New first-in-class drug therapy for heart failure

Kathryn WheelerFDA approved ivabradine (Corlanor; Amgen Inc.) in April 2015 for use in patients with stable, symptomatic chronic heart failure, who have a left ventricular ejection fraction ≤ 35% and are in normal sinus rhythm with a resting heart ≥ 75 beats per minute. Patients must also be taking maximally tolerated doses of beta-blockers or have a contraindication to their use.

Ivabradine lowers heart rate by inhibiting the I_f current originating in the pacemaker cells of the sinoatrial node. The I_f current is key to the autonomic regulation of spontaneous heartbeats and, therefore, rate control. Rate control is an important aspect of treatment for patients with heart failure. Ivabradine is approved for the reducing the risk of hospitalizations due to worsening heart failure in indicated patients.

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Efficacy

The approval of ivabradine was based on the outcomes of the SHIFT trial, in which 3,241 participants received ivabradine and 3,264 participants received placebo. Eligible participants had symptomatic heart failure; had a left ventricular ejection fraction of 35% or less in sinus rhythm with a heart rate of 70 beats per minute (bpm) or higher; had a hospitalization within the previous year for heart failure; and were on a stable beta-blocker maintenance therapy, if tolerated. Most participants were also on ACE inhibitors or angiotensin receptor blockers, spironolactone, and diuretics.

The primary endpoint of the study was a composite of cardiovascular death or hospital admission for worsening heart failure. The median follow-up period in the study was 22.9 months. A time-to-event analysis demonstrated an 18% reduction in the hazard ratio (HR) for the primary endpoint in the ivabradine participant group compared to the placebo group of participants. (HR: 0.82, 95%; CI: 0.75, 0.9, P<0.0001) However, the treatment effect is driven primarily by a reduction in hospitalization rates for worsening heart failure, not by a significant mortality benefit. Increasing benefit of ivabradine trended with an increase in heart rate at study initiation.

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Safety

Ivabradine is generally well tolerated. The most common adverse events related to ivabradine include bradycardia (10% of ivabradine participants) and luminous phenomena. These effects are related to the mechanism of action and the dose administered. Luminous phenomena, known as phosphenes, are transient alterations in the perception of light (enhanced brightness in limited areas of the field of vision, halos, decomposition of the image, or multiple images). These effects are transient and probably due to the effect of the drug on similar I_h channels in the retina; they are reversible with drug discontinuation. Other adverse effects related to use of ivabradine include atrial fibrillation, conduction disturbances (including sinus arrest and heart block), and blurred vision.

Ivabradine is contraindicated in patients with: acute decompensated heart failure; blood pressure < 90/50 mmHg; resting heart rate < 60 bpm (prior to ivabradine initiation); co-administration of strong CYP3A4 inducers; severe hepatic impairment if their heart rate is pacemaker-dependent; and sick sinus syndrome, sinoatrial block, or third-degree heart block, unless a functioning demand pacemaker is present.

Dosage

The starting dose of ivabradine is 5 mg twice daily. After two weeks of therapy, the patient’s heart rate should be assessed and ivabradine dosage adjusted to achieve a resting heart rate between 50 and 60 bpm. The dose should be increased by 2.5 mg twice daily for a heart rate > 60 bpm and decreased by 2.5 mg twice daily for resting heart rates < 50 bpm. No dose adjustment is needed for mild to moderate hepatic impairment or renal impairment (CrCl >/= 15 mL/min).

Ivabradine has not been studied in patients with severe hepatic (Child-Pugh class C) or renal impairment (CrCl < 15 mL/min). Ivabradine is metabolized by CYP3A4. Concomitant administration with inhibitors or inducers of CYP3A4 can alter the serum levels of ivabradine. Ivabradine should be taken with meals.

References

1. Corlanor [package insert]. Thousand Oaks, CA: Amgen, Inc. Issued April 2015.

2. DiFrancesco, D. The role of the funny current in pacemaker activity. Circ Res. 2010; 106(3):434–446.

3. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomized placebo-controlled study. Lancet. 2010; 376(9744):875–885.

Kathryn Wheeleris associate clinical professor, Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.