Ivabradine

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 [1] 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 [2] 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. The follow up period was three years. The primary endpoint 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 in angina

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.

References

1. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-16.
2. Swedberg K, Komajda M, Böhm M, Borer J, Robertson M, Tavazzi L, Ford I; SHIFT Investigators. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol. 2012;59:1938-45.