Critical evaluation of ivabradine for the management of chronic stable angina

Waqas Khan, Jeffrey S Borer
Division of Cardiovascular Medicine and the Department of Medicine, State University of New York Downstate Medical Center and College of Medicine, Brooklyn and New York, NY, USA

Abstract: Angina pectoris is the most common symptom of coronary artery disease (CAD). Angina results from an imbalance between myocardial oxygen supply and demand. Heart rate (HR) reduction can beneficially alter both elements of this imbalance by increasing diastolic filling time and reducing myocardial oxygen demand. Therefore, HR reduction is an accepted approach to angina prevention. ß-blockers, calcium-channel blockers, and long-acting nitrates are currently the cornerstones in prevention and management of stable angina. However, use of these treatments may be limited by adverse effects or development of tolerance. Thus, additional approaches to angina prevention may be useful for many patients with CAD. The discovery of the f-channel and the resulting current, I_f, that modulates the rate of spontaneous diastolic depolarization of sinoatrial nodal (SAN) myocytes led to the study of these channels as targets for lowering HR. This resulted in the development of a novel agent, ivabradine, a selective and specific I_f inhibitor. Ivabradine slows the slope of diastolic depolarization of the action potential in the SAN cells, decreasing HR at rest and during exercise, but has no other cardiovascular effects. In different subpopulations with chronic stable angina, ivabradine markedly improves exercise capacity and significantly decreases the number of ambient angina attacks. In a post-hoc analysis of the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the I_f inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction), ivabradine also reduced mortality, myocardial infarctions, and heart failure hospitalizations among patients with angina. To date, the drug has been well tolerated; transient visual disturbances and bradycardia are the only potentially important, though relatively infrequent, concerns and are readily reversible with drug cessation. This article will review and critically evaluate the data supporting use of ivabradine in patients with CAD and angina, both in preventing the symptom and, potentially, in altering the natural history of CAD.

Keywords: coronary artery disease, cardiovascular pharmacology, clinical trials