What is ivabradine, its mechanism of action, and the summary of clinical studies involving ivabradine (a heart rate reducer)?

What is Ivabradine?

Ivabradine is a selective heart rate-lowering medication that specifically inhibits the If (funny) current in the sinoatrial node, reducing heart rate without affecting myocardial contractility, blood pressure, or ventricular repolarization. 1, 2

Mechanism of Action

Ivabradine works through a unique and highly specific mechanism:

• Blocks hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that carry the If current, which is responsible for the spontaneous diastolic depolarization of sinoatrial pacemaker cells 1, 3

• Slows the rate of diastolic depolarization in the sinoatrial node, thereby reducing heart rate by approximately 10 bpm at rest and during exercise at recommended doses 1, 4

• Produces dose-dependent heart rate reduction that is proportional to baseline heart rate—patients with higher baseline heart rates experience greater reductions 1, 5

• No effect on myocardial contractility, blood pressure, or ventricular repolarization, making it uniquely valuable when beta-blockers or calcium channel blockers cause problematic hypotension 2, 3

• Blood pressure may actually increase slightly with ivabradine use, as the drug has no vasodilatory or negative inotropic effects 2

FDA-Approved Clinical Indications

Heart Failure with Reduced Ejection Fraction (HFrEF)

Ivabradine is indicated for patients with symptomatic chronic HFrEF (NYHA class II-III, LVEF ≤35%) who are in sinus rhythm with resting heart rate ≥70 bpm despite maximally tolerated beta-blocker therapy. 6

• Class IIa recommendation from ACC/AHA/HFSA guidelines for reducing heart failure hospitalizations and cardiovascular death 6

• Beta-blockers must be optimized first to target doses before considering ivabradine, given the proven mortality benefits of beta-blocker therapy 6

• Only 25% of patients in the pivotal SHIFT trial were on optimal beta-blocker doses, underscoring the importance of maximizing beta-blocker therapy first 6

Inappropriate Sinus Tachycardia (IST)

Ivabradine is reasonable for ongoing management in patients with symptomatic IST, particularly when beta-blockers or calcium channel blockers are ineffective or not tolerated due to hypotension. 6, 2

• Class IIa recommendation from ACC/AHA/HRS guidelines for symptomatic IST 6

• Preferred initial pharmacologic therapy according to the American Heart Association, as beta-blockers and calcium channel blockers often cause problematic hypotension in these patients 2

• Reduces daytime heart rate by approximately 14-20 bpm and significantly improves exercise tolerance and symptoms 2

Major Clinical Trials

SHIFT Trial (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial)

The SHIFT trial is the landmark study that established ivabradine's role in heart failure management. 6

• Enrolled 6,588 patients with NYHA class II-IV heart failure, LVEF ≤35%, sinus rhythm with heart rate ≥70 bpm, and a heart failure hospitalization in the previous 12 months 6

• Primary outcome: 18% relative risk reduction in the composite of cardiovascular death or heart failure hospitalization (P <0.0001) 6

• Heart failure hospitalization: 26% relative risk reduction, which drove the primary outcome benefit 6

• Absolute risk reduction: 4.2% for the primary composite endpoint, equating to a number needed to treat of 24 over 23 months 6

• Median follow-up: 23 months 6

• Background therapy: 84% on diuretics, 90% on beta-blockers, 79% on ACE inhibitors, 60% on mineralocorticoid receptor antagonists 6

• Adverse effects: 5% experienced symptomatic bradycardia (vs. 1% placebo), 3% reported visual side effects/phosphenes (vs. 1% placebo) 6

Study link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61198-1/fulltext

BEAUTIFUL Trial (Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Disease and Left-Ventricular Dysfunction)

The BEAUTIFUL trial evaluated ivabradine in patients with coronary artery disease and left ventricular dysfunction. 6

• Enrolled 10,917 patients with coronary heart disease and LVEF <40% 6

• Median follow-up: 19 months 6

• Primary outcome: No significant reduction in cardiovascular death, myocardial infarction, or heart failure hospitalization 6

• Safety data: Provided additional evidence that ivabradine is generally safe, with heart rate reductions of 6-8 bpm 6

Study link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61170-8/fulltext

Dosing and Administration

Initial dose: 5 mg twice daily with food 7, 1

• Dose adjustment: Based on heart rate response, with target heart rate between 50-60 bpm 7

• Maximum dose: 7.5 mg twice daily 1

• Dose plateau effect occurs at doses >20 mg twice daily, limiting the risk of severe bradycardia 1

Safety Profile and Adverse Effects

Ivabradine has an excellent safety profile demonstrated in large randomized trials involving over 17,000 patients. 2

Common Adverse Effects

• Phosphenes (visual brightness phenomena): Occur in approximately 15-16% of patients, described as transient enhanced brightness in limited areas of the visual field 1, 5, 8

• Bradycardia: Heart rate <55 bpm occurs in 3.2% of patients at recommended doses 8

• Visual symptoms are transient, do not interfere with quality of life, and lead to withdrawal in <1% of patients 8

• Severe sinus bradycardia is uncommon due to the plateau effect and proportional heart rate reduction 5, 8

Contraindications

Absolute contraindications include: 7, 2

• Atrial fibrillation: Ivabradine must be discontinued immediately if atrial fibrillation develops, as it increases the risk of this arrhythmia and loses efficacy in non-sinus rhythms 7

• Severe hepatic impairment (Child-Pugh C) 7, 1

• Strong CYP3A4 inhibitors 2

• Pregnancy: May cause fetal harm based on animal data 1

• Sick sinus syndrome: Should be avoided due to effects on the sinus node 5

Precautions

• Hypotension: Use with caution; reduce or discontinue if symptomatic bradycardia or severe hypotension occurs 7

• QT interval: Expectedly prolonged with heart rate reduction, but no direct effect on ventricular repolarization or torsadogenic potential after appropriate heart rate correction 5, 8

• No dose adjustment required for mild to moderate hepatic impairment or renal impairment with creatinine clearance 15-60 mL/min 1

Off-Label Uses Showing Promise

Postural Orthostatic Tachycardia Syndrome (POTS): Beneficial effects for heart rate lowering, with promising results in controlling heart rate in patients with POTS 9

Coronary computed tomography angiography: Effective as premedication for heart rate control 9

Chronic stable angina: Shown to be at least as effective as atenolol in improving exercise tolerance and reducing angina attacks 3