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

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