CHF and arrhythmias:
Indications for: CORLANOR
To reduce the risk of hospitalization for worsening heart failure in adults with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with resting heart rate ≥70bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Treatment of stable symptomatic heart failure due to dilated cardiomyopathy (DCM) in children ≥6mos old who are in sinus rhythm with an elevated heart rate.
Heart Failure in Adult Patients: SHIFT
The randomized, double-blind Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) compared the efficacy of Corlanor to placebo in 6558 adult patients with stable New York Heart Association (NYHA) class II to IV heart failure, left ventricular ejection fraction ≤ 35%, and resting heart rate ≥ 70 bpm. Eligible patients included the following:
Clinically stable for at least 4 weeks on an optimized and stable clinical regimen, which included maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and diuretics, with fluid retention and symptoms of congestion minimized.
Hospitalized for heart failure within 12 months prior to study entry.
Patients were randomly assigned to receive Corlanor 5 mg (or matching placebo) twice daily, followed by either an increase to 7.5 mg twice daily or decrease to 2.5 mg twice daily to maintain the resting heart rate between 50 and 60 bpm, as tolerated. The primary endpoint was a composite of the first occurrence of either hospitalization for worsening heart failure or cardiovascular death.
Most patients (89%) were taking beta-blockers, with 26% on guideline-defined target daily doses. Most patients were also taking ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). Few patients had an implantable cardioverter-defibrillator (ICD) (3.2%) or a cardiac resynchronization therapy (CRT) device (1.1%). Median follow-up was 22.9 months. At 1 month, 63%, 26%, and 8% of Corlanor-treated patients were taking 7.5, 5, and 2.5 mg BID, whereas 3% had withdrawn from the drug, primarily for bradycardia.
Results from SHIFT showed that Corlanor reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis (hazard ratio: 0.82; 95% CI, 0.75-0.90; P < 0.0001). The incidence of the primary composite endpoint occurred in 24.5% of patients in the Corlanor group vs 28.7% of patients in the placebo group. The treatment effect reflected only a reduction in the risk of hospitalization for worsening heart failure (15.6% for Corlanor vs 20.2% for placebo); there was no favorable effect on the mortality component of the primary endpoint. In the overall treatment population, Corlanor had no statistically significant benefit on cardiovascular death.
Most of the results show effects consistent with the overall study result. Corlanor’s benefit on the primary endpoint in SHIFT appeared to decrease as the dose of beta-blockers increased, with little if any benefit demonstrated in patients taking guideline-defined target doses of beta-blockers.
Heart Failure in Adult Patients: BEAUTIFUL and SIGNIFY: No benefit in stable coronary artery disease with or without stable heart failure
The randomized, double-blind, placebo-controlled Morbidity-mortality Evaluation of the If Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction Trial (BEAUTIFUL) evaluated the effects of ivabradine in 10,917 adults with coronary artery disease, impaired left ventricular systolic function (ejection fraction < 40%) and resting heart rate ≥ 60 bpm. Patients had stable symptoms of heart failure and/or angina for at least 3 months and were receiving conventional cardiovascular medications at stable doses for at least 1 month. Beta-blocker therapy was not required, nor was there a protocol mandate to achieve any specific dosing targets for patients who were taking beta-blockers.
Patients were randomly assigned 1:1 to receive Corlanor or placebo at an initial dose of 5 mg twice daily with the dose increased to 7.5 mg twice daily depending on resting heart rate and tolerability. The primary endpoint was the composite of time to first cardiovascular death, hospitalization for acute myocardial infarction, or hospitalization for new-onset or worsening heart failure. Most patients were NYHA class II (61.4%) or class III (23.2%) - none were class IV. Through a median follow-up of 19 months, Corlanor did not significantly affect the primary composite endpoint (HR 1.00; 95% CI, 0.91-1.10).
The randomized, double-blind Study Assessing the Morbi-mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease Trial (SIGNIFY) compared Corlanor to placebo in 19,102 adults with stable coronary artery disease but without clinically evident heart failure (NYHA class I). Beta-blocker therapy was not required. Patients were initiated at Corlanor 7.5 mg twice daily and the dose could be increased to as high as 10 mg twice daily or down-titrated to 5.0 mg twice daily to achieve a target heart rate of 55 to 60 bpm. The primary endpoint was a composite of the first occurrence of either cardiovascular death or myocardial infarction. Results showed that treatment with Corlanor did not significantly affect the primary composite endpoint through a median follow-up of 24.1 months (HR 1.08; 95% CI, 0.96-1.20).
Heart Failure in Pediatric Patients
Corlanor was evaluated for its effect on heart rate in a multi-center, randomized, double-blind, placebo-controlled trial in 116 children aged 6 months to less than 18 years with symptomatic DCM who were in sinus rhythm, NYHA/Ross class II to IV heart failure, and left ventricular ejection fraction ≤ 45%. Patients were required to be clinically stable for at least 4 weeks and on optimized medical therapy with a resting heart rate (HR) complying with the following criteria:
HR ≥ 105 bpm in the age-subset 6–12 months.
HR ≥ 95 bpm in the age-subset 1–3 years.
HR ≥ 75 bpm in the age-subset 3–5 years.
HR ≥ 70 bpm in the age-subset 5–18 years.
Patients were randomly assigned 2:1 to receive Corlanor or placebo. Patients received dose titration of Corlanor over a 2- to 8-week period to achieve a 20% heart rate reduction without inducing bradycardia.
At the end of the titration period, a significantly higher proportion of patients treated with Corlanor achieved the target heart rate reduction vs. placebo (72% vs. 16% respectively; Odds Ratio = 15; 95% CI, 5-47). A statistically significant reduction in HR was observed with Corlanor compared to placebo at the end of the titration period (-23 ± 11 bpm vs. -2 ± 12 bpm respectively).
Take with food. May use oral soln if unable to swallow tabs. ≥18yrs: Initially 5mg twice daily. Adjust dose after 2 weeks to achieve resting heart rate 50–60bpm (see full labeling); then adjust dose as needed based on resting heart rate and tolerability. Max: 7.5mg twice daily. History of conduction defects or if bradycardia can lead to hemodynamic compromise: initially 2.5mg twice daily.
<6mos: not established. Take with food. ≥6mos: <40kg (use oral soln with calibrated oral syringe): initially 0.05mg/kg twice daily. Adjust dose at 2-week intervals by 0.05mg/kg to achieve target heart rate reduction of ≥20%, based on tolerability. Max: 6mos–<1yr: 0.2mg/kg twice daily; ≥1yr: 0.3mg/kg twice daily, up to total of 7.5mg twice daily. ≥40kg (use tabs or oral soln): initially 2.5mg twice daily. Adjust dose at 2-week intervals by 2.5mg to achieve target heart rate reduction of ≥20%, based on tolerability. Max: 7.5mg twice daily. If bradycardia develops, reduce dose to the previous titration step. If bradycardia develops at the initial dose: consider reducing to 0.02mg/kg twice daily.
Acute decompensated heart failure. Clinically significant hypotension. Sick sinus syndrome, sinoatrial block, or 3rd degree AV block, unless paced. Clinically significant bradycardia. Severe hepatic impairment. Pacemaker dependence. Concomitant strong CYP3A4 inhibitors (eg, itraconazole, clarithromycin, telithromycin, nelfinavir, nefazodone).
Monitor cardiac rhythm regularly; discontinue if atrial fibrillation develops. Increased risk of bradycardia with sinus node dysfunction, conduction defects (eg, 1st or 2nd degree AV block, bundle branch block), ventricular dyssynchrony. Avoid in 2nd degree AV block, unless paced. Demand pacemakers set to rates ≥60bpm: not recommended. Embryo-fetal toxicity. Pregnancy: monitor (esp. 3rd trimester for preterm birth). Advise females of reproductive potential to use effective contraception during treatment. Nursing mothers: not recommended.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker.
See Contraindications. Avoid concomitant moderate CYP3A4 inhibitors (eg, diltiazem, verapamil, grapefruit juice). Avoid concomitant CYP3A4 inducers (eg, St. John's wort, rifampicin, barbiturates, phenytoin). Increased risk of bradycardia with concomitant negative chronotropes (eg, digoxin, amiodarone, beta-blockers); monitor.
Bradycardia, hypertension, atrial fibrillation, luminous phenomena (phosphenes); conduction disturbances.
Plasma levels decline with a distribution half-life of 2 hours and an effective half-life of approximately 6 hours. The excretion of metabolites occurs to a similar extent via feces and urine.
Generic Drug Availability:
Tabs—60; Ampules (5mL)—28