I f inhibition with ivabradine : electrophysiological effects and safety

Abstract

Ivabradine belongs to a new class of specific heart rate reducing agents that inhibit spontaneous pacemaker activity of the sinus node by selectively and specifically inhibiting the I(f) current; thus, allowing heart rate reduction without affecting myocardial contractility, relaxation and peripheral vascular resistance. In clinical studies involving >3500 patients and 800 healthy volunteers, ivabradine demonstrated a good safety profile during its clinical development. The most common adverse events were visual symptoms in 16.4% (n = 270) and sinus bradycardia < or =55 beats per minute in 3.2% (n = 53) of all patients treated with recommended doses of 5 mg and 7.5 mg twice daily. However, because the heart rate reducing effect of ivabradine is proportional to the resting heart rate and is associated with a clear trend to a plateau-dose effect, severe sinus bradycardia is uncommon. Less than 1% of patients withdrew from therapy because of untoward sinus bradycardia. The QT interval is prolonged in accordance with the reduction in heart rate; however, after appropriate correction for heart rate and in direct comparisons of the QT interval when the influence of the heart rate was controlled by atrial pacing, no significant effect of ivabradine on ventricular repolarization duration was demonstrated. Consequently, ivabradine has no direct torsadogenic potential. Because ivabradine also inhibits h-channels, which carry the I(h) current in the eye, it may cause luminous phenomena (phosphenes). Visual symptoms are transient, do not interfere with quality of life and have led to few withdrawals (<1%; 24 of 2545 patients); symptoms resolved during treatment in 77.5% (383 of 491) of patients. Since constitutionally active I(f) and I(h) currents are confined to the sinus node, retina and CNS neurons (ivabradine does not cross blood-brain barrier), ivabradine does not affect other tissues. The safety of ivabradine will be further assessed by postmarketing surveillance and during on-going clinical trials.