Cardiophile MD

Ivabradine is a selective inhibitor of the Funny Current (I_f) or the pacemaker current in the sinoatrial (SA) node. This results in pure heart rate reduction. This can have cardiovascular benefit when added to optimal medical management. It specifically binds the Funny channel and reduces the slope for diastolic depolarization and hence prolongs diastolic duration, thereby reducing the sinus rate. The greatest effect occurs when heart rates are highest. Ivabradine does not alter the ventricular repolarization, myocardial contractility or the blood pressure.

BEAUTIFUL Trial

BEAUTIFUL Study [Ferrari R et al. The BEAUTIFUL study: randomized trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction - baseline characteristics of the study population. Cardiology. 2008;110(4):271-82.] was a randomized, double-blind, placebo controlled study involving eleven thousand coronary artery disease patients on optimal medical management. They had a heart rate above sixty per minute and an ejection fraction less than forty percent. Eighty seven percent of them were on beta blockers, eighty nine percent on angiotensin converting enzyme blockers or angiotensin receptor blockers and twenty seven percent were on aldosterone antagonists. They were followed up for three year. The initial dosage was five milligrams twice daily and if the heart rate was more than sixty per minute at two weeks, it was increased to seven and a half milligrams.The primary endpoint was a composite of cardiovascular death and hospitalizations for myocardial infarctions and congestive heart failure. A subgroup analysis was also done in those with a basal heart rate above seventy per minute, which constituted about five thousand and four hundred patients. Though there was no difference in total cardiovascular mortality, ivabradine was found to reduce readmissions due to coronary artery disease in those with initial resting heart rate above seventy per minute. The rates of percutaneous coronary interventions were also reduced by thirty percent.

SHIFT Trial

SHIFT study was a randomized, double-blinded, placebo controlled trial involving about
six thousand and five hundred subjects in Class II – IV heart failure with left ventricular ejection fraction less than thirty five percent and a heart rate above seventy beats per minute. They have had an admission for heart failure in the previous two months and was on optimal medical management. Ninety percent of them were on beta blocker, eighty four percent on angiotensin converting enzyme inhibitors or angiotensin receptor blockers. They follow up period was three years. The primary end point was a composite of cardiovascular death or hospitalization for heart failure. Though there was no difference in the total cardiovascular mortality, ivabradine was found to reduce mortality due to heart failure and admissions for heart failure.

Indication for ivabradine

Currently ivabradine in indicated for the treatment of chronic stable angina in those with normal sinus rhythm, specially in those who cannot take or tolerate beta-blockers and in them whose angina is not controlled with beta-blockers and having a heart rate above sixty beats per minute.

Tolvaptan is vasopressin antagonist which acts on the V2 receptors in the renal tubules. Activation of V2 receptors increases water permeability in the renal collecting duct resulting in passive reabsorption of water. This causes aquaresis or free water clearance. Syndrome of inappropriate anti-diuretic hormone secretion (SIADH), heart failure and cirrhosis can be associated with increased secretion of arginine vasopressin (AVP). This leads to water retention or inadequate water excretion and hyponatremia (dilutional hyponatremia). Tolvaptan binds to V2 receptors and induces excretion of electrolyte-free water without altering the electrolyte excretion.

Tolvaptan: Indications

Tolvaptan is indicated for the treatment of hypervolemic and euvolemic hyponatremia, with serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction. Such situations occur with heart failure, cirrhosis, and SIADH.

Tolvaptan – Adverse Effects

As expected from its therapeutic action, important adverse effects of tolvaptan are increased thirst, dryness of mouth, increased urination and sometime dehydration leading to hypotension and syncope. Gastrointestinal hemorrhage may occur in those with cirrhosis liver. Hypernatremia and hyperkalemia are potential problems and very rarely osmotic demyelination is possible due to rapid correction of hyponatremia.

Tolvaptan – Contraindications

Tolvaptan is not the treatment when there is an urgent need to raise serum sodium acutely. It should also be proscribed in those with inability to sense or appropriately respond to thirst. Hypovolemic hyponatremia is not an indication for tolvaptan therapy. Concomitant use of strong CYP 3A inhibitors can increase the effect of tolvaptan. There is no point in giving tolvaptan to anuric patients as no fluid is delivered to renal collecting ducts, the site of action of tolvaptan.

Tolvaptan – Precautions

Serum sodium has to be closely monitored while initiating tolvaptan therapy. Too rapid correction (>12 mEq/L/24 hours) can cause osmotic demyelination (the erstwhile central pontine myelinolysis). Slower rates of correction may be considered in those susceptible patients who include those with severe malnutrition, alcoholism and advanced liver disease.