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Home , Ivabradine

STEPS New Drug Reviews

Ivabradine (Corlanor) for KYLE DAVIS, PharmD, BCPS, Ochsner Medical Center, New Orleans, Louisiana ERIC DIETRICH, PharmD, BCPS, University of Florida Colleges of Medicine and Pharmacy, Gainesville, Florida

STEPS new drug reviews Ivabradine (Corlanor) is labeled for the reduction of hospitalizations in patients with chronic cover Safety, Tolerability, systolic heart failure. It inhibits the so-called funny current within the , reduc- Effectiveness, Price, and 1 Simplicity. Each indepen- ing without lowering blood pressure. Ivabradine is added to preexisting maximal dent review is provided medical treatment. by authors who have no financial association with the drug manufacturer. Drug Dosage Dose form Cost* This series is coordinated by Allen F. Shaughnessy, Ivabradine (Corlanor) 5 mg twice daily 5- and 7.5-mg tablets $390 PharmD, MMedEd, Con- 2.5 mg twice daily in patients with tributing Editor. a history of conduction defects A collection of STEPS pub- lished in AFP is available *—Estimated retail price of one month’s treatment based on information obtained at http://www.goodrx.com (accessed February 16, 2016). at http://www.aafp.org/ afp/steps.

SAFETY and should therefore be avoided. Rifampin, , , and hyperten- phenytoin (Dilantin), and other inducers of sion may occur in patients taking ivabradine. CYP3A4 may reduce its effect.3 Ivabradine is As demonstrated in clinical trials, 5.3% to a U.S. Food and Drug Administration preg- 9% of patients will develop atrial fibril- nancy category D drug. lation vs. 3.8% to 8% of patients treated with placebo (number needed to treat to TOLERABILITY harm = 55 to 100). Bradycardia will occur Approximately one in six patients will dis- in 10% to 13% of patients, most notably in continue ivabradine due to adverse effects, those with cardiac conduction disorders, with 1% of discontinuations attributed to a low resting heart rate, and in patients bradycardia.2 On average, ivabradine reduces also taking digoxin, , , heart rate by 11 bpm. At the beginning of or amiodarone. Conduction disturbances treatment, patients may experience luminous such as sinus arrest and may phenomena (phosphenes) caused by a direct also occur.2,3 effect of the drug on the retina, described as Ivabradine is contraindicated in patients colored bright lights, image decomposition, with severe hepatic impairment, sick sinus halos, and enhanced brightness. These dis- syndrome, sinoatrial block, second- or third- turbances often resolve during treatment or degree atrioventricular block (unless a func- shortly after discontinuation.3 tioning demand pacemaker is present), a resting heart rate less than 60 beats per EFFECTIVENESS minute (bpm), or pacemaker dependence.3 Ivabradine was evaluated in a single study Ivabradine is metabolized by the cyto- of 6,505 patients with stable New York chrome P450 (CYP450) system. Verapamil, Heart Association class II to class IV diltiazem, macrolide antibiotics, protease systolic heart failure. These patients had inhibitors, and other moderate to strong been hospitalized at least once for heart CYP3A4 inhibitors may potentiate its effect failure in the previous 12 months and were ▲

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already receiving optimal therapy, includ- abnormalities should be initiated on a ing maximally tolerated dosages of beta reduced dosage of 2.5 mg twice daily. blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin recep- Bottom Line tor blockers (ARBs), spironolactone, and In patients with stable systolic heart failure diuretics. The addition of ivabradine sig- already on maximal therapy, nificantly reduces the combined outcome adding ivabradine may reduce the number of hospitalizations from heart failure and of hospitalizations related to heart failure cardiovascular death (24% vs. 29% for pla- (NNT for two years = 20), but it does not cebo; number needed to treat [NNT] for two reduce cardiovascular mortality. In addi- years = 26; 95% confidence interval, 18.5 to tion, many patients will not tolerate the 47.3).2 Specifically, ivabradine significantly drug and will stop taking it. Patients should reduces the rate of hospitalizations due to be monitored for the development of atrial heart failure by five percentage points from fibrillation and bradycardia. a baseline of 21% (NNT for two years = 20). Address correspondence to Kyle Davis, PharmD, BCPS, However, overall cardiovascular mortality is at [email protected]. Reprints are not available not significantly decreased. It may be associ- from the authors. ated with a reduction in heart failure–related Author disclosure: No relevant financial affiliations. mortality.2,4 Ivabradine has not been studied in patients with heart failure who have pre- REFERENCES served ejection fraction. 1. Joannides R, Moore N, Iacob M, et al. Comparative effects of ivabradine, a selective heart rate-lowering PRICE agent, and propranolol on systemic and cardiac hae- A one-month supply of ivabradine costs modynamics at rest and during exercise. Br J Clin Phar- macol. 2006;61(2):127-137. approximately $390. This is in addition to 2. Swedberg K, Komajda M, Böhm M, et al.; SHIFT the cost of maximally tolerated therapy with Investigators. Ivabradine and outcomes in chronic a , ACE inhibitor or ARB, aldo- heart failure (SHIFT): a randomised placebo-controlled study [published correction appears in Lancet. sterone antagonist, and diuretic. 2010;376(9757):1988]. Lancet. 2010;376(9744): 875-885. SIMPLICITY 3. National Institutes of Health. Daily Med. Drug label Before starting ivabradine, patients should information: Corlanor–ivabradine hydrochloride tab- let, film coated. http://dailymed.nlm.nih.gov/dailymed/ be on maximally tolerated dosages of a beta drugInfo.cfm?setid=92018a65-38f6-45f7-91d4- blocker, an ACE inhibitor or ARB, and an a34921b81d0d#section-3. Accessed October 12, 2015. aldosterone antagonist.5 They should have 4. Effect of metoprolol CR/XL in chronic heart failure: a resting heart rate greater than 70 bpm and Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999; stable symptoms. The starting dosage is 5 mg 353(9169):2001-2007. twice daily. After two weeks the dosage can 5. McMurray JJ, Adamopoulos S, Anker SD, et al.; ESC be increased to a maximum of 7.5 mg twice Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic daily in patients with a heart rate greater heart failure 2012: The Task Force for the Diagnosis and than 60 bpm. The dosage should be low- Treatment of Acute and Chronic Heart Failure 2012 of ered to 2.5 mg twice daily in patients with a the European Society of Cardiology. Developed in col- laboration with the Heart Failure Association (HFA) of heart rate less than 50 bpm and symptoms the ESC [published correction appears in Eur Heart J. of bradycardia. Patients with conduction 2013;34(2):158]. Eur Heart J. 2012;33(14):1787-1847. ■

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