How to Give Ivabradine
Initiate ivabradine at 5 mg twice daily with food in patients with symptomatic HFrEF (LVEF ≤35%), sinus rhythm, resting heart rate ≥70 bpm, who are already on maximally tolerated beta-blocker doses, then titrate to achieve a target heart rate of 50-60 bpm. 1
Patient Selection Criteria
Before prescribing ivabradine, confirm the following eligibility criteria:
- Heart failure status: NYHA class II-III with LVEF ≤35% 2
- Rhythm requirement: Sinus rhythm with resting heart rate ≥70 bpm 2
- Stability: Clinically stable for at least 4 weeks on guideline-directed medical therapy (GDMT) 2
- Beta-blocker optimization: Patient must be on maximum tolerated dose of beta-blocker (this is critical, as only 25% of trial patients were on optimal beta-blocker doses, yet beta-blockers have proven mortality benefits) 2
- Additional GDMT: Should include ACE inhibitor/ARB (or ARNI) and mineralocorticoid receptor antagonist 3
Special consideration: Patients with paroxysmal atrial fibrillation may be considered if they are in sinus rhythm >60% of the time 3
Dosing Protocol
Standard Initiation
Starting dose: 5 mg twice daily with food 4, 1
Dose titration schedule:
- Assess patient after 2 weeks 1
- Adjust dose based on resting heart rate and tolerability 1
- Maximum dose: 7.5 mg twice daily 4, 1
Dose Adjustment Algorithm
Use the following heart rate-based titration strategy 1:
- Heart rate >60 bpm: Increase dose by 2.5 mg twice daily (up to maximum 7.5 mg twice daily)
- Heart rate 50-60 bpm: Maintain current dose (this is the target range)
- Heart rate <50 bpm or symptomatic bradycardia: Decrease dose by 2.5 mg twice daily; if already on 2.5 mg twice daily, discontinue therapy
Special Populations Requiring Lower Starting Dose
Start at 2.5 mg twice daily in patients with 1:
- History of conduction defects (1st or 2nd degree AV block, bundle branch block)
- Patients in whom bradycardia could lead to hemodynamic compromise
- Sinus node dysfunction or ventricular dyssynchrony
Absolute Contraindications
Do not prescribe ivabradine in patients with 4, 3, 1:
- Acute decompensated heart failure
- Clinically significant hypotension or blood pressure <90/50 mmHg
- 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
- Recent myocardial infarction within 2 months
- Atrial fibrillation or other non-sinus rhythms
- Concomitant non-dihydropyridine calcium channel blockers (diltiazem, verapamil)
Special Clinical Scenarios
Patients with Low Blood Pressure
In treatment-naïve HFrEF patients with persistent low blood pressure who cannot tolerate beta-blockers, ivabradine may be used as a viable alternative, either alone or with low-dose beta-blockers, as it helps facilitate beta-blocker titration 2. This is particularly valuable because ivabradine reduces heart rate without affecting blood pressure 4.
Administration Considerations
- Always give with food to optimize absorption 4, 1
- For patients unable to swallow tablets, ivabradine oral solution can be used 1
- Initiate or up-titrate one drug at a time using small increments 2
Monitoring Requirements
Initial Monitoring (First 2 Weeks)
- Assess resting heart rate 1
- Evaluate for symptoms of bradycardia (dizziness, fatigue, syncope) 1
- Check for signs of hemodynamic compromise 1
Ongoing Monitoring
- Regularly monitor cardiac rhythm to detect atrial fibrillation (occurs in 5.0% per patient-year vs 3.9% with placebo) 1
- Assess for visual disturbances (phosphenes occur in 3-15% of patients but are usually transient) 5, 6
- Monitor for symptomatic bradycardia (occurred in 2.7% per patient-year in trials) 1
- Evaluate heart rate response and symptom control 5
Critical Safety Warnings
Atrial Fibrillation
Discontinue ivabradine immediately if atrial fibrillation develops, as it increases the risk of this arrhythmia and loses efficacy in non-sinus rhythms 4, 1. The ACC/AHA guidelines emphasize regular cardiac rhythm monitoring for this reason 2, 1.
Bradycardia Management
Risk factors for excessive bradycardia include 1:
- Sinus node dysfunction
- Conduction defects
- Ventricular dyssynchrony
- Concomitant use of other negative chronotropes (digoxin, diltiazem, verapamil, amiodarone)
Bradycardia may increase QT prolongation risk, potentially leading to severe ventricular arrhythmias including torsade de pointes, especially with concomitant QTc-prolonging drugs 1.
Fetal Toxicity
Ivabradine may cause fetal toxicity based on animal studies showing embryo-fetal toxicity and cardiac teratogenic effects at 1-3 times human exposures 1. Advise females of reproductive potential to use effective contraception 1.
Expected Clinical Benefits
The primary benefit of ivabradine is reduction in heart failure hospitalizations (this drove the composite endpoint benefit in the SHIFT trial) 2, 3. The effect on cardiovascular death is less consistent than hospitalization reduction 3. Importantly, ivabradine provides heart rate reduction without affecting myocardial contractility, relaxation, or peripheral vascular resistance 6, 7.
Common Pitfalls to Avoid
- Do not use ivabradine before optimizing beta-blocker therapy - beta-blockers have proven mortality benefits and must be maximized first 2
- Do not continue ivabradine if atrial fibrillation develops - it becomes ineffective and increases arrhythmia risk 4, 1
- Do not use in patients with coronary artery disease without heart failure - the SIGNIFY trial showed no benefit and potential harm in patients with activity-limiting angina 8
- Do not overlook drug interactions - strong CYP3A4 inhibitors are contraindicated 4, 3, 1