What are the indications for Ivabradine (Ivabradine) in older adults with symptomatic stable angina or heart failure with reduced ejection fraction, potentially with comorbidities such as hypertension, diabetes, or prior myocardial infarction?

Ivabradine Indications

Ivabradine is FDA-approved to reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with 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 (HFrEF)

Patient Selection Criteria

• Patients must meet ALL of the following criteria: 2, 3, 4
  • LVEF ≤35%
  • NYHA class II-III symptoms (stable, symptomatic chronic heart failure)
  • Sinus rhythm at rest
  • Resting heart rate ≥70 bpm
  • On maximally tolerated beta-blocker dose OR have beta-blocker contraindication
  • History of heart failure hospitalization within the preceding 12 months strengthens the indication 4

Critical Sequencing: Beta-Blocker Optimization First

• Beta-blockers must be optimized BEFORE considering ivabradine, as beta-blockers have proven mortality benefits while ivabradine does not 2, 3
• Only 25% of patients in the pivotal SHIFT trial were on optimal beta-blocker doses, yet the trial still showed benefit—this does not justify skipping beta-blocker optimization 2, 3
• Ivabradine is adjunctive therapy only, not first-line or foundational treatment 4

Expected Clinical Benefit

• Ivabradine reduces heart failure hospitalizations by approximately 20% but does NOT reduce mortality 3, 4
• The benefit is driven entirely by reduction in HF hospitalization, not cardiovascular death 2, 3
• Mean heart rate reduction of 6-8 bpm from baseline with mean LVEF improvement of 3.24% 4

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

When to Consider for Angina

• Ivabradine is preferable in patients with hypotension (systolic <130 mmHg or diastolic <80 mmHg) where blood pressure-lowering antianginal agents would impair coronary perfusion 2
• Demonstrates antianginal and anti-ischemic efficacy equivalent to beta-blockers and calcium channel blockers in patients with heart rate ≥70 bpm 3
• Consider when beta-blockers are contraindicated or inadequately control symptoms 2

Angina with Left Ventricular Dysfunction

• In patients with chronic stable angina and left ventricular systolic dysfunction, beta-blockers remain first-line due to mortality benefit 2
• If heart rate remains >70 bpm despite optimal beta-blockade, ivabradine should be considered 2

Absolute Contraindications

Ivabradine is contraindicated in: 1, 3, 5

• Acute decompensated heart failure
• Clinically significant hypotension (blood pressure <90/50 mmHg)
• Sick sinus syndrome, sinoatrial block, or 3rd degree AV block without functioning pacemaker
• Clinically significant bradycardia
• Severe hepatic impairment
• Pacemaker dependence (heart rate maintained exclusively by pacemaker)
• Atrial fibrillation—ivabradine is contraindicated in patients with chronic stable angina and atrial fibrillation 2, 5
• Concomitant use of strong CYP3A4 inhibitors
• Concurrent use with non-dihydropyridine calcium channel blockers (verapamil, diltiazem) 5, 4

Critical Safety Warnings

Atrial Fibrillation Risk

• Ivabradine increases atrial fibrillation risk: 5.0% per patient-year versus 3.9% with placebo 3, 1
• Regularly monitor cardiac rhythm and discontinue ivabradine immediately if atrial fibrillation develops 3, 5
• Ivabradine is ineffective in patients with atrial fibrillation due to selectivity for If channels 2
• Patients with paroxysmal AF may be considered only if in sinus rhythm at least 40% of the time 5

Bradycardia Risk

• Bradycardia occurred in 6.0% per patient-year (2.7% symptomatic) versus 1.3% with placebo 3, 1
• Risk factors include sinus node dysfunction, conduction defects (1st or 2nd degree AV block, bundle branch block), ventricular dyssynchrony, and concurrent negative chronotropes 1
• In patients with conduction defects or those in whom bradycardia could lead to hemodynamic compromise, initiate at 2.5 mg twice daily 1

Dosing and Monitoring

Starting Dose

• Recommended starting dose: 5 mg twice daily with food 1
• Assess patient after 2 weeks and adjust dose to achieve resting heart rate between 50-60 bpm 1
• Maximum dose: 7.5 mg twice daily 1

Dose Adjustments

• If heart rate >60 bpm: increase by 2.5 mg twice daily (up to maximum 7.5 mg twice daily) 1
• If heart rate 50-60 bpm: maintain current dose 1
• If heart rate <50 bpm or signs/symptoms of bradycardia: decrease by 2.5 mg twice daily; if on 2.5 mg twice daily, discontinue 1

Common Clinical Pitfalls

• Do NOT use ivabradine as first-line therapy—it is only adjunctive after beta-blocker optimization 3, 4
• Do NOT combine with non-dihydropyridine calcium channel blockers (diltiazem, verapamil) due to excessive heart rate lowering and increased ivabradine exposure 5, 4
• Do NOT use in patients with atrial fibrillation—it is contraindicated and may worsen arrhythmia burden 2, 5
• Do NOT use in decompensated heart failure—it may worsen cardiac output due to hemodynamic instability 3
• Avoid in patients with blood pressure <130/80 mmHg when used for angina, as lower thresholds may impair coronary perfusion 2