Ivabradine in Heart Failure with Reduced Ejection Fraction
Ivabradine should be added to guideline-directed medical therapy (GDMT) in patients with symptomatic HFrEF (LVEF ≤35%) who remain in sinus rhythm with a resting heart rate ≥70 bpm despite maximally tolerated beta-blocker therapy, as it reduces heart failure hospitalizations and cardiovascular death. 1
Patient Selection Criteria
Ivabradine is indicated specifically for patients meeting ALL of the following criteria:
- NYHA Class II-III symptoms despite optimal medical therapy 1
- LVEF ≤35% documented on echocardiography 1, 2
- Sinus rhythm (not atrial fibrillation, atrial flutter, or 100% paced rhythm) 1, 3
- Resting heart rate ≥70 bpm at rest 1, 2
- Maximally tolerated beta-blocker dose already achieved, or documented contraindication to beta-blockers 1, 2
- Stable chronic heart failure (not acute decompensation) 2
Critical Sequencing: Beta-Blockers First
Beta-blockers must be optimized before considering ivabradine. 1 The mortality benefits of beta-blockers are well-proven and dose-dependent, whereas ivabradine primarily reduces hospitalizations. 1 In the SHIFT trial, only 25% of patients were on optimal beta-blocker doses, which limits the generalizability of the findings. 1 Therefore, uptitrate beta-blockers to target doses as tolerated before assessing whether the patient still has elevated heart rate warranting ivabradine. 1
Expected Clinical Benefits
The primary benefit of ivabradine is reduction in heart failure hospitalizations, with the composite endpoint showing a 25% reduction in cardiovascular death or HF hospitalization in patients with heart rate >77 bpm. 4 This translates to a number needed to treat of 17 patients for 1 year to prevent one event. 4
Additional benefits include:
- Heart rate reduction of 6-10 bpm at therapeutic doses 3
- Improvement in LVEF (mean improvement of 3.24%) 5
- Reduction in left ventricular dimensions at 8 months 4
- Improvement in NYHA functional class (28% vs 23% with placebo) 4
- Quality of life improvement measured by Kansas City Cardiomyopathy Questionnaire 4
Dosing and Titration
Starting dose: 5 mg twice daily with food (or 2.5 mg twice daily in vulnerable adults) 2
Titration strategy: After 2 weeks, adjust dose based on heart rate with a maximum dose of 7.5 mg twice daily. 2 Target heart rate is 50-60 bpm. 6
Absolute Contraindications
Do not use ivabradine in patients with:
- Acute decompensated heart failure 2
- Atrial fibrillation or atrial flutter (ivabradine loses efficacy and increases AF risk) 3, 6, 2
- Clinically significant bradycardia or hypotension 2
- Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block without functioning pacemaker 2
- Heart rate maintained exclusively by pacemaker 2
- Severe hepatic impairment 3, 6, 2
- Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, nefazodone, ritonavir) 3, 2
- Pregnancy 3, 2
Common Adverse Effects and Monitoring
The most common adverse effects (≥1% incidence) are:
- Bradycardia (both symptomatic and asymptomatic, with 3-4 fold increased risk) 2, 5
- Phosphenes (visual brightness phenomena, typically transient) 3, 2
- Atrial fibrillation (monitor closely; discontinue immediately if AF develops) 6, 2
- Hypertension (blood pressure may slightly increase, which can be advantageous when beta-blockers cause hypotension) 3, 2
Monitor heart rate regularly during treatment and reduce dose or discontinue if symptomatic bradycardia occurs. 2
Unique Advantage: Blood Pressure Neutral
Ivabradine causes no decrease in blood pressure—in fact, blood pressure may slightly increase. 3 This makes ivabradine uniquely valuable in patients with low blood pressure where beta-blocker optimization is limited by hypotension. 3 Unlike beta-blockers or calcium channel blockers, ivabradine selectively inhibits the If current in the sinoatrial node without affecting myocardial contractility or vascular tone. 3, 6
Strength of Evidence
The recommendation carries a Class IIa (moderate) recommendation with Level B-R (randomized) evidence from the 2022 AHA/ACC/HFSA guidelines. 1 The SHIFT trial enrolled 6,505 patients and demonstrated efficacy, though benefits were most pronounced in the subgroup with heart rate ≥77 bpm at baseline. 1, 4 A 2024 meta-analysis of 18,972 patients from nine RCTs confirmed reduction in HF mortality (RR 0.79) and HF hospitalization (RR 0.80). 5
Clinical Pitfalls to Avoid
- Do not use ivabradine as a substitute for beta-blocker optimization—it is adjunctive therapy only 1
- Do not continue ivabradine if atrial fibrillation develops—it loses efficacy and increases AF risk 6, 2
- Do not use in second-degree AV block (not recommended) 2
- Avoid CYP3A4 inhibitors and inducers which significantly alter ivabradine levels 2
- Counsel females of reproductive potential to use effective contraception due to fetal toxicity risk 2