Ivabradine

Mechanism of Action

Ivabradine blocks the channel responsible for the cardiac pacemaker current, I(f), which regulates heart rate. This results in prolonged diastolic time and reduced heart rate.[4]

Rapid resting heart rate can lead to detrimental effects on left ventricular function and has been associated with negative outcomes in patients with cardiovascular disease. Therefore, reducing resting heart rate to reduce cardiovascular morbidity and mortality is a therapeutic target among drug manufacturers. Ivabradine reduces heart rate but does not affect myocardial contraction, relaxation, or ventricular repolarization.  

Administration

Ivabradine is available as tablets to be taken by mouth.

• The initial dose should be 5 mg, twice a day.
• The dose can be adjusted after 2 weeks based on the heart rate.
• The maximum dose is 7.5 mg, twice a day.
• Patients with conduction defects or bradycardia can be initiated on 2.5 mg, twice a day.
• The reduction in heart rate depends on the baseline heart rate and the ivabradine dose.

Dose Adjustment

• If the heart rate is more than 60, increase the dose by 2.5 mg, twice a day, up to 7.5 mg twice a day.
• If the heart rate is 50-60 bpm, continue the current dose.
• If the heart rate is less than 50 or the patient is experiencing symptoms of bradycardia, decrease the dose by 2.5 mg twice a day. If the dose is 2.5 mg twice daily, stop therapy.

Clinical Evidence

The SHIFT trial was a double-blind, placebo-controlled study of patients with symptomatic heart failure, ejection fraction (EF) less than or equal to 35%, in sinus rhythm with a heart rate of at least 70 beats per minute, who had been admitted for heart failure within the past year and were on stable heart failure treatment including beta-blockers. Patients received ivabradine titrated to 7.5 mg twice a day or placebo. The goal was to determine if ivabradine would decrease hospitalizations and/or mortality due to heart failure. Ivabradine reduced the primary endpoint, which was a composite of hospital admissions due to heart failure and mortality. Bradycardia and visual adverse effects (phosphenes) occurred more in patients receiving ivabradine than those in the placebo group.[5][6][7][8]

The BEAUTIFUL trial was a randomized, placebo-controlled, multinational trial to test whether reducing heart rate with ivabradine affected cardiovascular morbidity and mortality in patients with coronary artery disease and EF less than 40%. Patients had a resting heart rate of at least 60 beats per minute. Patients received ivabradine 5 mg twice a day with a goal of 7.5 mg twice a day versus placebo. Most patients were also on beta-blocker therapy. Ivabradine did not affect the primary composite endpoint of cardiovascular mortality, hospital admissions for myocardial infarctions, or worsening heart failure. In patients with heartbeats of 70 or greater, ivabradine reduced hospital admissions due to fatal or non-fatal myocardial infarction. 

SIGNIFY was a randomized trial that tested the addition of ivabradine to standard therapy in patients with stable coronary artery disease but no heart failure. Patients had to be at least 55 years old with a heart rate of 70 beats or more. The goal heart rate was 55 to 60 beats per minute. Patients received 10 mg of ivabradine twice a day or a placebo. The primary endpoint was a composite of death or nonfatal myocardial infarction. After 28 months, there was no significant difference between ivabradine and placebo. Bradycardia occurred more with ivabradine compared to placebo. The primary endpoint was higher in patients in the ivabradine group who initially had angina that limited activity.

Adverse Effects

The most common adverse effects include bradycardia, atrial fibrillation, high blood pressure, and phosphenes.

Ivabradine can cause bradycardia, sinus arrest, and heart block. Sinus node dysfunction, first- or second-degree atrioventricular block, bundle branch block, ventricular dyssynchrony, and or concomitant use of other heart-rate reducing drugs increase the risk of bradycardia. In the SHIFT trial, symptomatic bradycardia occurred in 5% of patients taking ivabradine compared to 1% in the placebo group. Asymptomatic bradycardia occurred in 6% of patients on ivabradine compared to 1% in the placebo group. Bradycardia led to permanent withdrawal from the study in 1% of patients on ivabradine and less than 1% of those in the placebo group.

Ivabradine is metabolized by CYP3A4. Concomitant use of verapamil or diltiazem with ivabradine should be avoided. Verapamil and diltiazem are CYP3A4 inhibitors; they increase ivabradine levels and hence the risk of bradycardia. 

QT prolongation, torsade de pointes, and other arrhythmias may occur as a result of ivabradine-induced bradycardia.  

Ivabradine increases the risk of atrial fibrillation. Discontinue ivabradine if atrial fibrillation occurs.

Visual effects (phosphenes) were observed in clinical trials. It has been proposed that this is due to ivabradine's inhibition of I(h) current in the retina. In the SHIFT trial, known phosphenes occurred in 3% of patients taking the ivabradine compared to less than 1% in the placebo group. This difference in the occurrence of phosphenes was statistically significant.

Ivabradine has been shown to cause fetal toxicity in animal studies.

Postmarketing adverse effects of ivabradine include syncope, hypotension, angioedema, erythema, rash, pruritis vertigo, and diplopia.

Contraindications

Ivabradine is contraindicated in the following situations:

• Decompensated heart failure
• Blood pressure less than 90/50
• Conduction abnormalities, e.g., sick sinus syndrome, sinoatrial block, or third-degree AV block, unless a pacemaker determines the heart rate
• Severe liver impairment
• Patients taking cytochrome P450 3A4 (CYP3A4) inhibitors
• Resting heart rate less than 60 before therapy initiation

Monitoring

• Monitor cardiac rhythm
• Monitor heart rate
• Monitor for symptoms of bradycardia
• Monitor pregnant women for preterm birth with chronic heart failure in the third trimester of pregnancy

Toxicity

Fetuses of pregnant rats had embryo-fetal toxicity and cardiac teratogenic effects when treated at exposures 1 to 3 times the human exposures at the maximum recommended human dose. No adequate studies of ivabradine in pregnant women provide information on the drug's possible risk to the mother or fetus. Contraception is recommended in female patients taking ivabradine.

Enhancing Healthcare Team Outcomes

Ivabradine is FDA-approved in the United States for use in patients with symptoms due to stable heart failure and an ejection fraction of 35% or less to reduce their risk of hospital admission for worsening heart failure. The management of patients with heart failure is usually by an interprofessional team that includes a cardiologist, intensivist, internist, nephrologist, pulmonologist, family clinician, nursing staff, and pharmacist. Healthcare providers who prescribe ivabradine should monitor the patient's heart rate regularly. The drug can cause bradycardia, and concomitant beta-blocker agents are not recommended.[9][10] Interprofessional communication and coordination will increase the effectiveness of ivabradine therapy while minimizing adverse effects and interactions, thereby improving patient outcomes. [Level 5]