By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
Ivabradine blocks the hyperpolarization-activated cyclic nucleotide-gated channel responsible for the cardiac pacemaker.1,2 The drug acts mainly at the sinoatrial node. Ivabradine was reviewed under the FDA’s priority review program and received fast track designation, which provides for expedited review and approval. Ivabradine is marketed by Amgen as Corlanor®.
INDICATIONS
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% in patients who are in sinus rhythm with resting heart rate of ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.1
DOSAGE
The recommended starting dose is 5 mg twice daily with meals.1 After 2 weeks, based on heart rate, the dose should be adjusted. The maximum dose is 7.5 mg twice daily. In patients with conduction defects or in whom bradycardia could compromise hemodynamics, the starting dose should be 2.5 mg twice daily. No dosage adjustment is required for patients with mild or moderate liver impairment or those with creatinine clearance 15 to 60 mL/min. It is contraindicated in patients with severe hepatic impairment. Ivabradine is available as 5 mg and 7.5 mg tablets.
POTENTIAL ADVANTAGES
Ivabradine offers an agent with a different mechanism of action for treatment of heart failure. Treatment resulted in a reduction of hospitalization.1
POTENTIAL DISADVANTAGES
Ivabradine did not show benefit in overall mortality or cardiovascular mortality.1 Common adverse events (compared to placebo) were hypertension (8.9% vs 7.8%) and atrial fibrillation (8.3% vs 6.6%). Visual brightness (phosphenes) was reported in 2.8% compared to 0.5%. Ivabradine is contraindicated or should be avoided in patients on strong or moderate cytochrome CYP3A4 inhibitors or 3A4 inducers.1 Embryo-fetal toxicity and teratogenicity have been shown in animal reproductive studies.1
COMMENTS
The efficacy and safety of ivabradine were evaluated in a randomized, double-blind, placebo-controlled study (n = 6558) in adult participants with stable NYHA class II to IV heart failure with left ventricular ejection fraction of ≤ 35% and resting heart rate ≥ 70 bpm.1,3 Participants had to be clinically stable for at least 4 weeks but hospitalized for heart failure within the past 12 months. Eighty-nine percent were on beta-blockers; however, only 26% were on guideline-defined target daily doses. Participants were randomized to ivabradine 5 mg twice daily or matching placebo. The dose could be increased to 7.5 mg twice daily or decreased to 2.5 mg twice daily. The primary efficacy endpoint was combined hospitalization for worsening heart failure or cardiovascular death based on time-to-event. The annual incidence rate was 14.5% patient-year for ivabradine compared to 17.7% for placebo (hazard ratio, 0.82; 95% confidence interval, 0.75-0.90). The drug effect was primarily in decreased hospitalization (9.2% patients-year vs 12.7%). The benefit of ivabradine appears to be inversely related to the dose of beta-blockers on board. Little benefit is observed in patients on guideline defined target dose of beta-blockers.1 Ivabradine showed no benefit in two large studies in subjects with stable coronary artery disease with or without stable heart failure.4,5 The first study (n = 12,473) enrolled subjects with coronary artery disease (CAD) and a left ejection fraction of ≤ 40%.4 After a median follow-up of 19 months, the addition of ivabradine did not improve the primary composite outcome (CV death, hospital admission for acute MI, or new onset/worsening heart failure) compared to placebo. The second study (n = 19,103) enrolled subjects with stable CAD without heart failure and heart rate of 70 beats per min or greater.5 In addition, about two-thirds had activity-limiting angina. Similarly, after a median follow-up of 27.8 months, the addition of ivabradine showed no improvement in outcomes (CV death or nonfatal MI) compared to placebo.
CLINICAL IMPLICATIONS
Ivabradine is the first-in-class drug for the treatment of heart failure. Its effect in reducing heart rate, by acting on the SA node, was most prominent at a higher heart rate thus minimizing the risk of bradycardia. Its role in therapy seems limited to those who need heart rate reduction and are unable to tolerate an effective dose of a beta blocker. The wholesale cost is $375 for a 30-day supply.
REFERENCES
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Corlanor Prescribing Information. Amgen. April 2015.
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Nawarskas JJ, et al. Ivabradine: A unique and intriguing medication for treating cardiovascular disease. Cardiol Rev 2015; April 1 Epub ahead of print].
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Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-885.
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Fox K, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfrunction (BEAUTIFUL): A randomised, double-blind, placebo-controlled trial. Lancet 2008;372:807-816.
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Fox K, et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371:1091-1099.
