By: Svetlana Akbasheva, Staff Editor

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For years, the medications that have been the mainstay of therapy for chronic heart failure have been angiotensin converting enzyme (ACE) inhibitors (or angiotensin receptor blockers), beta-blockers, loop diuretics, and aldosterone antagonists, with the occasional addition of digoxin or the hydralazine/isosorbide dinitrate combination.¹ Now, a novel medicine is trying to make its way into this exclusive circle. On April 15^th 2015, the FDA approved Amgen’s ivabradine (Corlanor^®) for the indication of reducing hospitalizations in chronic heart failure patients.²

The utility of ivabradine in heart failure is attributed to its mechanism of slowing down the heart rate by blocking the activation pathway of the cardiac pacemaker I_f current. Unlike other medications that exhibit negative chronotropic effects, ivabradine is unique in that it exclusively affects heart rate and has no effect on the force of contraction of the heart. It is important to note that ivabradine is not indicated for all chronic heart failure patients. Ideal candidates are those with a left ventricular ejection fraction ≤ 35% and a baseline heart rate of at least 70 beats per minute who are at maximum therapeutic doses of or have contraindications to beta-blocker therapy.³

Ivabradine has several important contraindications that must be ruled out prior to initiating therapy. Patients with acute decompensated heart failure should not receive ivabradine. In addition, patients with a baseline resting heart rate of less than 60 beats per minute or whose blood pressure is below 90/50 mmHg are excluded from therapy. Patients with sick sinus syndrome, sinoatrial block, or 3^rd degree AV block may receive this medication only if they have a functioning demand pacemaker. However, any patient that is fully dependent on a pacemaker to maintain their heart rate should not receive ivabradine.

Since ivabradine is primarily metabolized by CYP3A4, concurrent use of strong inhibitors of this enzyme is contraindicated due to the risk of drug buildup and toxicity. Although moderate CYP3A4 inhibitors such as diltiazem, verapamil, and grapefruit juice are not contraindicated, they should be avoided. Finally, severe hepatic impairment, indicated by a Child-Pugh score of C, precludes the use of ivabradine.³

For patients starting ivabradine therapy, the target is to achieve a heart rate of 50 to 60 beats per minute. Initiation with a dose of 5 mg twice daily with food is recommended. However, an exception is patients with a history of conduction defects or in whom bradycardia could be dangerous; this population should begin with the lower dose of 2.5 mg twice daily. After initiating therapy, dose adjustments should be made until the target heart rate is achieved. For patients with a heart rate above 60 beats per minute on their current regimen, the dose may be increased by 2.5 mg twice daily up to the maximum recommended dosage of 7.5 mg twice daily.

Conversely, patients whose heart rate drops below 50 beats per minute should have their dose decreased by 2.5 mg twice daily. If a patient’s heart rate remains under 50 even at the lowest dose of 2.5 mg twice daily, then ivabradine should be discontinued. Although ivabradine does not require any dosage adjustments in mild to moderate hepatic or renal impairment, it has not been studied in patients with a creatinine clearance less than 15 ml/min.³

The most severe adverse effects of ivabradine seen in clinical trials are atrial fibrillation and bradycardia. Patients’ cardiac rhythm should be assessed periodically while on ivabradine and the medication should be discontinued if atrial fibrillation is confirmed. Bradycardia is particularly risky in patients who are also on beta-blockers or other negative chronotropes. Ivabradine can also cause visual disturbances, often characterized by increased visual brightness, due to its effects on receptors in the retina. In addition, animal studies have shown that ivabradine can cause fetal toxicity, so women of childbearing age should avoid getting pregnant while on this medication.³

It is important to distinguish that the Systolic Heart Failure Treatment with I_f inhibitor Ivabradine Trial (SHIFT), which showed a decreased rate of hospitalizations with ivabradine compared to placebo, showed no effect of ivabradine on mortality from heart failure. In addition, two other trials showed no benefit of ivabradine in delaying cardiovascular death or myocardial infarction in patients with stable coronary artery disease, both with and without heart failure.³ Thus, each patient must be carefully assessed to see whether the anticipated benefit with this new medication is justified for his or her particular condition.

SOURCES:

1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327.
2. FDA approves Corlanor to treat heart failure. Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm442978.htm. Updated 04/17/2015. Accessed 04/25/2015.
3. Corlanor (ivabradine) [package insert]. Thousand Oaks, CA: Amgen Inc.; Revised April 2015.

[pubmed_related keyword1=”chronic” keyword2=”heart” keyword3=”failure”]

 

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