Novel If current inhibitor ivabradine: safety considerations

Ivabradine is a novel heart-rate-lowering agent that acts specifically on the sinoatrial node by selectively inhibiting the I(f) current, which is the current predominantly responsible for the slow diastolic depolarization of pacemaker cells. Unlike many rate-lowering agents, ivabradine reduces heart rate in a dose-dependent manner both at rest and during exercise without producing any negative inotropic or vasoconstrictor effect. The bradycardic effect of ivabradine is proportional to the resting heart rate, such that the effect tends to plateau. Thus, extreme sinus bradycardia is uncommon. Less than 1% of patients withdrew from therapy because of untoward sinus bradycardia. The QT interval is expectedly prolonged with the reduction in heart rate, but 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, although, for obvious reasons, the specific bradycardic drug should not be administered with agents which have known rate-lowering and/or QTprolonging effects. Ivabradine has little effect on the atrioventricular node and ventricular refractoriness, but because of its effect on the sinus node, it should be avoided in patients with sick sinus syndrome. The physiological significance of upregulation of the I(f) current in the His-Purkinje system and ventricular myocardium due to ionic remodeling in pathophysiological conditions, such as end-stage heart failure, and the effects of ivabradine have yet to be explored. Because ivabradine also binds to hyperpolarization voltage-gated channels which carry the I(h) current in the eye, transient, dose-dependent changes of the electroretinogram resulting in mild to moderate visual side effects (phenomes) may occur in approximately 15% of patients exposed to ivabradine. Ivabradine does not cross the blood-brain barrier and therefore, has no effect on the I(h) current in central nervous system neurons. The safety of ivabradine has been assessed in a development program that enrolled over 3,500 patients and 800 healthy volunteers in 36 countries from Europe, North and South America, Africa, Asia and Australia, 1,200 of whom were exposed to ivabradine for over 1 year. Ivabradine has been associated with a good safety profile during its clinical development and its safety will be further assessed by postmarketing surveillance and during on-going clinical trials.