2. Clinical syndrome that
can result from any
structural or functional
cardiac disorder that
impairs the ability of the
ventricle to fill with or
eject blood
3. Hyponatremia
Hyponatremia affects 15–28% of hospitalized
patients with heart failure.
Worst clinical outcome
Independent risk factor for increased mortality,
from congestive heart failure.
4. Frequency of Hyponatremia can range upto
58% in pts hospitalized for chronic HF and 49%
in cirrhosis of liver
5. Persistent hyponatremia was an independent predictor of
mortality, heart failure hospitalization, & death or
rehospitalization
every 3 mmol/L
decrease in
sodium level
increased the risk
of 6-month
mortality by 23%.
Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE)
In patients Na <120 mEq/L, mortality described as
high as 60%
6. Hyponatremia
Hypervolaem Hypovolaemi
Euvolaemic
ic c
ECF is ECF is
ECF is Normal
increased decreased
Increased Increased
AVP is
secretion of secretion of
normal
AVP AVP
Diarrhea, vomiting,
Heart Failure blood loss
SIADH
Cirrhosis of & Diuretics
liver
Glenmark Pharmaceuticals Ltd
7. Clinical presentation of Hyponatremia:
Neurological
Signs, symptoms, and consequences of hyponatremia
Serum [Na+] Serum [Na+] Serum [Na+]
130-135 mEq/L 120-130 mEq/L <120 mEq/L
Asymptomatic Malaise Headache
• Headache • Unsteadiness • Restlessness
• Nausea • Headache • Lethargy
• Vomiting • Nausea • Seizures
• Fatigue • Vomiting • Brain-stem herniation
• Confusion • Fatigue • Respiratory arrest
• Muscle cramps • Confusion • Death
• Depressed reflexes • Muscle cramps
The most severe consequences of hyponatremia include
seizures, coma & death
8. Arginine vasopressin (AVP)
A nonapeptide hormone
Synthesized in the hypothalamus and stored in the
posterior pituitary.
AVP predominately mediates serum sodium and
serum osmolality by increasing water retention in
the kidney (antidiuresis).
It’s a antidiuretic hormone
10. Conventional treatment of hyponatremia
in HF
Restriction of fluid intake (<1L/day)
Hypertonic saline administration
Diuretics
Salt capsules
But often these therapeutic approaches are
ineffective.
11. RECENT INTRODUCTION OF ARGININE
VASOPRESSIN ANTAGONISTS HAS
PROVIDED NEW THERAPEUTIC OPTION
FOR THE TREATMENT OF
HYPONATREMIA
12. Rationale of vasopressin antagonist in ADHF
Edema and hyponatremia are frequently associated
with ADHF
Levels of AVP are elevated in these patients.
It is rational that pharmacologic antagonism of V2
receptors would relieve these symptoms.
14. Tolvaptan
Oral selective vasopressin V2 receptor
antagonist without intrinsic agonist
properties.
29 times more selective for V2 receptors
than for V1a receptors
Produces significant aquaresis (water
diuresis without electrolyte excretion) and
increase in serum sodium.
15. Tolvaptan Binds to V2-receptor and blocks the activation of V2 receptor
by endogenous vasopressin. Results in increase electrolyte free water
excretion
TOLVAP
TAN
16. Single dose Tolvaptan 30 mg vs. Furosemide 80
mg in HF
Both agents produced similar diuretic
Furosemide increased urinary sodium and
potassium excretion and decreased renal blood
flow when compared with tolvaptan (P<.05 for
all).
Tolvaptan is an effective aquaretic agent with
apparently few adverse effects on renal
hemodynamics or serum electrolytes in patients
with heart failure.
Costello-Boerrigter et al Am J Physiol Renal Physiol. 2006;290:F273–F278.
17. Kinetics
Rapid absorption after oral administration
The elimination half-life 6 to 8 hours.
The apparent total
clearance of tolvaptan was
reduced by approximately
50% in patients with heart
failure
19. 3 potential indications
ADHF
Euvolemic hyponatremia/ SIADH
ADHF : drug holds the most promise, as this is by
far the most common and costly of these 2
conditions.
21. Tolvaptan in clinical trials in HF
ACTIV (Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in
Congestive Heart Failure):
Patients receiving tolvaptan experienced a 2-kg weight loss after 24 hours of
therapy versus those who received placebo
No decreases in BP or heart rate, No hypokalemia or worsening renal function
22. Tolvaptan in clinical trials in HF
SALT 1 and SALT 2 two identical trials in
pts with euvolaemic and hypervolaemic
hyponatremia associated with HF,
Cirrhosis of liver and SIADH
SALT (Study of Ascending Levels of Tolvaptan in
Hyponatremia)
23. SALT 1 and SALT 2
Tolvaptan is safe and effective in correcting serum sodium in
patients with euvolemic or hypervolemic hyponatremia.
24. SALT 1 and SALT 2 conclusion
Tolvaptan is effective in correcting hyponatremia in
patients with heart failure, cirrhosis, or syndrome of
inappropriate antidiuretic hormone
25.
26. EVEREST program
EVEREST program was designed to further assess
the short- and long-term safety and efficacy of
tolvaptan.
This program consisted of 3 trials: 2 identical
short-term trials (Trials A and B), which took place
during the inpatient period,
and 1 long-term outcome study, which included all
patients from the short-term trials who received
≥60 days of therapy with tolvaptan or placebo.
27. Tolvaptan in clinical trials in HF
Effects of Oral Tolvaptan in Patients
Hospitalized Worsening Heart Failure: The
EVEREST Outcome Trial
28. Changes in Serum sodium levels EVEREST trial
Serum sodium Conc. significantly increased in
tolvaptan group compared to placebo group. This
effect was observed since day 1 & persisted throughout
the follow-up period
29. EVEREST program: long term outcome study
N= 4,133 patients from the short-term studies who received either tolvaptan 30
mg/d or placebo for ≥60 days.
Primary end points
All-cause mortality (superiority and noninferiority)
Cardiovascular death or hospitalization for heart failure (superiority only).
Results : During a median follow-up of 9.9 months, there were no differences
between tolvaptan and placebo in all-cause mortality or the composite of
cardiovascular death or hospitalization for heart failure
Decrease in body weight and increases in serum sodium, were maintained
through 40 weeks of treatment.
an excellent safety profile with long-term therapy, demonstrating no
deleterious effects on serum electrolytes, BP, or renal function.
Overall, this study demonstrated that long-term tolvaptan therapy had no effect,
either favorable or unfavorable, on all-cause mortality, cardiovascular mortality,
or subsequent hospitalization for worsening heart failure.
30. Acute decompensated heart failure (ADHF)
Tolvaptan is safe and effective in relieving the signs
and symptoms
Set apart from other therapies as
Does not affect mortality
does not adversely affect renal function, blood pressure, or
serum potassium in this patient population.
32. Adverse events
The most common are thirst (7.8%–16%), dry
mouth (4.2%–13%), and polyuria (3.3%)
As was mentioned earlier, tolvaptan has negligible
effects on renal function, BP, cardiac rhythm, and
serum electrolytes (other than sodium), which
distinguishes it from every other therapy currently
available to treat ADHF.
33. Contraindications
Urgent need to raise serum sodium acutely
Hypovolemic hyponatremia
Concomitant use of strong CYP 3A inhibitors
Anuric patients
34. Current status
In US :
Tolvaptan is approved for the treatment
of euvolaemic and hypervolaemic
hyponatraemia associated with heart
failure, cirrhosis and SIADH
In the EU:
Tolvaptan is approved for use in adults
with hyponatraemia secondary to SIADH
35. Tolvaptan
Composition : Tolvaptan 15, and 30 mg
Dosage form: Oral tablet
Administration: once daily
36. Diuretics ,ACEI & vasopressin antagonist reduces
the number of sacks on the wagon
Hyponatremia in HF isfrequently associated with reduced diuretic efficacy due todiminished distal tubular sodium delivery and secondary hyperaldosteronism.A combination of hypertonic saline solution (HSS) andloop diuretics is often added to fluid restriction, but thismore aggressive treatment is usually advocated for patientswith severe hyponatremia who have profound neurologicalsymptoms