What are the indications and contraindications for ivabradine?

Ivabradine: Indications and Contraindications

Ivabradine is indicated to reduce heart failure hospitalization in adult patients with stable, symptomatic chronic HFrEF (LVEF ≤35%) who are in sinus rhythm with resting heart rate ≥70 bpm and are on maximally tolerated beta-blocker doses or have a beta-blocker contraindication. 1

Primary Indication: Heart Failure with Reduced Ejection Fraction

The FDA-approved indication is specifically for HFrEF patients meeting all of the following criteria: 1

• LVEF ≤35% 2
• NYHA class II-III symptoms (stable, symptomatic chronic heart failure) 2
• Sinus rhythm with resting heart rate ≥70 bpm 2
• On maximally tolerated beta-blocker dose OR have beta-blocker contraindication 2
• Prior heart failure hospitalization within 12 months 2

Critical Prescribing Requirements

Beta-blocker optimization must occur FIRST before considering ivabradine, as only 25% of patients in the pivotal SHIFT trial were on optimal beta-blocker doses, yet beta-blockers have proven mortality benefits that ivabradine does not. 2 The benefit of ivabradine was driven entirely by reduction in HF hospitalization, not mortality. 2

Starting dose is 5 mg twice daily with food, adjusted after 2 weeks to achieve resting heart rate 50-60 bpm (maximum 7.5 mg twice daily). 1 For patients ≥75 years old or with conduction defects, start at 2.5 mg twice daily. 2, 1

Secondary Indication: Chronic Stable Angina (Off-Label in US)

While not FDA-approved in the United States for angina, ivabradine demonstrates antianginal and anti-ischemic efficacy equivalent to beta-blockers and calcium channel blockers in patients with heart rate ≥70 bpm. 2, 3, 4, 5 In patients with hypotension where blood pressure-lowering agents are problematic, ivabradine is preferable as it reduces heart rate without affecting blood pressure or contractility. 2, 3

Absolute Contraindications

Ivabradine is absolutely contraindicated in the following conditions: 1

Cardiac Contraindications

• Acute decompensated heart failure 1
• Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block (unless functioning demand pacemaker present) 1
• Clinically significant bradycardia 1
• Pacemaker dependence (heart rate maintained exclusively by pacemaker) 1
• Atrial fibrillation or atrial flutter - ivabradine is ineffective in non-sinus rhythms and increases AF risk 6, 3, 7, 1

Drug Interactions

• Concomitant use of strong CYP3A4 inhibitors (ketoconazole, clarithromycin, nefazodone, ritonavir, nelfinavir) 1
• Concurrent use with verapamil or diltiazem - these increase ivabradine exposure and contribute to excessive heart rate lowering 2, 6, 3, 1

Other Contraindications

• Severe hepatic impairment 1
• Clinically significant hypotension 1
• Pregnancy - causes fetal toxicity and cardiac teratogenic effects in animal studies 1

Critical Safety Warnings and Monitoring

Atrial Fibrillation Risk

Ivabradine increases atrial fibrillation risk (5.0% vs 3.9% per patient-year with placebo). 1 Regularly monitor cardiac rhythm and discontinue immediately if AF develops. 6, 3, 7, 1 A history of paroxysmal AF is not an absolute contraindication, but sinus rhythm must be present at least 40% of the time. 2, 6, 3

Bradycardia and Conduction Disturbances

Bradycardia occurred in 6.0% per patient-year (2.7% symptomatic) versus 1.3% with placebo. 1 Risk factors include sinus node dysfunction, conduction defects (1st or 2nd-degree AV block, bundle branch block), ventricular dyssynchrony, and concurrent negative chronotropes (digoxin, diltiazem, verapamil, amiodarone). 1

Bradycardia may increase QT prolongation risk, potentially leading to torsade de pointes, especially with concurrent QTc-prolonging drugs. 3, 1 Avoid use in 2nd-degree AV block unless a functioning demand pacemaker is present. 1

Visual Disturbances

Phosphenes (transient visual brightness) occur in 5.4% of patients but are mild, transitory, and rarely lead to discontinuation (<1%). 3

Common Clinical Pitfalls

Do NOT use ivabradine as first-line therapy - it is adjunctive therapy only after beta-blocker optimization. 2

Do NOT combine with non-dihydropyridine calcium channel blockers (diltiazem, verapamil) - this is clearly contraindicated due to excessive heart rate lowering and increased ivabradine exposure. 2, 6, 3, 1

Do NOT use in patients with persistent or permanent atrial fibrillation - ivabradine is ineffective and contraindicated in non-sinus rhythms. 2, 6, 3

Do NOT use in patients with recent MI (within 2 months) - these patients were excluded from the SHIFT trial. 2