1. Ian M. Carrese PA-S2 South University PA Program July 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
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

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/euvolemic hyponatremia, 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/euvolemic hyponatremia (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