What is the use of ivabradine (Ivabradine) in patients with symptomatic stable angina or heart failure?

Use of Ivabradine in Heart Failure and Stable Angina

Ivabradine is indicated to reduce heart failure hospitalization 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, and for symptomatic relief of stable angina in patients with heart rate ≥70 bpm who cannot tolerate or remain symptomatic on beta-blockers. 1, 2

Heart Failure with Reduced Ejection Fraction (HFrEF)

Primary Indication and Evidence

• Ivabradine reduces HF hospitalization by 26% when added to guideline-directed medical therapy in appropriate patients. 3
• The ACC/AHA gives ivabradine a Class IIa recommendation (Level B-R) for patients with NYHA class II-III symptoms, LVEF ≤35%, sinus rhythm, and resting heart rate ≥70 bpm on maximally tolerated beta-blockers. 1
• The benefit is driven primarily by reduction in heart failure hospitalization, not cardiovascular mortality. 1

Critical Prerequisites Before Starting

• Patients must be on maximally tolerated doses of beta-blockers before considering ivabradine—only 25% of patients in the pivotal SHIFT trial were on optimal beta-blocker doses, highlighting that beta-blocker optimization takes priority given proven mortality benefits. 1
• Patients must be in sinus rhythm; a history of paroxysmal atrial fibrillation is acceptable only if sinus rhythm is present at least 40% of the time. 3
• Patients should have been hospitalized for HF in the preceding 12 months and on stable guideline-directed therapy for 4 weeks. 1

Dosing Algorithm for HFrEF

• Start at 5 mg twice daily with food (or 2.5 mg twice daily in patients ≥75 years old, those with conduction defects, or those at risk for hemodynamic compromise from bradycardia). 3, 2
• Assess after 2 weeks and adjust based on resting heart rate: 2
  • Heart rate >60 bpm: Increase by 2.5 mg twice daily up to maximum 7.5 mg twice daily
  • Heart rate 50-60 bpm: Maintain current dose
  • Heart rate <50 bpm or symptomatic bradycardia: Decrease by 2.5 mg twice daily; discontinue if already on 2.5 mg twice daily

Stable Angina Pectoris

When to Use Ivabradine for Angina

• Ivabradine is recommended for symptomatic relief in patients with chronic stable angina who have heart rate ≥70 bpm and cannot tolerate beta-blockers or remain symptomatic despite beta-blocker therapy. 1
• The European Medicines Agency concluded that ivabradine at appropriate doses (up to 7.5 mg twice daily) is useful for symptom relief and quality of life improvement in suitable patients. 1

Combination Therapy Approach

• When angina persists despite beta-blocker therapy, adding ivabradine is more efficient than uptitrating beta-blockers due to synergistic effects. 1
• Ivabradine can be combined with beta-blockers, nitrates, or amlodipine for additive antianginal benefit. 1
• The ESC gives ivabradine a Class I recommendation (Level A) when added to beta-blockers for persistent angina in HF patients. 1

Critical Limitation for Angina Without Heart Failure

• In patients with stable angina and preserved left ventricular function (no HF), ivabradine improves symptoms but does NOT improve cardiovascular outcomes and may increase risk. 1
• The SIGNIFY trial showed a potential increase in cardiovascular death and nonfatal MI in the chronic stable angina subgroup (CCS class ≥2), particularly at higher doses or with concomitant diltiazem/verapamil use. 1, 4
• This means ivabradine should be used for symptom control only in angina patients without HFrEF, not for prognostic benefit. 1, 4

Absolute Contraindications

Cardiac Contraindications

• Atrial fibrillation: Ivabradine is absolutely contraindicated in patients with chronic stable angina and atrial fibrillation due to increased arrhythmia incidence. 3, 5, 2
• Acute decompensated heart failure 2
• Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block without a functioning pacemaker 2
• Pacemaker dependence (heart rate maintained exclusively by pacemaker) 2
• Clinically significant bradycardia or hypotension 2

Drug Interactions

• Concomitant use with diltiazem or verapamil is clearly contraindicated due to excessive heart rate lowering and increased ivabradine exposure. 1, 3, 5
• Strong CYP3A4 inhibitors are contraindicated. 2

Other Contraindications

• Severe hepatic impairment 2
• Blood pressure <90/50 mmHg 6

Safety Monitoring and Adverse Effects

Atrial Fibrillation Risk

• Ivabradine increases the absolute incidence of atrial fibrillation by 0.7% (5.0% per patient-year vs 3.9% with placebo in SHIFT). 1, 2
• Regular cardiac rhythm monitoring is mandatory; discontinue immediately if atrial fibrillation develops. 3, 5, 2

Bradycardia

• Bradycardia occurred in 6.0% per patient-year with ivabradine (2.7% symptomatic) vs 1.3% with placebo. 2
• Treatment withdrawal due to bradycardia occurred in only 1% of patients in SHIFT despite 89% being on beta-blockers. 1
• Bradycardia may increase QT prolongation risk, potentially leading to torsade de pointes. 3

Visual Symptoms (Phosphenes)

• Phosphenes occur in 5.4% of patients, are mild and transitory, and rarely lead to treatment withdrawal (<1%). 1, 3
• These are caused by If channels in the retina that resemble those in the sinus node. 1

Clinical Scenarios Favoring Ivabradine

Hypotension

• In patients with hypotension, ivabradine is preferable to other antianginal agents that lower blood pressure since it reduces heart rate without affecting blood pressure or contractility. 3

Beta-Blocker Intolerance in HF

• Ivabradine is a Class IIa recommendation as an alternative to beta-blockers in HF patients who cannot tolerate beta-blockers. 1
• However, data on efficacy in this population are more limited than for add-on therapy. 1

Common Pitfalls to Avoid

• Do not use ivabradine before optimizing beta-blocker therapy in HFrEF—beta-blockers have proven mortality benefit that ivabradine lacks. 1
• Do not use ivabradine for prognostic benefit in stable angina without HFrEF—it is for symptom control only in this population. 1, 4
• Do not combine with diltiazem or verapamil under any circumstances. 1, 3, 5
• Do not continue ivabradine if atrial fibrillation develops. 3, 5, 2
• Do not use in patients with recent MI (within 2 months)—these patients were excluded from the SHIFT trial. 1