Ivabradine Dosing and Management
Heart Failure with Reduced Ejection Fraction (HFrEF)
For patients with stable, symptomatic chronic heart failure (LVEF ≤35%) in sinus rhythm with resting heart rate ≥70 bpm on maximally tolerated beta-blockers, start ivabradine at 5 mg twice daily with meals, assess after 2 weeks, and titrate to achieve a resting heart rate between 50-60 bpm, with a maximum dose of 7.5 mg twice daily. 1, 2
Initial Dosing Strategy
- Standard starting dose: 5 mg twice daily with meals for patients on maximally tolerated beta-blocker doses with persistent resting heart rate ≥70 bpm 1, 2
- Reduced starting dose: 2.5 mg twice daily for patients with history of conduction defects, age ≥75 years, or those in whom bradycardia could lead to hemodynamic compromise 1, 2
Dose Titration Protocol
After 2 weeks of initial therapy, adjust dosing based on resting heart rate 2:
- Heart rate >60 bpm: Increase dose by 2.5 mg twice daily (maximum 7.5 mg twice daily) 2
- Heart rate 50-60 bpm: Maintain current dose 2
- Heart rate <50 bpm or signs/symptoms of bradycardia: Decrease dose by 2.5 mg twice daily; if already on 2.5 mg twice daily, discontinue therapy 2
Patient Selection Criteria
Ivabradine is indicated specifically for 1, 2:
- Stable, symptomatic chronic HFrEF (LVEF ≤35%) 1
- Sinus rhythm (not for persistent/chronic atrial fibrillation or 100% atrial pacing) 1
- Resting heart rate ≥70 bpm despite maximally tolerated beta-blocker therapy 1
- History of HF hospitalization (based on SHIFT trial enrollment) 1
Important nuance: A history of paroxysmal atrial fibrillation is NOT a contraindication—nearly 10% of SHIFT trial patients had paroxysmal AF, with a requirement for sinus rhythm at least 40% of the time 1
Evidence Base
The SHIFT trial demonstrated an 18% relative risk reduction in cardiovascular death or HF hospitalization (p<0.0001), with a 26% reduction in HF hospitalization specifically 1. The absolute risk reduction was 4.2%, equating to a number needed to treat of 24 over 23 months 1. Benefits were particularly notable in patients with contraindications to beta-blockers, those on ≤50% of target beta-blocker doses, and those with baseline heart rate ≥77 bpm 1.
Inappropriate Sinus Tachycardia (IST)
For symptomatic IST patients, particularly when beta-blockers are not tolerated or have failed, start ivabradine at 5 mg twice daily and titrate to 7.5 mg twice daily based on heart rate response and symptom control. 1, 3, 4, 5
Dosing for IST
- Initial dose: 5 mg twice daily 1, 3
- Dose range: 2.5-7.5 mg twice daily 3
- Maximum dose: 7.5 mg twice daily 1, 3
Clinical Efficacy in IST
Research demonstrates significant heart rate reductions with ivabradine in IST patients 4, 5:
- Mean heart rate decreased from 97±6 bpm to 79±8 bpm 4
- Maximum heart rate decreased from 155±18 bpm to 132±16 bpm 4
- Quality of life scores improved significantly (SF-36 score: 57±23 to 76±20, p<0.001) 4
Notably, after 1 year of treatment, 80% of patients who discontinued ivabradine maintained normal heart rates, suggesting potential disease-modifying effects beyond simple rate control 4
Absolute Contraindications
Ivabradine must NOT be used in patients with 1, 2:
- Acute decompensated heart failure 2
- Blood pressure <90/50 mmHg 1, 2
- Severe hepatic impairment 1, 2
- Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block (unless functioning pacemaker present) 2
- Pacemaker dependence (heart rate maintained exclusively by pacemaker) 2
- Concomitant strong CYP3A4 inhibitors (boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telaprevir, posaconazole, voriconazole) 1, 2
- Concomitant strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St. John's wort) 1
- Concomitant diltiazem, verapamil, or grapefruit juice 1
Monitoring Requirements
Regular Assessments
- Heart rate monitoring: Assess resting heart rate at 2 weeks after initiation or dose change, then regularly during ongoing therapy 1, 2
- Cardiac rhythm monitoring: Regularly monitor for development of atrial fibrillation; discontinue ivabradine if AF develops 2
- Drug interaction screening: Verify no concomitant strong CYP3A4 inhibitors or inducers 1, 6
When Combining with Beta-Blockers
Monitor closely for excessive bradycardia when ivabradine is combined with beta-blockers 6, 3. The combination may provide superior heart rate control in refractory cases but requires careful titration 3.
Common Adverse Effects
Phosphenes (Visual Brightness Phenomena)
- Occur in 3-15% of patients taking ivabradine 6, 7, 3
- Typically transient and rarely require discontinuation 6, 7, 3
- Described as enhanced brightness in limited areas of the visual field 6
Bradycardia
- Occurred in 6.0% per patient-year in SHIFT trial (2.7% symptomatic, 3.4% asymptomatic) versus 1.3% in placebo 2
- Risk factors include sinus node dysfunction, conduction defects, ventricular dyssynchrony, and use of other negative chronotropes 2
Atrial Fibrillation
- Increased risk: 5.0% per patient-year with ivabradine versus 3.9% with placebo in SHIFT 1, 2
- Requires regular cardiac rhythm monitoring and discontinuation if AF develops 2
Critical Pitfalls to Avoid
Do not use ivabradine in patients with atrial fibrillation or atrial flutter—it only works in sinus rhythm and increases AF risk 1, 2
Do not automatically attribute tremors to ivabradine—tremor is not an established side effect; investigate beta-blocker effects, metabolic derangements (thyroid, electrolytes, hypoglycemia), or neurological conditions first 6
Do not use in decompensated heart failure—ivabradine is only for stable, chronic HF 1, 2
Do not combine with strong CYP3A4 inhibitors or inducers—this is an absolute contraindication due to significant drug-drug interactions 1, 2
Do not use as first-line therapy—ivabradine is adjunctive to maximally tolerated beta-blocker therapy in HFrEF, not a replacement 1