Ian M. Carrese PA-S2 South University PA Program July 21, 2012

Ian M. Carrese PA-S2South University PA ProgramJuly 21, 2012Hyponatremia, Heart Failure, and the role of Tolvaptan (Samsca)

Hyponatremia, Heart Failure, and the role of Tolvaptan (Samsca)Authors: John B. OConnell, MD and Addis Alemayehu, PharmDFunding: Heart Failure Consultants, Sunset, SC and Otsuka America Pharmaceutical, Inc., Rockville, MDJournal: Postgraduate MedicineDisclaimerOtsuka funded this study and is the manufacturer of TolvaptanOtsuka 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

PharmacologyTolvaptan is a selective V2-receptor antagonistConivaptan is a dual V1A/V2-receptor antagonistThis study suggests that Tolvaptan has a 1.8-times greater affinity for the V2-receptor than Arginine Vasopressin (AVP)Physiology ReviewHyponatremia is characterized by serum Na levels of less than 135 mEq/LNa is freely filterable at the glomerulusH20 reabsorption is independent of ADH until it reaches the collecting duct systemHyponatremia is a common finding in heart failure (HF) patients

ObjectivesDoes 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?DesignACTIV trial in CHFEarly randomized phase 2 trial

VICTOR trialRandomized, controlled phase 2 trialNYHA Class II-III HF with LVEF 40% and signs of congestion such as rales and edemaDesignSALT-1 and SALT-2 trialsHospitalized patients onlyRandomized, controlled, double-blinded placebo phase 3 studyAll patients had hyper/euvolemic hyponatremia (N=448)31% of patients had HFThe remainder suffered from SIADH or cirrhosis of the liver as an underlying causeDesignEVEREST Study: Efficacy of Vasopressin Antagonism in HF Outcome Study with TolvaptanPhase 3 randomized, controlled, double-blinded placebo study4133 hospitalized patients with HFMust be allocated and selected for study within 48hrs of admissionDid not specify NYHA classificationSetting/PatientsThis presentation will focus on the SALT-1, SALT-2 and EVEREST trialsThere was no information in the article specifying age, race, socioeconomic statistics

Inclusion/ExclusionSALT-1, SALT-2 and EVEREST studies were only conducted on inpatientsSALT-1 and SALT-2 patient populations must have met the criteria for NYHA Class II-III HFIntervention for SALT-1 and SALT-2Patients were randomized to Tolvaptan or placebo for 30 daysStarting dose was 15mg daily with a F/U assessment in 7 daysDuring the first four days, Tolvaptan was titrated up to 60mg daily in order to achieve serum Na level 135mEq/LMost patients were discharged on day four, but a 30 day F/U was conductedEVEREST InterventionPatients received Tolvaptan 30mg or placebo within 48hrs of admissionAdditional HF medications were administered at the discretion of the physicianPatients received Tolvaptan for a minimum of 60 daysMain Outcome of SALT-1 and SALT-2

Main Outcome: EVERESTThere was a significant decrease in both body weight and patient-assessed dyspnea (P