Ivabradine is a selective inhibitor of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel that reduces heart rate by blocking the “funny current” in the sinoatrial node.
Tradename Corlanor.
Unlike beta-blockers and calcium channel blockers, ivabradine lowers heart rate without affecting blood pressure, myocardial contractility, or intracardiac conduction.
Ivabradine works by selectively blocking the intracellular aspect of the HCN transmembrane channel in sinoatrial nodal cells, which conducts a slow inward-depolarizing mixed sodium-potassium current.
This inhibition reduces the slope of diastolic depolarization of the pacemaker action potential, thereby slowing heart rate.
The drug exhibits use-dependent blockade, becoming more potent at faster heart rates—a particularly favorable attribute.
The therapeutic dose ranges from 2.5 to 7.5 mg administered twice daily, with peak plasma concentration occurring approximately 1 hour under fasting conditions.
Ivabradine undergoes extensive first-pass hepatic metabolism by cytochrome P450 enzyme CYP3A4.
In the United States, ivabradine (brand name Corlanor) is FDA-approved for:
Adult heart failure: 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 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
Pediatric heart failure: For treatment of stable symptomatic heart failure due to dilated cardiomyopathy in pediatric patients aged 6 months and older who are in sinus rhythm with an elevated heart rate.
Efficacy in heart failure: SHIFT trial (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) randomized 6,505 patients with NYHA class II-IV symptoms, LVEF ≤35%, and sinus rates ≥70 bpm to ivabradine versus placebo for a median of 23 months.
The trial demonstrated: 18% relative risk reduction endpoint of cardiovascular death or hospital admission for worsening heart failure.
Heart failure hospitalizations: 26% relative risk reduction.
Heart failure mortality: 26% relative risk reduction
Ivabradine did not reduce cardiovascular or all-cause mortality.
The treatment benefit was driven primarily by reduction in heart failure hospitalizations, which is why the FDA-approved indication is restricted to reducing hospitalization risk rather than mortality.
Ivabradine achieved an average heart rate reduction of 8 bpm in SHIFT, compared to 12 bpm reduction with beta-blockers in meta-analyses.
Benefits were particularly notable in patients with contraindications to beta-blockers, those on beta-blocker doses ≤50% of guideline-directed targets, and those with baseline heart rate ≥77 bpm.
A post-hoc analysis found that at baseline heart rate ≥75 bpm, time to benefit was shorter: primary outcome reduction occurred at 67 days, heart failure hospitalization at 78 days, and cardiovascular death at 169 days.
Ivabradine improves left ventricular ejection fraction promotes left ventricular reverse remodeling, and increases exercise capacity, though it does not significantly improve quality of life or reduce cardiovascular mortality.
Dosing
Starting dose: 5 mg orally twice daily with meals for most patients; 2.5 mg twice daily for patients with history of conduction defects.
Maximum dose: 7.5 mg twice daily
Target heart rate: 50-60 bpm if possible.
Dosing should be adjusted based on resting heart rate and tolerability. If minimal symptom improvement occurs, the drug should be discontinued.
Ivabradine is contraindicated in:
Acute decompensated heart failure
Clinically significant hypotension
Sick sinus syndrome, sinoatrial block, or 3rd degree AV block (unless functioning demand pacemaker present)
Clinically significant bradycardia
Severe hepatic impairment
Pacemaker dependence (heart rate maintained exclusively by pacemaker)
Concomitant use of strong CYP3A4 inhibitors
Ivabradine is not recommended in patients with 2nd degree AV block and should be avoided in those with known atrial or ventricular arrhythmias.
Adverse Effects
Most common cardiovascular adverse effect: Bradycardia, occurring at a rate of 6.0% per patient-year (2.7% symptomatic, 3.4% asymptomatic) compared to 1.3% with placebo.
Symptomatic bradycardia may manifest as dizziness or fatigue.
Atrial fibrillation: Ivabradine increases the risk of atrial fibrillation.
In SHIFT, the rate was 5.0% per patient-year with ivabradine versus 3.9% with placebo.
A meta-analysis demonstrated a 15% increased relative risk for atrial fibrillation.
Regular cardiac rhythm monitoring is recommended, and ivabradine should be discontinued if atrial fibrillation develops.
The most common non-cardiovascular adverse effect, consisting of transient brightness within the visual field due to effects on the hyperpolarization-activated current in the retina: These are typically mild, transient, and frequently improve over time.
In SHIFT, phosphenes occurred in 3% of ivabradine patients versus 1% on placebo.[5]
Fetal toxicity: Ivabradine may cause fetal toxicity based on animal studies. Women of reproductive potential should use effective contraception during treatment.[2][3]
Drug Interactions
Ivabradine is primarily metabolized by CYP3A4.
Strong CYP3A4 inhibitors include azole antifungals like itraconazole, macrolide antibiotics like clarithromycin, HIV protease inhibitors like nelfinavir, nefazodons, are contraindicated due to increased ivabradine plasma concentrations that may exacerbate bradycardia.
Moderate CYP3A4 inhibitors diltiazem, verapamil, grapefruit juice: concomitant use should be avoided.
CYP3A4 inducers (St. John’s wort, rifampicin, barbiturates, phenytoin): Avoid concomitant use as they can lower ivabradine efficacy.
The risk of bradycardia increases with concomitant administration of drugs that slow heart rate (digoxin, amiodarone, beta-blockers).
Heart rate monitoring should be done in patients taking ivabradine with other negative chronotropes.
Specific drug-drug interaction studies showed no clinically significant effect of ivabradine on the pharmacokinetics and pharmacodynamics of simvastatin.
Ivabradine is indicated only for patients in sinus rhythm, not those with persistent or chronic atrial fibrillation or those experiencing 100% atrial pacing.
A history of paroxysmal atrial fibrillation is not a contraindication; in SHIFT, nearly 10% of patients had paroxysmal atrial fibrillation history, with a requirement for sinus rhythm at least 40% of the time.
Beta-blockers remain the preferred therapy for heart rate reduction in HFrEF due to their mortality benefits, which were not demonstrated with ivabradine.
Patients should be on maximally tolerated doses of beta-blockers before considering ivabradine.
Ivabradine has not been shown to be effective for chronic stable angina in the absence of heart failure.
The SIGNIFY trial showed higher rates of death and nonfatal myocardial infarction in angina patients receiving ivabradine compared to placebo, and it should not be used for angina without heart failure.
In patients with inappropriate sinus tachycardia or postural orthostatic tachycardia syndrome, it has shown promise.