Introduction
Ivabradine is a novel cardiovascular agent that represents the first selective and specific inhibitor of the I(f) current in sinoatrial node cells. Marketed under the brand name Corlanor in the United States and Procoralan in other countries, this medication offers a unique mechanism for heart rate reduction without affecting myocardial contractility or conduction. Approved by the FDA in 2015, ivabradine provides an important therapeutic option for patients with certain cardiovascular conditions where heart rate control is clinically indicated.
Mechanism of Action
Ivabradine exerts its pharmacological effects through selective and specific inhibition of the I(f) current ("funny" current) in cardiac pacemaker cells of the sinoatrial node. The I(f) current is a mixed sodium-potassium inward current that plays a crucial role in spontaneous diastolic depolarization and pacemaker activity. By binding to the HCN4 (hyperpolarization-activated cyclic nucleotide-gated) channels from the intracellular side, ivabradine slows the rate of diastolic depolarization, thereby reducing heart rate. Importantly, this mechanism is distinct from beta-blockers and calcium channel blockers, as it does not affect myocardial contractility, atrioventricular conduction, or ventricular repolarization.
Indications
- Chronic Heart Failure: Ivabradine is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
- Stable Angina: In many countries outside the US, ivabradine is approved for the symptomatic treatment of chronic stable angina pectoris in adults with normal sinus rhythm who have a contraindication or intolerance to beta-blockers.
Dosage and Administration
Initial Dose: 5 mg twice daily with meals Titration: After 2 weeks, adjust dose based on resting heart rate and tolerability Maximum Dose: 7.5 mg twice daily Dose Adjustment: Reduce to 2.5 mg twice daily in patients with conduction defects or considering adverse effects Renal Impairment: No dose adjustment necessary Hepatic Impairment: Use with caution in moderate impairment; contraindicated in severe impairment Elderly Patients: Initiate with lower doses and titrate carefullyPharmacokinetics
Absorption: Rapid and almost complete (≈90%) with peak plasma concentrations achieved within 1 hour under fasting conditions. Food intake increases absorption and reduces rate variability. Distribution: Volume of distribution approximately 100 L. Plasma protein binding is about 70%, primarily to albumin. Metabolism: Primarily metabolized by CYP3A4 via N-demethylation and oxidation. The main active metabolite is N-desmethyl ivabradine (S18982). Elimination: Terminal half-life is approximately 2 hours in extensive metabolizers and 12 hours in poor metabolizers. Excretion is primarily via feces (≈58%) and urine (≈25%).Contraindications
- Resting heart rate <60 beats per minute prior to treatment
- Severe hepatic impairment
- Blood pressure <90/50 mmHg
- Acute decompensated heart failure
- Pacemaker dependence
- Sick sinus syndrome, sinoatrial block, or 3rd-degree AV block
- Concomitant use of strong CYP3A4 inhibitors
- Pregnancy and breastfeeding
- Hypersensitivity to ivabradine or any component of the formulation
Warnings and Precautions
Atrial Fibrillation: Increased risk of atrial fibrillation (5% vs 3.9% placebo); monitor regularly Bradycardia: May cause significant bradycardia; assess heart rate regularly QT Prolongation: Mild dose-related QT prolongation observed Visual Effects: May cause luminous phenomena (phosphenes) due to retinal HCN channel inhibition Hepatic Impairment: Use caution in moderate impairment; contraindicated in severe Conduction Disturbances: Use cautiously in patients with conduction defects Acute Heart Failure: Not recommended in acutely decompensated patientsDrug Interactions
Strong CYP3A4 Inhibitors: Contraindicated (ketoconazole, clarithromycin, nefazodone, HIV protease inhibitors) Moderate CYP3A4 Inhibitors: Use with caution and consider dose reduction (diltiazem, verapamil, grapefruit juice) CYP3A4 Inducers: May decrease ivabradine levels (rifampin, phenobarbital, phenytoin) Heart Rate Reducing Drugs: Additive bradycardia risk with beta-blockers, amiodarone, digoxin, diltiazem, verapamil QT Prolonging Drugs: Potential additive effect on QT intervalAdverse Effects
Very Common (>10%): Bradycardia, luminous phenomena (phosphenes) Common (1-10%): Atrial fibrillation, hypertension, blurred vision, diplopia, dizziness, headache, ventricular extrasystoles Uncommon (0.1-1%): Second-degree AV block, syncope, palpitations, nausea, constipation, diarrhea, rash, urticaria, angioedema Rare (<0.1%): Third-degree AV block, erythema, pruritusMonitoring Parameters
- Resting heart rate at initiation, after dose changes, and regularly during treatment
- ECG to monitor for bradycardia and conduction abnormalities
- Blood pressure regularly
- Visual symptoms and ophthalmologic evaluation if visual disturbances persist
- Signs and symptoms of atrial fibrillation
- Renal and hepatic function periodically
- Clinical status for heart failure symptoms and signs of decompensation
Patient Education
- Take ivabradine exactly as prescribed, usually twice daily with meals
- Do not stop taking suddenly without consulting your healthcare provider
- Be aware that ivabradine may cause visual phenomena described as transient enhanced brightness, colored lights, or multiple images
- Report any dizziness, fatigue, or unusual visual symptoms to your doctor
- Inform all healthcare providers about all medications you're taking
- Avoid grapefruit and grapefruit juice while taking this medication
- Regular follow-up appointments are essential for monitoring your response
- Use caution when driving or operating machinery until you know how ivabradine affects you
- Report any symptoms of heart failure worsening (increased shortness of breath, swelling, weight gain)
References
1. FDA Prescribing Information: Corlanor (ivabradine). 2019. 2. Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-885. 3. Borer JS, et al. Efficacy and safety of ivabradine in patients with severe chronic heart failure. Circulation. 2015;131(19):1699-1707. 4. Tardif JC, et al. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26(23):2529-2536. 5. DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010;106(3):434-446. 6. McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. 7. Fox K, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807-816.