IVABRADINE (CORLANOR®)

• ACRONYMS AND DEFINITIONS

• AH interval - The time from the initial rapid deflection of the atrial wave to the initial rapid deflection of the His bundle (H) potential; it approximates the conduction time through the AV node (normally 50-120 msec)
• AV - Atrioventricular
• CAD - Coronary artery disease
• EF - Ejection Fraction
• HF - Heart failure
• HFrEF - Heart failure with reduced ejection fraction
• NYHA - New York Heart Association heart failure classification
• SBP - systolic blood pressure
• sGC - soluble guanylate cyclase

• DRUGS IN CLASS

• Ivabradine (Corlanor®) is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker. It is the only drug available in this class.

• MECHANISM OF ACTION

• Ivabradine blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I_f current, which regulates heart rate. In clinical electrophysiology studies, the cardiac effects were most pronounced in the sinoatrial (SA) node, but prolongation of the Atrial-His bundle (AH) interval has occurred as has PR interval prolongation. There was no effect on ventricular repolarization and no effects on myocardial contractility
• Ivabradine can also inhibit the retinal current I_h. I_h is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of I_h by ivabradine may underlie the luminous phenomena experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field.

• FDA-APPROVED INDICATION

• Heart failure with reduced ejection fraction (adults)
• Ivabradine is indicated to reduce the risk of hospitalization for worsening heart failure in adult 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.


• Heart failure due to dilated cardiomyopathy (pediatric)
• Ivabradine is indicated for the treatment of stable symptomatic heart failure due to dilated cardiomyopathy (DCM) in pediatric patients aged 6 months and older, who are in sinus rhythm with an elevated heart rate.

• HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)

• Overview
• The effects of ivabradine on heart failure with reduced ejection fraction were evaluated in the SHIFT study detailed below

• Professional recommendations
• See AHA HFrEF treatment recommendations

• CORONARY ARTERY DISEASE

• Overview
• The SIGNIFY study reviewed below looked at the effects of ivabradine in patients with stable CAD and no clinical signs of heart failure. The study did not find that ivabradine was beneficial in these patients.

• STUDY
  SIGNIFY study - Ivabradine vs Placebo in Patients with Stable CAD and No Clinical Signs of Heart Failure, NEJM (2014) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=18,102 | length = median 27.8 months) in patients with stable CAD and no clinical signs of heart failure
• Treatment: Ivabradine 5 - 10 mg twice daily vs Placebo. Ivabradine dose was adjusted based on heart rate. Average ivabradine dose was 8.2 mg twice daily.
• Primary outcome: Composite of death from cardiovascular causes or nonfatal myocardial infarction
• Results:
• Primary outcome: Ivabradine 6.8%, Placebo 6.4% (p=0.20)
• All-cause mortality: Ivabradine 5.1%, Placebo 4.8% (p=0.35)
• Findings: Among patients who had stable coronary artery disease without clinical heart failure, the addition of ivabradine to standard background therapy to reduce the heart rate did not improve outcomes

• SIDE EFFECTS

• Heart rate decrease
• Ivabradine slows the heart rate, and this can increase the risk of bradycardia. In the SHIFT study, only patients with a resting heart rate ≥ 70 bpm were enrolled. Bradycardia occurred in 10% of ivabradine-treated patients and 2.2% of placebo-treated patients. In the ivabradine group, the average heart rate decreased by 15.4 bpm at 28 days. The average decrease at 1 year was 9.1 bpm (placebo-adjusted).
• Patients treated with ivabradine should have their pulse monitored closely, and ivabradine doses should be adjusted appropriately (see dosing below)

• Hypertension
• In the SHIFT trial, ivabradine-treated patients had a slightly higher incidence of hypertension when compared to placebo-treated patients (8.9% vs 7.8%). The significance of this is unknown.

• Atrial fibrillation
• In the SHIFT trial, ivabradine-treated patients had a slightly higher incidence of atrial fibrillation when compared to placebo-treated patients (5% per patient-year vs 3.9% per patient-year). The mechanism by which ivabradine increases the risk of atrial fibrillation is unknown.
• Patients treated with ivabradine should be monitored for signs and symptoms of atrial fibrillation

• Vision changes
• Ivabradine inhibits the retinal current I_h. I_h is involved in curtailing retinal responses to bright light stimuli. Patients treated with ivabradine may experience phosphenes which are described as transiently enhanced brightness in a limited area of the visual field, halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency). In the SHIFT trial, phosphenes were reported by 3% of ivabradine-treated patients and 1% of placebo-treated patients. Onset was generally within the first 2 months of therapy, and most patients reported mild to moderate symptoms. Phosphenes lead to treatment discontinuation in < 1% of patients, and most resolved during or after treatment.

• CONTRAINDICATIONS

• Acute decompensated heart failure
• Clinically significant hypotension
• Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present
• Clinically significant bradycardia
• Severe hepatic impairment
• Pacemaker dependence (heart rate maintained exclusively by the pacemaker)
• Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors

• PRECAUTIONS

• Kidney disease
• CrCl ≥ 15 ml/min - no dose adjustment necessary
• CrCl < 15 ml/min - has not been studied. Manufacturer makes no specific recommendation.

• Liver disease
• Mild to moderate (Child-Pugh A or B) - no dose adjustment necessary
• Severe (Child-Pugh C) - DO NOT USE. Has not been studied, and increased exposure is expected.

• Pregnancy
• Ivabradine may cause fetal toxicity when administered to pregnant women based on findings in animal studies. Embryo-fetal toxicity and cardiac teratogenic effects were observed in fetuses of pregnant rats treated during organogenesis at exposures 1 to 3 times the human exposures. Women of reproductive potential should use contraception while taking ivabradine.

• Conduction abnormalities
• Ivabradine slows the heart rate (see heart rate decrease above). Bradycardia, sinus arrest, and heart block have occurred in patients receiving ivabradine. Risk factors for bradycardia include sinus node dysfunction, conduction defects (e.g. 1st or 2nd degree AV block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (e.g. digoxin, diltiazem, verapamil, amiodarone). Bradycardia may also increase the risk of QT prolongation and other ventricular arrhythmias including torsades de pointes. Do not use ivabradine in patients with 2nd degree atrioventricular block unless a functioning demand pacemaker is present.

• Pacemakers
• Ivabradine dosing is based on heart rate reduction with a target heart rate of 50 - 60 bpm in adults. Patients with demand pacemakers set to a rate ≥ 60 beats per minute cannot achieve a target heart rate < 60 beats per minute, and ivabradine is not recommended in these patients.

• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.


• Ivabradine
• CYP3A4 moderate and strong inhibitors - DO NOT COMBINE. Ivabradine is a CYP3A4 sensitive substrate, and CYP3A4 moderate and strong inhibitors increase its exposure.
• CYP3A4 inducers - DO NOT COMBINE. Ivabradine is a CYP3A4 sensitive substrate, and CYP3A4 inducers reduce its exposure.
• Medications that slow the heart rate - Ivabradine slows the heart rate. When it is taken with other medications that slow the heart rate, the effect may be potentiated. Many patients with heart failure take beta blockers. In ivabradine trials, inclusion criteria required that beta blocker therapy be stable with a resting heart rate ≥ 70 bpm. Monitor heart rate closely when combining ivabradine with negative chronotropes.
• Medications that slow the heart rate include:
  • Amiodarone (Cordarone®)
  • Beta blockers
  • Calcium channel blockers (diltiazem and verapamil)
  • Clonidine (Catapres®)
  • Digoxin (Lanoxin®)
  • Fingolimod (Gilenya®)
  • Siponimod (Mayzent®)

• Metabolism and clearance
• CYP3A4 - sensitive substrate

• DOSING

• Dosage forms
• Tablets
• 5 mg
• 7.5 mg
• No generic. Cost > $150/month
• Oral solution
• 5 mg/5 ml ampule
• Comes in carton with 28 ampules
• No generic. Cost > $150/month

• Dosing (adults)
• Starting: 5 mg twice daily with food. Assess patient after two weeks and adjust dose to achieve a resting heart rate of 50 - 60 bpm as shown in table below.
• Max: 7.5 mg twice daily with food
• In patients with a history of conduction defects or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily
• Food delays absorption and increases overall exposure
• 5 mg tablets are scored so that they can be cut in half

• Dosing (pediatric)
• See Corlanor PI [sec 2] for pediatric recommendations

• LONG-TERM SAFETY

• Ivabradine was FDA-approved in 2015. When used appropriately, it appears to be safe.

• BIBLIOGRAPHY

• 1 - Ivabradine PI
• 2 - PMID 20801500 - Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study, Lancet (2010)