Characterization of the Heart Rate-Lowering Action of Ivabradine, a Selective I f Current Inhibitor

Ivabradine is a heart rate-lowering agent devoid of other direct cardiovascular effects that has been approved for treatment of patients with stable angina pectoris. The heart rate-lowering action of ivabradine, and its relation to clinical effects, was characterized during its development program in clinical and preclinical studies. Ivabradine selectively inhibits If in sinoatrial node cells, reducing diastolic depolarization rate and heart rate. At therapeutic concentrations, ivabradine has no action on other cardiac or vascular ion channels or receptors. Heart rate reduction with ivabradine is dose dependent and tends to a maximum or plateau level at high doses. With repeated oral dosing, the heart rate-lowering effect of ivabradine is near maximal in 2 weeks, maximal within 4 weeks, and is maintained without development of pharmacological tolerance during long-term treatment. On cessation of treatment, heart rate returns rapidly and progressively to pretreatment levels without rebound tachycardia or untoward cardiovascular events. In patients with stable angina, the reduction in heart rate is greatest in patients with the highest pretreatment heart rate, a property that should minimize the potential for ivabradine to produce excessive bradycardia. Heart rate lowering with ivabradine is associated with increases in indices of heart rate variability and causes no more than minimal changes in blood pressure. The characteristics of the heart rate-lowering action of ivabradine make it suitable for a range of patients including those for whom other antianginal agents may be contraindicated or not acceptably tolerated. They also suggest that management of treatment should be relatively simple in most patients.