An Expert Report on Ivabradine (DB09083)

Executive Summary

[Ivabradine is a first-in-class cardiovascular therapeutic agent that functions as a selective and specific inhibitor of the cardiac pacemaker current, designated as If​.][1][ This unique mechanism of action establishes it as a "pure" heart-rate-lowering drug, distinguishing it from traditional negative chronotropic agents such as beta-blockers and non-dihydropyridine calcium channel blockers.][3][ Its primary therapeutic effect is achieved by acting on the sinoatrial (SA) node, the heart's natural pacemaker, to reduce heart rate without deleteriously affecting myocardial contractility, intracardiac conduction, or ventricular repolarization.][5]

[The clinical utility of ivabradine is most firmly established in the management of chronic heart failure with reduced ejection fraction (HFrEF). The landmark Systolic Heart failure treatment with the If​ inhibitor ivabradine Trial (SHIFT) demonstrated that, when added to optimal guideline-directed medical therapy, ivabradine significantly reduces the risk of hospitalization for worsening heart failure in a specific subset of patients.][3][ Its role in chronic stable angina is more complex; while it provides symptomatic relief comparable to standard agents, its impact on hard cardiovascular outcomes has been a subject of considerable investigation, leading to different regulatory approvals globally.][1]

[This regulatory divergence is a key feature of ivabradine's clinical landscape. The U.S. Food and Drug Administration (FDA) has approved it primarily for the HFrEF indication validated by the SHIFT trial.][10][ In contrast, the European Medicines Agency (EMA) has authorized its use for both HFrEF and the symptomatic treatment of chronic stable angina, reflecting a different interpretation of the overall risk-benefit profile.][12]