How does pure heart rate lowering impact on cardiac tolerability?

By selectively and specifically inhibiting the cardiac pacemaker I_f current, the I_f inhibitors lower heart rate without compromising myocardial contractility, haemodynamic status, or the electrophysiological properties of the heart. The first agent in this class, ivabradine, has completed its large clinical development programme, for which the cardiac tolerability data cover nearly 5000 patients, about 3500 of whom received the agent. Examination of the data shows that I_f inhibition with ivabradine constitutes an effective anti-anginal and anti-ischaemic therapy; cardiac adverse events were reported at a rate that is acceptable for a population with stable angina. Among the other adverse events, the most frequently reported were visual symptoms, which are related to retinal I_h inhibition and often resolve during treatment. Ivabradine is associated with significant increases in sinus node recovery time and uncorrected QT interval, which are related to heart rate, but had no significant effect on any other electrophysiological parameter. Correction of the QT interval using a population correction formula confirmed that ivabradine has no significant effect on the duration of ventricular repolarization, i.e. no proarrhythmic effect. Ivabradine produced no negative inotropic effect even in the presence of left ventricular (LV) systolic dysfunction. Preliminary clinical data suggest that ivabradine has a beneficial effect on cardiac performance and LV geometry. These results are currently being tested in the ongoing morBidity–mortality EvAlUaTion of the I_f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study.