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

Ian M. Carrese PA-S2 South University PA Program July 21, 2012. Hyponatremia , Heart Failure, and the role of Tolvaptan ( Samsca ). Hyponatremia , Heart Failure, and the role of Tolvaptan ( Samsca ). Authors: John B. O’Connell, MD and Addis Alemayehu , PharmD

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

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

  2. Hyponatremia, Heart Failure, and the role of Tolvaptan (Samsca) Authors: John B. O’Connell, MD and Addis Alemayehu, PharmD Funding: Heart Failure Consultants, Sunset, SC and Otsuka America Pharmaceutical, Inc., Rockville, MD Journal: Postgraduate Medicine

  3. Disclaimer Otsuka funded this study and is the manufacturer of Tolvaptan Otsukamanufactures 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

  4. Pharmacology Tolvaptan is a selective V2-receptor antagonist Conivaptan is a dual V1A/V2-receptor antagonist This study suggests that Tolvaptan has a 1.8-times greater affinity for the V2-receptor than Arginine Vasopressin (AVP)

  5. Physiology Review 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

  6. Objectives Does Tolvaptan increase serum Na in patients with hyper/euvolemichyponatremia, especially HF patients? Is it safe to use, are there any adverse affects of Tolvaptan usage?

  7. Design 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

  8. Design SALT-1 and SALT-2 trials Hospitalized patients only Randomized, controlled, double-blinded placebo phase 3 study All patients had hyper/euvolemichyponatremia (N=448) 31% of patients had HF The remainder suffered from SIADH or cirrhosis of the liver as an underlying cause

  9. Design 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

  10. Setting/Patients 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

  11. Inclusion/Exclusion 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

  12. Intervention for SALT-1 and SALT-2 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

  13. EVEREST Intervention 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

  14. Main Outcome of SALT-1 and SALT-2

  15. Main Outcome: EVEREST There was a significant decrease in both body weight and patient-assessed dyspnea (P<0.001 for both statistics) Decreased body weight was associated with corresponding decreased in symptoms (dyspnea) This suggests Tolvaptan helped reduce pulmonary congestion by correcting hyponatremia

  16. Results of SALT-1 and SALT-2 Suggest that Tolvaptan was superior to placebo in safely correcting hyponatremia in patients with presenting Na levels of < 130 mEq/L and < 125 mEq After 7 days of discontinuation of Tolvaptan, Na levels returned to baseline levels of hyponatremia similar to those on placebo

  17. Results of SALT-1 and SALT-2 Treatment with Tolvaptan was superior to fluid restriction

  18. Results of EVEREST Tolvaptan reduced physician-assessed signs of HF such as orthopnea, dyspnea and the presence of rales on physical exam A lower mean dose of furosemide was needed to treat these patients This suggests that Tolvaptan may reduce the need of loop diuretics when diuresing HF patients

  19. Conclusion In the SALT-1, SALT-2 and EVEREST studies, treatment with Tolvaptan was superior to both placebo and fluid restriction in concert or used singularly

  20. Comments Although it is extremely difficult financially to conduct third party studies of most drugs, especially “boutique” drugs like Tolvaptan and Conivaptan, results from studies funded by the manufacturing pharmaceutical company should be interpreted with a grain of Na (pun intended)

  21. Comments Tolvaptan is extremely expensive, but may be a necessary treatment for hyponatremia that is refractory to fluid restriction and other measures in HF patients. One 15mg pill is $300 A one month supply is $3000-$10k It is not covered by Medicare I would give the studies a Class 1b rating on statistical significance

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