What are the indications for Ivabradine (Ivabradine)?

Indications for Ivabradine

Ivabradine is FDA-approved to reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. 1

Primary FDA-Approved Indication

• Heart failure with reduced ejection fraction (HFrEF): Ivabradine reduces heart failure hospitalization risk by 26% when added to guideline-directed medical therapy in patients with LVEF ≤35%, NYHA class II-III symptoms, sinus rhythm, and heart rate ≥70 bpm despite optimal beta-blocker therapy. 2, 1

• The drug should be considered specifically when heart rate remains elevated (>70 bpm) despite optimal β-blockade or when beta-blockers are contraindicated or not tolerated. 3, 2

Off-Label Indications Supported by Guidelines

Chronic Stable Angina

• The European Medicines Agency concluded that ivabradine (at appropriate doses up to 7.5 mg twice daily) is a useful therapeutic option to relieve symptoms and improve quality of life in patients with chronic stable angina in sinus rhythm with heart rate ≥70 bpm who cannot tolerate or whose symptoms are inadequately controlled with β-blockers. 3

• Ivabradine provides antianginal efficacy similar to other antianginal agents and offers additional benefits when combined with other antianginal drugs (except diltiazem and verapamil, which are contraindicated). 3

• The synergistic effect between β-blockers and ivabradine suggests that adding ivabradine is more efficient than uptitrating β-blockers in symptomatic patients already receiving beta-blocker therapy. 3

• Important caveat: The SIGNIFY trial showed that ivabradine does not affect outcomes in patients with preserved left ventricular function and stable coronary disease without clinical heart failure, and may potentially increase cardiovascular events in certain subgroups. 3, 4

Inappropriate Sinus Tachycardia

• Ivabradine is recommended for patients with inappropriate sinus tachycardia who are symptomatic and do not respond to or tolerate beta-blockers or calcium channel blockers. 5, 6

Specific Clinical Scenarios Where Ivabradine is Preferred

• Hypotension: In patients with hypotension, ivabradine is preferable to other antianginal agents that lower blood pressure, as it reduces heart rate without affecting blood pressure or myocardial contractility. 2

• Need for heart rate reduction without hemodynamic effects: When elevated heart rate (>70 bpm) requires reduction without affecting blood pressure or contractility, ivabradine is the appropriate choice. 2

Mechanism of Action Context

• Ivabradine selectively inhibits the If current in the sinoatrial node, reducing the slope of slow diastolic depolarization and thereby selectively reducing heart rate without negative inotropic or lusitropic effects. 3, 7

• The If inhibition is "use-dependent"—heart rate reduction is greater when initial heart rate is high and lower when initial heart rate is low. 3

Critical Contraindications

• Atrial fibrillation: Ivabradine is contraindicated in patients with atrial fibrillation, as it increases the incidence of this arrhythmia (by 0.7% absolute increase) and loses efficacy in non-sinus rhythms. 2, 5

• Combination with diltiazem or verapamil: This combination is clearly contraindicated due to excessive heart rate lowering. 3, 2

• Acute decompensated heart failure, clinically significant hypotension or bradycardia, sick sinus syndrome, sinoatrial block or 3rd degree AV block (unless pacemaker present), severe hepatic impairment, and strong CYP3A4 inhibitors. 1

Dosing Algorithm

• Standard starting dose: 5 mg twice daily with food. 1

• Vulnerable adults (age ≥75 years): Start at 2.5 mg twice daily. 2, 1

• After 2 weeks, adjust dose based on heart rate with a target of 50-60 bpm; maximum dose is 7.5 mg twice daily. 5, 1

Safety Monitoring Requirements

• Ensure patients are in sinus rhythm before initiating therapy; a history of paroxysmal atrial fibrillation is not an absolute contraindication if sinus rhythm is present at least 40% of the time. 2

• Monitor regularly for atrial fibrillation development and discontinue immediately if it occurs. 2, 5

• Visual symptoms (phosphenes) occur in 5.4% of patients but are mild, transitory, and rarely lead to treatment withdrawal (<1%). 3, 2

• Bradycardia may increase the risk of QT prolongation, which may lead to severe ventricular arrhythmias including torsade de pointes. 2