La découverte de l’ivabradine (Procoralan^®), inhibiteur sélectif du courant pacemaker I_f : Une nouvelle approche thérapeutique des cardiopathies ischémiques

The discovery of the selective I_f current inhibitor ivabradine (Procoralan^®): a new therapeutic approach to ischemic heart disease

Institut de Recherches Servier, Division Pathologies cardiaques et vasculaires, 11, rue des Moulineaux, 92150 Suresnes, France

^* jean-paul.vilaine@fr.netgrs.com

Résumé

L’inhibition du courant pacemaker If est une cible idéale pour réduire de façon sélective la fréquence cardiaque et constitue une approche thérapeutique attractive pour les cardiopathies ischémiques. Les études précliniques montrent que l’ivabradine (Procoralan^®) inhibe le courant I_f du noeud sinusal, réduit de façon sélective la fréquence cardiaque au repos et à l’exercice, respecte la contractilité myocardique, la conduction auriculo-ventriculaire et la repolarisation ventriculaire et limite de façon aussi efficace qu’un β-bloquant l’ischémie myocardique induite par l’exercice, tout en préservant mieux la contractilité myocardique régionale. Ces données ont été confirmées chez l’homme, démontrant, en particulier, l’activité anti-ischémique au moins équivalente à celle d’un β-bloquant chez les patients ayant un angor stable. De grands essais cliniques en cours visent maintenant à déterminer l’intérêt de l’ivabradine dans l’insuffisance cardiaque d’origine ischémique et à tester sa capacité à améliorer le pronostic des cardiopathies ischémiques en réduisant la mortalité et la survenue d’événements cardiovasculaires majeurs.

Abstract

Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries and its prevalence is predicted to grow with the current aging of the population in these countries. In spite of the rapid pace of progress and increasing use of myocardial revascularization procedures, in particular percutaneous coronary interventions, the medical treatment of coronary artery disease has lost none of its relevance in the majority of patients, though conventional drugs have their limitations and the pharmacological approach to ischemic heart disease needs to be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement in quality of life. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most ischemic episodes, but also as an independent predictor of mortality, inhibition of the pacemaker I_f current in view of inducing a direct and selective decrease in heart rate represents an ideal conceptual target and an attractive therapeutic approach to coronary artery disease. The screening of original benzocycloalkane compounds at the Servier Research Institute resulted in the selection of ivabradine (Procoralan^®) for clinical development. Preclinical data showed that ivabradine inhibits the I_f current originating in the sinus node, induces a selective reduction in heart rate both at rest and during exercise, preserves myocardial contractility, atrioventricular conduction and ventricular repolarization and prevents exercise-induced myocardial ischemia as effectively as a β-blocker while offering better protection of regional myocardial contractility. These data were confirmed in humans, in particular the anti-ischemic efficacy of ivabradine, at least as effective as that of a β-blocker in patients with stable angina. Large ongoing clinical trials are seeking to assess the therapeutic value of ivabradine in ischemic heart failure and its potential for improving the prognosis of coronary artery disease by reducing mortality and the occurrence of major cardiovascular events.