Heart rate slowing by If inhibition:: therapeutic utility from clinical trials

Myocardial ischaemia results from an excess of myocardial oxygen demand in comparison with available supply. Heart rate is a primary determinant of oxygen demand and thus its reduction is a well-accepted strategy for the prevention of angina pectoris, a highly debilitating symptom of coronary artery disease, but does not usually presage imminent myocardial infarction or death. Currently available drugs that reduce heart rate are commonly associated with adverse effects, which may limit their use in many patients. Therefore, it is important to develop additional alternatives with different pharmacological effects. The inward sodium-potassium-mediated I-f current of sinoatrial node cell membranes (functionally absent elsewhere in the myocardium) modulates sinoatrial diastolic depolarization rate and, thus, heart rate. Heart rate reduction can be achieved by modulating or blocking this current. Ivabradine, a highly selective I-f current inhibitor, can reduce heart rate by clinically useful decrements at doses that are devoid of other direct cardiovascular effects and generally are well tolerated. The only dose-related adverse effects are visual (phosphenes, stroboscopic effect, and non-typical blurred vision), which occur in 2-15% of patients receiving 2.5-10 mg orally twice daily, usually are no more than mildly bothersome, are fully reversible spontaneously or with cessation of therapy, and are not associated with retinal damage. Clinical trials involving more than 5000 patients indicate that ivabradine as monotherapy is effective in preventing angina. Effects are seen at doses as low as 2.5 mg twice daily. Preliminary data suggest that when employed at 7.5 or 10 mg twice daily, angina prevention with ivabradine is equivalent to that achieved with atenolol 100 mg daily and with amlodipine 10 mg daily.