When is Ivabradine (Ivabradine) indicated and what is the recommended dosage for patients with tachycardia (heart rate above 70 beats per minute)?

Ivabradine Indications and Dosing

Ivabradine is indicated to reduce heart failure hospitalizations in patients with symptomatic chronic HFrEF (LVEF ≤35%) who are in sinus rhythm with resting heart rate ≥70 bpm despite maximally tolerated beta-blocker therapy, with a starting dose of 5 mg twice daily with food. 1, 2

Specific Indication Criteria

Patient must meet ALL of the following criteria:

• Heart failure with reduced ejection fraction (LVEF ≤35%) 1, 2
• NYHA functional class II-III symptoms (stable chronic heart failure, not acute decompensation) 1
• Sinus rhythm (not atrial fibrillation or other arrhythmias) 1, 2
• Resting heart rate ≥70 beats per minute 1, 2
• On maximally tolerated dose of beta-blocker OR have contraindication to beta-blocker use 1, 2
• Stable on guideline-directed medical therapy for at least 4 weeks 1
• History of heart failure hospitalization within the preceding 12 months 1

Critical Caveat About Beta-Blocker Optimization

Beta-blockers MUST be uptitrated to target doses 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. 1 Ivabradine's primary benefit is reducing heart failure hospitalizations, NOT mortality. 1

Dosing Algorithm

Initial Dosing

• Standard starting dose: 5 mg twice daily with food 2
• Lower starting dose (2.5 mg twice daily): Use in patients with history of conduction defects or those in whom bradycardia could cause hemodynamic compromise 2

Dose Titration (Assess after 2 weeks, then adjust as needed)

Based on resting heart rate: 2

• Heart rate >60 bpm: Increase by 2.5 mg twice daily (maximum 7.5 mg twice daily)
• Heart rate 50-60 bpm: Maintain current dose
• Heart rate <50 bpm OR signs/symptoms of bradycardia: Decrease by 2.5 mg twice daily; if already on 2.5 mg twice daily, discontinue therapy

Target resting heart rate: 50-60 beats per minute 3, 2

Absolute Contraindications

Do NOT use ivabradine in patients with: 2

• Acute decompensated heart failure
• Clinically significant hypotension
• Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block (unless functioning demand pacemaker present)
• Clinically significant bradycardia
• Severe hepatic impairment
• Pacemaker dependence (heart rate maintained exclusively by pacemaker)
• Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir, ritonavir)
• History of angioedema (though this applies to ARNI therapy, not specifically mentioned for ivabradine)

Critical Monitoring Requirements

Atrial Fibrillation Risk

Ivabradine increases the risk of atrial fibrillation (5.0% per patient-year vs 3.9% with placebo in SHIFT trial). 2 Regularly monitor cardiac rhythm and IMMEDIATELY discontinue ivabradine if atrial fibrillation develops, as the drug loses efficacy in non-sinus rhythms and increases AF risk. 3, 2

Bradycardia Monitoring

Bradycardia occurred in 6.0% per patient-year with ivabradine (2.7% symptomatic; 3.4% asymptomatic) versus 1.3% with placebo. 2, 4 Monitor for symptomatic bradycardia, sinus arrest, and heart block, particularly in patients with:

• Sinus node dysfunction
• Conduction defects (1st or 2nd-degree AV block, bundle branch block)
• Ventricular dyssynchrony
• Concurrent use of other negative chronotropes 2

Expected Clinical Outcomes

Ivabradine reduces: 1, 4

• Heart failure hospitalizations (primary benefit)
• Composite endpoint of cardiovascular death or HF hospitalization
• Resting heart rate by approximately 12 beats per minute
• Improves LVEF by approximately 3%

Ivabradine does NOT significantly reduce: 1

• All-cause mortality as a standalone endpoint
• Cardiovascular mortality (benefit driven primarily by hospitalization reduction)

Real-World Application

In optimally managed HFrEF populations where guideline-directed medical therapy is properly implemented, only approximately 17% of patients meet criteria for ivabradine therapy. 5 This emphasizes the importance of maximizing beta-blocker therapy first, as most patients achieve adequate heart rate control with optimal beta-blocker dosing alone.

Pregnancy Considerations

Ivabradine may cause fetal toxicity. 2 Advise females of reproductive potential to use effective contraception during treatment, as embryo-fetal toxicity and cardiac teratogenic effects occurred in animal studies at exposures 1-3 times the maximum recommended human dose.