Clinical syndrome thatcan result from anystructural or functionalcardiac disorder thatimpairs the ability of theventricle to fill with oreject 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 upto58% in pts hospitalized for chronic HF and 49%in cirrhosis of liver
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%
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 liverGlenmark Pharmaceuticals Ltd
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
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 Free water reabsorpti onon (KI 2006)
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.
RECENT INTRODUCTION OF ARGININE VASOPRESSIN ANTAGONISTS HASPROVIDED 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.
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 TOLVAP TAN
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
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.
TolvaptanACUTE DECOMPENSATEDHEART FAILURE (ADHF)
Tolvaptan in clinical trials in HFACTIV (Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist inCongestive Heart Failure):Patients receiving tolvaptan experienced a 2-kg weight loss after 24 hours oftherapy versus those who received placeboNo decreases in BP or heart rate, No hypokalemia or worsening renal function
Tolvaptan in clinical trials in HFSALT 1 and SALT 2 two identical trials inpts with euvolaemic and hypervolaemichyponatremia associated with HF,Cirrhosis of liver and SIADH SALT (Study of Ascending Levels of Tolvaptan in Hyponatremia)
SALT 1 and SALT 2Tolvaptan 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 HFEffects of Oral Tolvaptan in PatientsHospitalized Worsening Heart Failure: TheEVEREST 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.
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 acutely Hypovolemic hyponatremia Concomitant use of strong CYP 3A inhibitors Anuric 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