vaprisol) Both drugs are Vasopressin (ADH) receptor antagonists causing the excretion of free H20 Slide 4 Tolvaptan is a selective V 2 -receptor antagonist Conivaptan is a dual V 1A /V 2 -receptor antagonist This study suggests that Tolvaptan has a 1.8-times greater affinity for the V 2 - receptor than Arginine Vasopressin (AVP) Slide 5 Hyponatremia is characterized by serum Na levels of less than 135 mEq/L Na is freely filterable at the glomerulus H20 reabsorption is independent of ADH until it reaches the collecting duct system Hyponatremia is a common finding in heart failure (HF) patients Slide 6 Does Tolvaptan increase serum Na in patients with hyper/euvolemic hyponatremia, especially HF patients? Is it safe to use, are there any adverse affects of Tolvaptan usage? Slide 7 ACTIV trial in CHF Early randomized phase 2 trial VICTOR trial Randomized, controlled phase 2 trial NYHA Class II-III HF with LVEF 40% and signs of congestion such as rales and edema Slide 8 SALT-1 and SALT-2 trials Hospitalized patients only Randomized, controlled, double-blinded placebo phase 3 study All patients had hyper/euvolemic hyponatremia (N=448) 31% of patients had HF The remainder suffered from SIADH or cirrhosis of the liver as an underlying cause Slide 9 EVEREST Study: Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan Phase 3 randomized, controlled, double- blinded placebo study 4133 hospitalized patients with HF Must be allocated and selected for study within 48hrs of admission Did not specify NYHA classification Slide 10 This presentation will focus on the SALT- 1, SALT-2 and EVEREST trials There was no information in the article specifying age, race, socioeconomic statistics Slide 11 SALT-1, SALT-2 and EVEREST studies were only conducted on inpatients SALT-1 and SALT-2 patient populations must have met the criteria for NYHA Class II-III HF Slide 12 Patients were randomized to Tolvaptan or placebo for 30 days Starting dose was 15mg daily with a F/U assessment in 7 days During the first four days, Tolvaptan was titrated up to 60mg daily in order to achieve serum Na level 135mEq/L Most patients were discharged on day four, but a 30 day F/U was conducted Slide 13 Patients received Tolvaptan 30mg or placebo within 48hrs of admission Additional HF medications were administered at the discretion of the physician Patients received Tolvaptan for a minimum of 60 days Slide 14 Slide 15 There was a significant decrease in both body weight and patient-assessed dyspnea (P