What are the indications and contraindications of ivabradine?

Ivabradine: Indications and Contraindications

Primary Indication

Ivabradine is indicated 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.

Key Clinical Indications

Heart Failure with Reduced Ejection Fraction

• Ivabradine should be considered when heart rate remains elevated (>70 bpm) despite optimal β-blockade in patients with heart failure and reduced ejection fraction 2.
• The SHIFT trial demonstrated a prognostic benefit of adding ivabradine to evidence-based optimal therapy in patients with overt heart failure and reduced ejection fraction 2.
• Ivabradine reduces the risk of heart failure hospitalization by 26% when added to guideline-directed medical therapy 2.

Chronic Stable Angina

• Ivabradine is effective for symptomatic treatment of chronic stable angina in patients with heart rate ≥70 bpm who cannot tolerate or whose symptoms are inadequately controlled with β-blockers 2.
• The drug can be safely and usefully added to β-blockers when heart rate remains elevated (≥70 bpm) 2.
• Ivabradine provides antianginal and anti-ischemic effects similar to other antianginal agents, with benefits seen in the subgroup with chronic stable angina and heart failure 2.

Specific Clinical Scenarios for Use

• In patients with hypotension (systolic BP <130 mmHg, diastolic BP <80 mmHg), ivabradine is preferable to other antianginal agents that lower blood pressure 2.
• Ivabradine is appropriate when elevated heart rate (>70 bpm) is present and requires reduction without affecting blood pressure or contractility 2.

Absolute Contraindications

Ivabradine is absolutely contraindicated in the following conditions 1:

• Acute decompensated heart failure 1
• Clinically significant hypotension 1
• Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block (unless a functioning demand pacemaker is present) 1
• Clinically significant bradycardia 1
• Severe hepatic impairment 1
• Pacemaker dependence (heart rate maintained exclusively by the pacemaker) 1
• Concomitant use of strong CYP3A4 inhibitors 1

Critical Contraindication: Atrial Fibrillation

• Ivabradine is contraindicated in patients with chronic stable angina and atrial fibrillation 2.
• Due to its selectivity for If channels, ivabradine is ineffective in patients with atrial fibrillation and may even increase the incidence of the arrhythmia 2.
• Meta-analysis showed treatment with ivabradine is associated with a relative risk of atrial fibrillation of 1.15 2.
• The SIGNIFY trial showed significantly more atrial arrhythmias in patients treated with ivabradine (5.3%) versus placebo (3.8%) 2.
• Ivabradine increases the risk of atrial fibrillation and requires regular cardiac rhythm monitoring; discontinue if atrial fibrillation develops 1.

Drug Interactions and Combination Contraindications

Absolutely Avoid

• Combining ivabradine with diltiazem or verapamil is clearly contraindicated 2.
• Concurrent use of verapamil or diltiazem will increase ivabradine exposure, may contribute to heart rate lowering, and should be avoided 1.

Use with Caution

• Avoid use in patients with 2nd-degree atrioventricular block unless a functioning demand pacemaker is present 1.
• Risk factors for bradycardia include sinus node dysfunction, conduction defects (1st or 2nd-degree AV block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (digoxin, diltiazem, verapamil, amiodarone) 1.

Dosing Considerations Based on Risk

Standard Dosing

• The recommended starting dose is 5 mg twice daily with food 1.
• Assess patient after two weeks and adjust dose to achieve resting heart rate between 50-60 bpm 1.
• Maximum dose is 7.5 mg twice daily 1.

High-Risk Patients Requiring Lower Initial Dose

• In patients with a history of conduction defects or in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily before increasing the dose 1.
• In adult patients age ≥75 years, consider starting at 2.5 mg twice daily 2.

Important Safety Warnings

Bradycardia and Conduction Disturbances

• Bradycardia, sinus arrest, and heart block have occurred with ivabradine 1.
• The rate of bradycardia was 6.0% per patient-year in patients treated with ivabradine (2.7% symptomatic; 3.4% asymptomatic) versus 1.3% per patient-year with placebo 1.
• Bradycardia may increase the risk of QT prolongation, which may lead to severe ventricular arrhythmias, including torsade de pointes 1.

Fetal Toxicity

• Ivabradine may cause fetal toxicity when administered to pregnant women based on animal studies 1.
• Advise females of reproductive potential to use effective contraception when taking ivabradine 1.

Visual Side Effects

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

Common Pitfalls to Avoid

• Do not use ivabradine in patients with any form of atrial fibrillation (persistent, chronic, or frequent paroxysmal) 2.
• Never combine with non-dihydropyridine calcium channel blockers (diltiazem, verapamil) 2.
• Do not use in patients with resting heart rate <70 bpm unless already on therapy and tolerating well 1.
• Ensure patients are in sinus rhythm before initiating therapy; a history of paroxysmal AF is not an absolute contraindication if sinus rhythm is present at least 40% of the time 2.