The discovery of the selective I(f) current inhibitor ivabradine. A new therapeutic approach to ischemic heart disease

Abstract

Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries, despite the advances in pharmacological treatments, risk factor control and the beneficial effect of myocardial revascularization procedures. Medical anti-ischemic treatment is still essential in most patients, but should be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement of the quality of life and symptom control. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most of the ischemic episodes but also as an independent predictor of mortality, inhibition of the pacemaker I(f) current to induce a direct and selective decrease in heart rate represents an attractive therapeutic approach for coronary artery disease. The screening of original benzocycloalkane compounds, at Servier Research Institute, has led to the selection of ivabradine for clinical development. Preclinical data showed that ivabradine inhibits the I(f) current of the sinus node, induces a selective reduction in heart rate, both at rest and during exercise, preserves myocardial contractility, atrio-ventricular conduction and ventricular repolarization. Ivabradine prevents exercise-induced myocardial ischemia as effectively as a beta-blocker while offering better protection of regional myocardial contractility. These data have been confirmed in humans, and in particular, the anti-ischemic efficacy of ivabradine, at least as effective as a beta-blocker, in patients with stable angina. Large ongoing clinical trials aim to assess the therapeutic value of ivabradine to improve the prognosis of patients with stable coronary disease and left ventricular systolic dysfunction by reducing mortality and the occurrence of major cardiovascular events.