Advances in Cardiovascular Pharmacotherapy. II. Ivabradine, an Inhibitor of the Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel.

Ivabradine selectively reduces heart rate by inhibiting the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the sinoatrial node. Unlike other medications that produce negative chronotropic effects [beta-blockers, calcium channel blockers], ivabradine does not affect systemic, pulmonary, and coronary hemodynamics. Despite several proof-of-concept clinical studies suggesting that ivabradine may exert anti-ischemic effects, two large randomized trials did not support its use in patients with chronic stable angina. Preliminary data also did not support the use of ivabradine in patients with acute ST-segment elevation myocardial infarction or acutely decompensated heart failure. However, ivabradine improved outcome in patients with heart failure with reduced ejection fraction (HFrEF), leading to its approval by the Food and Drug Administration, but the drug failed to do so in those with heart failure with preserved ejection fraction (HFpEF). Ivabradine may also be useful in cardiac electrophysiology disorders characterized by tachycardia (e.g., inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome), but it has not yet gained wide acceptance for these indications. In this article, the authors briefly review the structure and function of the cardiac HCN channel; discuss the development and actions of drugs, including ivabradine, that modulate the channel's activity; describe in detail the potential clinical applications of ivabradine in patients with coronary artery disease, HFrEF and HFpEF, and cardiac electrophysiology; comment on the adverse effects of ivabradine therapy; and finally, consider the potential anesthetic implications of ivabradine in patients undergoing noncardiac and cardiac surgery.