When is Ivabradine (Ivabradine) indicated for use in patients with heart failure with reduced ejection fraction (HFrEF) and what is the typical dosing regimen?

Ivabradine Use in Heart Failure with Reduced Ejection Fraction (HFrEF)

Ivabradine is indicated for patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute, and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. 1, 2

Indications for Ivabradine

Ivabradine should be prescribed when all the following criteria are met:

• Stable, symptomatic chronic heart failure
• Left ventricular ejection fraction ≤35%
• Sinus rhythm (not atrial fibrillation or flutter)
• Resting heart rate ≥70 beats per minute
• Either:
  • On maximally tolerated doses of beta-blockers, or
  • Have a contraindication to beta-blocker use
• History of heart failure hospitalization within the previous 12 months (preferred but not mandatory) 2, 1

Important Considerations

• Beta-blockers should be optimized to maximum tolerated doses before initiating ivabradine due to their proven mortality benefits 2
• Ivabradine is an adjunctive therapy to reduce heart rate in patients who cannot achieve adequate rate control with beta-blockers alone 3
• The greatest benefit is observed in patients with baseline heart rate ≥75 bpm 4

Contraindications

Ivabradine should NOT be used in patients with:

• Acute decompensated heart failure
• Clinically significant hypotension
• Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block (unless functioning pacemaker present)
• Clinically significant bradycardia
• Severe hepatic impairment
• Pacemaker dependence (heart rate maintained exclusively by pacemaker)
• Concomitant use of strong CYP3A4 inhibitors 1, 2

Dosing Regimen

1. Initial dose:

   • Standard starting dose: 5 mg twice daily with food 1, 2
   • For vulnerable patients (≥75 years, history of conduction defects, or risk of hemodynamic compromise): 2.5 mg twice daily 2, 1

2. Dose adjustment:

   • Assess heart rate after two weeks of treatment
   • Target resting heart rate between 50-60 bpm
   • Adjust dose according to heart rate:

     • 60 bpm: Increase by 2.5 mg twice daily (maximum 7.5 mg twice daily)

     • 50-60 bpm: Maintain current dose
     • <50 bpm or signs of bradycardia: Decrease by 2.5 mg twice daily; discontinue if current dose is 2.5 mg twice daily 1

3. Ongoing monitoring:

   • Regular assessment of heart rate
   • Monitor for development of atrial fibrillation (5% per patient-year) 2
   • Watch for visual disturbances/phosphenes (3% of patients) 2

Clinical Benefits

Ivabradine therapy provides several important benefits:

• Reduces risk of heart failure hospitalization by 30% 2, 5
• Reduces the composite endpoint of cardiovascular death or heart failure hospitalization by 18-25% 2, 4
• Improves left ventricular ejection fraction (mean increase of 3.24%) 2, 5
• Improves quality of life and exercise tolerance 6
• Number needed to treat for 1 year is 17 in patients with heart rate >77 bpm 4

Common Adverse Effects

• Bradycardia (6.0% per patient-year; 2.7% symptomatic) 2, 1
• Visual disturbances/phosphenes (3% of patients) 2
• Atrial fibrillation (5% per patient-year) 2, 1

Clinical Pearls

• Regularly monitor cardiac rhythm and discontinue ivabradine if atrial fibrillation develops 1
• The drug should be taken with food to reduce pharmacokinetic variability 2
• In real-world practice, only about 17% of HFrEF patients may be eligible for ivabradine when guideline-directed medical therapy is optimized 7
• Patients with higher baseline heart rates (≥77 bpm) derive greater benefit from ivabradine therapy 4
• Ivabradine has been shown to improve both systolic and diastolic function in HFrEF patients 6

By following these guidelines for patient selection and dosing, ivabradine can be effectively used to reduce hospitalizations and improve outcomes in appropriate HFrEF patients.