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DR AWADHESH SHARMA
Tolvaptan- emerging drug
HEART FAILURE
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
Hyponatremia
Hyponatremia affects 15–28% of hospitalized patients with heart failure.
Worst clinical outcome
Independent risk factor for increased mortality, from congestive heart failure.
Frequency of Hyponatremia can range upto 58% in pts hospitalized for chronic HF and 49% in cirrhosis of liver
Drugs 2010
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%
Cardiology in review 2010:18;313-321
Hyponatremia
Glenmark Pharmaceuticals Ltd
Hypervolaemic
Euvolaemic
Hypovolaemic
ECF is increased
ECF is Normal
ECF is decreased
Increased secretion of
AVP
Increased secretion of
AVP
AVP is normal
SIADH
Diarrhea, vomiting, blood
loss & Diuretics
Heart Failure Cirrhosis of
liver
Clinical presentation of Hyponatremia: Neurological
Signs, symptoms, and consequences of hyponatremia
Serum [Na+] 130-135 mEq/L
Serum [Na+] 120-130 mEq/L
Serum [Na+] <120 mEq/L
Asymptomatic• Headache• Nausea
• Vomiting• Fatigue
• Confusion• Muscle cramps
• Depressed reflexes
Malaise• Unsteadiness
• Headache• Nausea
• Vomiting• Fatigue
• Confusion• Muscle cramps
Headache• Restlessness
• Lethargy• Seizures
• Brain-stem herniation• Respiratory arrest
• Death
The most severe consequences of hyponatremia include
seizures, coma & death
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
Vasopressin Receptor Location & Functions
(KI 2006)
Free water reabsorptionon
Conventional treatment of hyponatremia in HF
Restriction of fluid intake (<1L/day)Hypertonic saline administrationDiureticsSalt capsules
But often these therapeutic approaches are ineffective.
RECENT INTRODUCTION OF ARGININE VASOPRESSIN
ANTAGONISTS HAS PROVIDED NEW THERAPEUTIC OPTION FOR THE TREATMENT OF HYPONATREMIA
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.
Vasopressin receptor antagonist
ConivaptanTolvaptanLixivaptanSatavaptan
Conivaptan(V2 & V1a),i/v formulation only
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.
Tolvaptan Binds to V2-receptor and blocks the activation of V2 receptor by endogenous vasopressin. Results in increase
electrolyte free water excretion
TOLVAPTAN
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.
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
Tolvaptan
3 potential indications
ADHFEuvolemic hyponatremia/ SIADH
ADHF : drug holds the most promise, as this is by far the most common and costly of these 2 conditions.
ACUTE DECOMPENSATED
HEART FAILURE (ADHF)
Tolvaptan
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
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)
SALT 1 and SALT 2
Tolvaptan is safe and effective in correcting serum sodium in patients with euvolemic or hypervolemic
hyponatremia.
SALT 1 and SALT 2 conclusion
Tolvaptan is effective in correcting hyponatremia in patients with heart failure, cirrhosis, or syndrome of inappropriate antidiuretic hormone
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.
Tolvaptan in clinical trials in HF
Effects of Oral Tolvaptan in Patients Hospitalized Worsening Heart Failure: The EVEREST Outcome Trial
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
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.
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.
TOLVAPTAN
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.
Contraindications
Urgent need to raise serum sodium acutelyHypovolemic hyponatremiaConcomitant use of strong CYP 3A inhibitorsAnuric patients
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
Tolvaptan
Composition : Tolvaptan 15, and 30 mg
Dosage form: Oral tablet
Administration: once daily
Diuretics ,ACEI & vasopressin antagonist reduces the number of sacks on the wagon
THANK YOU
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