Ivadradine - ProCEs3.proce.com/res/pdf/hpjfdr/2015Oct.pdfthe maximum tolerated dose of beta-blockers or have a contraindication to beta-blocker use.1,2 Ivabradine was approved by the

806 Volume 50, October 2015

Formulary Drug Reviews

Ivadradine

Dennis J. Cada, PharmD, FASHP, FASCP (Editor)*; Ross Bindler, PharmD†; and Danial E. Baker, PharmD, FASHP, FASCP‡

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page sum-mary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also avail-able on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more informa-tion about The Formulary Monograph Service, call The Formulary at 800-322-4349. The October 2015 monograph topics are sacubitril/valsartan, daclatasvir, sonidegib, alirocumab, and sodium zirconium cyclosilicate. The Safety MUE is on sacubitril/valsartan.

*Founder and Contributing Editor, The Formulary; †Drug Information Resident, College of Pharmacy, Washington State Univer-sity Spokane; ‡Director, Drug Information Center, and Professor of Pharmacy Practice, College of Pharmacy, Washington State University Spokane. The authors indicate no relationships that could be perceived as a conflict of interest.

Generic Name: Ivabradine

Proprietary Name: Corlanor (Amgen)

Approval Rating: 1P

Therapeutic Class: I(f) Current Inhibitors in Sinoatrial Node

Similar Drugs: None

Sound- or Look-Alike Names: Ibuprofen, Imbruvica, Invirase

INDICATIONSIvabradine is approved by the US Food and Drug

Administration (FDA) to reduce the risk of hospitaliza-tion (due to worsening heart failure) in adult patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction (LVEF) of 35% or less, who are in sinus rhythm with a resting heart rate of at least 70 beats per minute (bpm), and who are receiving the maximum tolerated dose of beta-blockers or have a contraindication to beta-blocker use.1,2 Ivabradine

was approved by the European Medicines Agency in 2005 for the symptomatic treatment of stable angina; in 2012, the drug was approved for chronic heart fail-ure in patients with elevated heart rate.3,4 The release of preliminary results from the SIGNIFY study in May 2014 prompted the European Medicines Agency to review the marketing status of ivabradine.5

Multiple confirmatory studies of the SHIFT trial have been conducted since its conclusion, indicat-ing that, compared with placebo, ivabradine therapy results in a significant decrease in New York Heart Association (NYHA) class and a significant reduc-tion in heart rate when administered to patients with a heart rate above 70 bpm. Possible improve-ment in patient quality of life has also been noted.6-11 Ivabradine may also decrease aortic stiffness after 1 year of treatment.8

A few studies have also evaluated the potential role of ivabradine in the treatment of sinus tachy-cardia, postural orthostatic tachycardia syndrome, vasovagal syncope, and multiple organ dysfunc-tion.12-14 Other ivabradine trials evaluated its effects on the following: left ventricular remodeling in a

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Hospital Pharmacy 807


perfused heart after myocardial infarction, cardio-genic shock, as a bridge agent in atrial tachycardia, for prevention of dobutamine-induced increased heart rate in patients with heart failure, tachycar-dia in a renal transplant patient, in a patient with nemaline myopathy and heart failure, and with con-current lisinopril and a multivitamin supplement for the treatment of anthracycline-induced severe cardiotoxicity.15-21

CLINICAL PHARMACOLOGYIvabradine and its active metabolite, S-18982,

selectively inhibit the If current, which is the pri-mary modulator of diastolic depolarization (the pacemaker current), at the sinoatrial node.1,22 Due to effects on the sinoatrial node, ivabradine delays phase 4 depolarization, resulting in bradycardia with no effects on ventricular repolarization or myo-cardial contractility.1,14 If is a sodium and potassium inward current important in diastolic pacemaker depolarization and is activated by cardiomyocyte hyperpolarization.23

At regular therapeutic concentrations, ivabradine and S-18982 have no major action on other cardiac or vascular ion channels and no direct effects on car-diomyocyte contractility or electrochemical conduc-tion within the heart.22 The heart rate–lowering effect of ivabradine appears to occur without negative ino-tropic effects or vascular constriction effects.1,23 The reduction in heart rate is dose dependent, and the size of the effect is dependent on the patient’s baseline heart rate (eg, greater reductions in heart rate occur in patients with higher baseline heart rate). The average reduction in heart rate with recommended ivabradine doses is 10 bpm at rest and during exercise.1

Ivabradine can also interact with the Ih current, which closely resembles the If current and is located in the retina, possibly altering the visual system.1

PHARMACOKINETICSIvabradine exhibits nearly linear pharmacokinet-

ics between the oral dosages of 0.5 and 24 mg, with no apparent effect due to patient age.1 Patients with a creatinine clearance (CrCl) between 15 and 60 mL/min demonstrated an approximately 20% decrease in elimination for both ivabradine and its metabolite (S-18982), compared with those with a CrCl greater than 60 mL/min.3 In patients with a Child-Pugh score of up to 7 (mild hepatic impairment), ivabradine and S-18982 area under the curve (AUC) was approxi-mately 20% higher than in patients with normal hepatic function.3

Ivabradine is rapidly absorbed following oral administration, and maximum plasma concentration (Cmax) is achieved 1 hour following oral administra-tion.1 Due to the film coating and first-pass elimina-tion in the gut and liver, the absolute bioavailability is about 40%.1 When ivabradine was administered with food, absorption was delayed by approximately 1 hour and increased exposure by 20% to 40%.1

Protein binding is approximately 70%, and vol-ume of distribution at steady state is approximately 100 L.1

The main mechanism for metabolism of ivabradine is through the liver and gut via oxidation by cytochrome P450 (CYP-450) 3A4; ivabradine is metabolized by N-desmethylation to S-18982, an active metabolite in humans.1 S-18982 is equipo-tent to ivabradine and circulates at concentrations approximately 40% that of ivabradine. The distribu-tion half-life of ivabradine is 2 hours and its effec-tive half-life is approximately 6 hours; the half-life of S-18982 is 11 hours.1,22 Ivabradine does not induce or inhibit CYP3A4.3

Clearance of ivabradine is primarily via urine and feces, with a total clearance of 24 L/h and kidney clearance of 4.2 L/h.1 Equal amounts of metabolites are excreted through the urine and feces, and about 4% of the dose is excreted unchanged in the urine.1

When ivabradine 0.2 mg/kg was administered intravenously (IV) via a 15-second slow bolus push to 14 patients with supraventricular tachyarrhythmia but normal baseline electrophysiology, mean heart rate was decreased by 12.9 and 14.1 bpm at 30 min-utes and at 1 hour, respectively.23 Patient QT intervals also increased at both 30 minutes and 1 hour, but when corrected QT intervals were calculated using the Bazett formula, there were no changes from baseline.23 Sinus node recovery time increased from baseline at 1 hour after administration.23 There were no other changes in major electrophysiological parameters.23

No significant ivabradine pharmacokinetic differ-ences, including AUC and Cmax, were found between patients with or without type 2 diabetes mellitus.22

COMPARATIVE EFFICACYIndication: Chronic Heart Failure

Guidelines Guideline: 2013 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guideline for the management of heart failure: A report of the ACCF/AHA Task Force on Practice Guidelines

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Reference: Yancy CW, et al, 201324 Comments: According to the guidelines, all comor-bidities in patients with chronic heart failure, such as hypertension and lipid disorders, should be adequately treated. Medications currently recom-mended for the treatment of chronic heart fail-ure include angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers, evi-dence-based beta-blockers, thiazide-type diuretics, loop diuretics in patients with volume overload, hydralazine or nitrates in patients who are symp-tomatic and self-identify as African American, as well as aldosterone antagonists in persons with a CrCl above 30 mL/min and potassium levels less than 5 mEq/dL. Digoxin use can have some ben-efit in the treatment of symptoms in patients with chronic heart failure.

Studies Drug: Ivabradine 7.5 mg vs Placebo

Reference: Swedberg K, et al, 2010; Swedberg K, et al, 2010; Ekman I, et al, 2011; Tardif JC, et al, 2011; Swedberg K, et al, 2012; Reil JC, et al, 2013; Borer JS, et al, 2014; Fox K, et al, 2013; Bohm M, et al, 2013 (SHIFT Trial)25-33 Study Design: Randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-group study Study Funding: Servier Patients: Patients had to be 18 years and older with NYHA class II, III, or IV chronic heart fail-ure with optimized and unchanged treatment for at least the past 4 weeks and a prior hospitalization for worsening heart failure within the past year. Also, patients had to have a resting heart rate of at least 70 bpm and left ventricular systolic dysfunc-tion documented by an ejection fraction of 35% or less within the past 3 months. Key exclusion crite-ria included myocardial infarction (MI) within the past 2 months or a scheduled coronary revascular-ization, severe primary valvular disease or sched-uled valvular surgery, stroke or transient ischemic accident within the previous 4 weeks, myocarditis, congenital heart diseases, currently listed for a car-diac transplant, diseases affecting the cardiomyo-cytes’ ability to transmit action potentials, severe or uncontrolled hypertension, systolic blood pressure of less than 85 mm Hg while sitting, symptomatic hypotension, and/or known moderate severe liver

disease, renal disease, or anemia. The SHIFT trial included 6,558 patients randomized to ivabradine (n = 3,268) or placebo (n = 3,290). Of the patients randomized, 27 were excluded from analysis in the ivabradine group (n = 3,241) and 26 were excluded from the placebo arm (n = 3,264); exclusions from analysis were due to no study drug being dispensed (n = 7) or removal of the study center because of invalid data detected upon study audit (n = 46). Median follow-up was 22.9 months. Intervention: Permuted-block randomization occurred following a 7- to 30-day run-in period, with stratification by center and by treatment with or without a beta-blocker at study entry. Patients received ivabradine 5 mg twice daily titrated to a goal of 7.5 mg twice daily or matching placebo twice daily. The ivabradine dose was titrated up to 7.5 mg twice daily, if the patient’s resting heart rate was at least 60 bpm following a 14-day trial period; if patient’s resting heart rate was between 50 and 60 bpm, the dose remained at 5 mg twice daily. If resting heart rate was 50 bpm or less or if the patient was experiencing any signs and/or symp-toms of bradycardia, the dose was decreased to 2.5 mg twice daily. The study treatment was added to previous background cardiovascular therapy, which was optimized according to contemporary guidelines. Results Primary Endpoint(s) • Composite endpoint consisting of the first

cardiovascular event leading to death or hos-pitalization for worsening heart failure in the modified intention-to-treat (ITT) population (ivabradine, n = 3,241; placebo, n = 3,264). In the ivabradine group, death occurred in 793 patients (24%) due to a cardiovascular cause or hospital admission for worsening heart fail-ure compared with 937 patients (29%) in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.75 to 0.9; P < .001); number needed to treat was 20.

Secondary Endpoint(s) • The composite of the first cardiovascular event

leading to patient death or hospitalization for worsening heart failure in patients receiving at least 50% of the target daily dose of patient-specific beta-blocker at baseline, according to the European Society of Cardiology guidelines:

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0 Of the patients included in the modified ITT population, 1,581 from the ivabradine arm (56%) and 1,600 in the placebo group (56%) were taking beta-blocker doses at least 50% of the target daily dose for the specific agent at inclusion; beta-blockers included carvedilol (46% in the ivabradine group; 44% in the placebo group), bisoprolol (24%; 26%), metoprolol succinate (14%; 14%) or tartrate (10%; 11%), nebivolol (3%; 3%), or another beta-blocker not included in the guidelines (2%; 2%). In subjects included in this subgroup analysis, there were no dif-ferences in the primary composite endpoint between the ivabradine and placebo groups (HR, 0.9; 95% CI, 0.77 to 1.04; P = .155), although there was a difference favoring ivabradine for the secondary endpoint of hospitalization for worsening heart failure (HR, 0.81; 95% CI, 0.67 to 0.97; P = .021).

0 In a secondary study of the SHIFT data focus-ing on the effects of ivabradine in congestive heart failure and determining whether beta-blockers had an influence on outcomes, 6,398 patients were included for analysis; 107 sub-jects were excluded for use of a nonrecom-mended beta-blocker.29 Patients not taking a beta-blocker at baseline (HR, 0.71; 95% CI, 0.55 to 0.93; P = .012), taking less than 25% of the recommended dose (HR, 0.74; 95% CI, 0.59 to 0.92; P = .007), or taking 25% to less than 50% of the recommended dose (HR, 0.81; 95% CI, 0.68 to 0.98; P = .029) were more likely to have a first cardiac event lead-ing to death or hospitalization for worsening heart failure.29 When the composite endpoint was separated by baseline beta-blocker use, it had no impact on cardiovascular death; but patients not taking a beta-blocker (HR, 0.62; 95% CI, 0.45 to 0.85; P = .003), tak-ing less than 25% of the recommended dose (HR, 0.68; 95% CI, 0.52 to 0.89; P = .005), or taking 25% to less than 50% of the rec-ommended dose (HR, 0.74; 95% CI, 0.59 to 0.93; P = .009) had a higher risk of hospital-ization for worsening heart failure.29

Endpoint(s) • All-cause mortality in the modified ITT popu-

lation: All-cause mortality was reported in 503 patients in the ivabradine group (16%) and 552 patients (17%) in the placebo arm (HR, 0.9; 95% CI, 0.8 to 1.02; P = .092).

• Any cardiovascular-related death in the modified ITT population: Cardiovascular death occurred in 503 patients (14%) in the ivabradine group and 491 patients (15%) in the placebo group (HR, 0.91; 95% CI, 0.8 to 1.03; P = .128).

• Hospitalization for worsening heart failure in the modified ITT study population: There were 514 patients (16%) randomized to the ivabradine arm admitted to a hospital for wors-ening heart failure compared with 672 patients (21%) from the placebo group (HR, 0.74; 95% CI, 0.66 to 0.83; P < .001); number needed to treat was 20.

• Any cardiovascular hospitalization in the modified ITT study population: Hospitaliza-tion due to a cardiovascular event occurred in 977 patients (30%) in the ivabradine arm and 1,122 subjects (34%) in the placebo arm (HR, 0.85; 95% CI, 0.78 to 0.92; P < .001); number needed to treat was 25.

• Death due to heart failure in the modified ITT population: 113 patients (3%) in the ivabradine group experienced death due to worsening heart failure, while death occurred in 151 patients (5%) randomized to receive placebo (HR, 0.74; 95% CI, 0.58 to 0.94; P = .014); number needed to treat was 50.

• Composite endpoint of cardiovascular death, hospitalization for worsening heart failure, or hospitalization for a nonfatal MI in the modi-fied ITT study population: 825 patients (25%) in the ivabradine group experienced a cardio-vascular death, hospitalization for worsening of heart failure, or nonfatal MI, compared with 979 patients (30%) in the placebo arm (HR, 0.82; 95% CI, 0.74 to 0.89; P < .001); number needed to treat was 20.

• Any changes in functionality, assessed via NYHA classification, and changes in clinical symptoms of the heart (assessed by the patient and/or investigator via global assessment ques-tionnaires) in the modified ITT population. For the last recorded value, 887 patients (28%) in the ivabradine group and 776 patients (24%) in the placebo group had documented improve-ment in NYHA class (P = .01). The patient-reported global assessment improved in 2,118 patients (72%) receiving ivabradine and 2,017 subjects (68%) in the placebo group (P < .001); physician-reported global assessment improved in 1,888 patients (61%) in the ivabradine arm

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and 1,772 (57%) in the placebo arm (P = .001). The number needed to treat for each outcome was 25.

Subgroup analysis or substudies of this study population

• Age: Ivabradine was favored in all patients except those 65 years and older (HR, 0.89; 95% CI, 0.77-1.02) and those with a resting baseline heart rate of less than 77 bpm (HR, 0.93; 95% CI, 0.8-1.08).26 Another substudy evaluated the impact of age (<53 years, < 60 years, 60 years to <69 years, and ≥69 years and older). In all age groups, ivabradine therapy demonstrated sig-nificant reductions in the composite endpoint of cardiovascular death or hospital admission for worsening heart failure, cardiovascular death alone, admission to a hospital for worsening heart failure alone, or death due to heart failure compared with placebo therapy. There was also a significant P value for the interaction between age and all endpoints, except cardiovascular death.35

• Health-related quality of life: 1,944 of the 6,505 patients in the main SHIFT study popula-tion completed the Kansas City Cardiomyopa-thy Questionnaire; both the overall summary score and clinical summary score were included to assess the effects of heart rate reduction on health-related quality of life. Kansas City Car-diomyopathy Questionnaire scores were higher at month 12 of treatment in the ivabradine group (n = 842) compared with the placebo arm (n = 839); patients receiving ivabradine had a clinical summary score of 1.8 points higher (95% CI, 0.3-3.42; P = .018) and an overall summary score of 2.4 points higher (95% CI, 0.91-3.85; P < .001) than placebo.27

• Impact on heart rate: There was a decrease in heart rate at month 12 in the ivabradine group (n = 881) compared with placebo (n = 876) (estimated decrease of −10.1 [95% CI, −11.1 to −9; P < .001]).27 An 8-month substudy examined the effects of ivabradine’s reduction in heart rate on left ventricular remodeling and function in 411 patients from the SHIFT trial (ivabradine, n = 208; placebo, n = 203).28 A substudy separated SHIFT study participants into categories based on resting heart rate: those with a resting heart rate of 75 bpm or greater (n = 4,150) and those with a resting heart rate below 75 bpm (n = 2,351).33

Patients with a heart rate of 75 bpm or greater and randomized to receive ivabradine (n = 2,052) had reduced risks of cardiovascu-lar death or hospitalization due to heart failure (HR, 0.76; 95% CI, 0.68 to 0.85; P < .0001), cardiovascular mortality (HR, 0.83; 95% CI, 0.71 to 0.97; P = .017), hospitalization due to worsening heart failure (HR, 0.7; 95% CI, 0.61 to 0.8; P < .001), all-cause mortality (HR, 0.83; 95% CI, 0.72 to 0.96; P = .011), death due to heart failure (HR, 0.61; 95% CI, 0.46 to 0.81; P < 0.001), cardiovascular hospitalization (HR, 0.79; 95% CI, 0.71 to 0.88; P < .001), and hos-pitalization due to any cause (HR, 0.82; 95% CI, 0.75 to 0.9; P < .001) compared with pla-cebo (n = 2,098); no differences were observed when the same endpoints were examined in patients with a heart rate less than 75 bpm (n = 2,351), regardless of whether the patients received ivabradine (n = 1,188) or placebo (n = 1,163).33 Also, in patients with a heart rate above 75 bpm at randomization and who had a heart rate reduction of greater than 10 bpm at day 28 of the trial, ivabradine reduced the risks of death due to a cardiovascular cause or hospitalization due to heart failure (HR, 0.63; 95% CI, 0.46 to 0.85; P = .003), cardiovascu-lar mortality (HR, 0.63; 95% CI, 0.42 to 0.92; P =0.018), admission to a hospital for heart fail-ure (HR, 0.56; 95% CI, 0.39 to 0.8; P = .002), and death due to heart failure (HR, 0.47; 95% CI, 0.0285; P = .029). In patients with a heart rate of less than 75 bpm at baseline and who had a reduction of at least 10 bpm, ivabradine reduced only the risk of hospital admission for heart failure (HR, 0.44; 95% CI, 0.27 to 0.72; P = .001).33 In a 24-hour Holter substudy, the heart rate–lowering effects of ivabradine were examined at baseline and at 8 months after randomization to either ivabradine (n = 298) or placebo (n = 304) titrated to the maximum dose of 7.5 mg twice daily. After 8 months, patients in the ivabradine group experienced a reduction of 9.3 bpm per day in heart rate from baseline (P < .001), while those randomized to placebo had a 1.2 bpm reduction per day (P < .001 for the difference between placebo and ivabradine). Heart rate was lowered with-out affecting patient safety in terms of increased risk of bradycardia, ventricular arrhythmias, or supraventricular arrhythmias.37

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• Left ventricular end-systolic volume index: After 8 months of treatment, the ivabradine group had better left ventricular end-systolic volume index (estimate, −5.8 mL; 95% CI, −8.8 to −2.7; P < .001), left ventricular end-systolic volume (estimate, −11.2 mL; 95% CI, −17.1 to −5.4; P < .001), left ventricular end-diastolic volume index (estimate, −5.5 mL/m2; 95% CI, −8.9 to −2; P = .002), left ventricular end- diastolic volume (estimate, −10.9 mL; 95% CI, −17.6 to −4.2; P = .001), and LVEF (estimate, 2.7%; 95% CI, 1.3% to 4.2%; P < .001) com-pared with placebo.28

• Left bundle branch block: When results of the SHIFT study were examined for the effects of ivabradine in patients with heart failure and left bundle branch block, ivabradine use did not reduce the risk of the primary endpoint (P = .43), its individual components of hospital-ization due to heart failure (P = .197) or cardio-vascular death (P = .211), or all-cause mortality (P = .452).30

• More severe disease: Another substudy exam-ined the effects of ivabradine therapy in patients with severe heart failure (NYHA class IV), or patients with LVEF of 20% or less; compared with placebo and in patients with a heart rate of 75 bpm or higher, ivabradine reduced the risks of cardiovascular death (HR, 0.68; 95% CI, 0.48 to 0.97; P = .034), hospitalization for worsening heart failure (HR, 0.7; 95% CI, 0.5 to 0.99; P = .042) (with reductions in composite score of either 1 of the 2 [HR, 0.75; 95% CI, 0.57 to 0.99; P = .045]), rate of all-cause death (HR, 0.66; 95% CI, 0.47 to 0.93; P = .018), and mortality due to heart failure (HR, 0.41; 95% CI, 0.22 to 0.77; P = .005).31

• Impact of blood pressure: Evaluated on the composite endpoint of cardiovascular mortality and hospitalization for worsening heart failure and the secondary endpoints of the 2 compos-ites of all-cause mortality and heart rate–related mortality. Patients were grouped by systolic blood pressure: below 115 mm Hg, 115 mm Hg to less than 130 mm Hg, and 130 mm Hg and higher. The efficacy and safety of ivabradine were not negatively impacted by patient base-line blood pressure.34

• Renal function: Of the 6,505 patients ran-domized in the SHIFT trial, baseline creatinine and at least 1 follow-up measurement were

available for 6,160 patients to assess changes in renal function. Worsening renal function was defined as a creatinine increase of at least 0.3 mg/dL and at least a 25% increase from the baseline level. No differences in renal function were observed after 24 months between the ivabradine-treated and placebo patients. Over-all, 1,029 (17%) patients had worsening renal function that was directly related to baseline heart rate, with an incremental risk of 5% for every 5 bpm increase in baseline heart rate (P = .003). Patients with worsening renal failure also had an increased risk of cardiovascular death or hospital admission due to worsening heart failure (HR, 1.38; P < .001) and all-cause mor-tality (HR, 1.42; P < .001). However, the group treated with ivabradine had a lower risk of car-diovascular death or hospitalization for wors-ening heart failure compared with the control group, regardless of whether patients had renal dysfunction (HR, 0.82; P = .023) or not (HR, 0.81; P < .001) at baseline (P value for interac-tion = .89).36

Comments: There were higher numbers of with-drawals in the ivabradine group compared with the placebo arm (HR, 1.14; 95% CI, 1.02 to 1.27; P = .017), but a higher number of serious adverse events was reported in the placebo arm (P = .025). Subjects taking ivabradine experienced more bra-dycardia events (P < .001) and phosphine-type visual disturbances (P < .001). In a pooled analysis that included all patients in the SHIFT trial (n = 6,505) and subjects from the BEAUTIFUL trial (n = 5,392) with a resting heart rate of at least 70 bpm, ivabradine showed superior results compared with placebo in reducing the risk of the composite endpoint of cardiovascular death or hospitalization for heart failure (HR, 0.87; 95% CI, 0.8 to 0.94; P < .001); hospitalization for heart failure (HR, 0.8; 95% CI, 0.73 to 0.89; P < .001); the composite endpoint of cardiovascular death, hospitalization for heart failure, or MI (HR, 0.85; 95% CI, 0.79 to 0.91; P < .001); hospitaliza-tion for MI (HR, 0.77; 95% CI, 0.63 to 0.94; P = .009); and cardiovascular death or nonfatal MI (HR, 0.9; 95% CI, 0.81 to 0.98; P = .023). How-ever, there were no statistical differences between ivabradine and placebo for death due to a cardio-vascular cause (HR, 0.94; 95% CI, 0.85 to 1.05; P = .272) and all-cause mortality (HR, 0.96; 95%

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CI, 0.87 to 1.05; P = .356).32 All patients with a resting heart rate of less than 75 bpm (n = 7,632) were examined, and patients receiving ivabradine (n = 3,812) demonstrated reductions in cardiovas-cular mortality (HR, 0.88; 95% CI, 0.78 to 1; P = .049), hospitalization due to heart failure (HR, 0.78; 95% CI, 0.7 to 0.87; P < .001), the compos-ite of the 2 (HR, 0.82; 95% CI, 0.75 to 0.9; P < .001), and total mortality (HR, 0.89; 95% CI, 0.8 to 1; P = .048).32 In subjects with left ventricular dysfunction, defined as an ejection fraction of 35% or less, NYHA class II, III, or IV heart failure, and a resting heart rate of at least 70 bpm (n = 9,236), subjects in the ivabradine group (n = 4,604), when compared with those in the placebo arm (n = 4,632), demonstrated reductions in the com-posite endpoint of cardiovascular mortality and hospitalization for heart failure (HR, 0.87; 95% CI, 0.8 to 0.94; P < .01) and hospitalizations for heart failure alone (HR, 0.8; 95% CI, 0.73 to 0.89; P < .001), but had no effects on the rates of car-diovascular mortality alone (HR, 0.96; 95% CI, 0.86 to 108; P = .506) or all-cause mortality (HR, 0.96; 95% CI, 0.87 to 1.07; P = .487).32 Finally, the composite endpoint of cardiovascular death or hospitalization for heart failure was examined in patients with a resting heart rate of 70 bpm or less and with heart failure of differing NYHA class; ivabradine reduced the rate of the composite outcome compared with placebo in patients with LVEF of 40% or less and NYHA class I or greater heart failure (n = 11,897; HR, 0.87; 95% CI, 0.8 to 0.94; P < .001), patients with LVEF of 35% or less and NYHA class I or greater heart failure (n = 10,127; HR, 0.88; 95% CI, 0.81 to 0.86; P = .002), and patients with LVEF of 35% and NYHA class II or greater heart failure (n = 9,236; HR, 0.87; 95% CI, 0.8 to 0.94; P < .001).32 In a small exploratory study, ivabradine was suc-cessfully used with dobutamine in patients with both stable (n = 22) and unstable (n = 9) heart fail-ure.38 The addition of ivabradine to dobutamine resulted in a decreased heart rate while increasing the left ventricular ejection fraction in patients with stable heart failure; those with unstable heart failure experienced a reduced heart rate and n-terminal pro-b-type natriuretic peptide levels, as well as improved systolic blood pressure, urine output, and central venous oxygen saturation.38

In a small observational, open-label, longitudinal and retrospective study of patients with acute decom-pensated systolic heart failure with an elevated heart rate (n = 10), ivabradine was administered in the cardiac intensive care unit. Heart rate was evaluated within 24 hours after the first dose and at hospital dis-charge. Ivabradine was given orally at a dose of 5 mg twice daily, with a lower dose of 2.5 mg twice daily for patients older than 75 years. There was a reduc-tion in heart rate and systolic blood pressure within 24 hours of the first dose as well as at discharge, with no other changes in cardiac function noted.39 Limitations: The study protocol excluded patients taking nondihydropyridine calcium channel block-ers, class 1 antiarrhythmics, and/or strong CYP3A4 inhibitors. Patients taking medications associated with prolongation of the QT interval, specifically amiodarone, bepridil, sotalol, and imipraminic tri-cyclic antidepressants, were not recommended for inclusion in the study. The study was conducted entirely outside the United States. Finally, the sub-studies were performed after completion of the main trials, and many used smaller patient popula-tions to test for conclusions that were not identified in the larger randomized control trial.

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONSContraindications

Multiple contraindications to the use of ivabradine exist, including hypersensitivity to ivabradine or any of its components (lactose mono-hydrate, maize starch, maltodextrin, magnesium stea-rate, colloidal silicon dioxide, hypromellose, titanium dioxide, polyethylene glycol 6000, yellow iron oxide, red iron oxide), resting heart rate below 60 bpm prior to initiation of therapy, blood pressure below 90/50 mm Hg, acute decompensated heart failure, sick sinus syndrome, sinoatrial block, dependency on a pace-maker, third-degree atrioventricular block (unless there is a functioning demand pacemaker present), severe hepatic impairment, or concurrent use of a moderate and strong CYP3A4 inhibitor (eg, diltia-zem, verapamil, grapefruit juice, azole antifungals, macrolide antibiotics, HIV antiretroviral protease inhibitors, nefazodone).1

Warnings and Precautions There is a potential risk of fetal toxicity associ-

ated with ivabradine use; embryofetal toxicity and

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teratogenic effects to the heart were seen in the fetuses of pregnant rats administered doses 1 to 3 times the amount in human exposures at the maximum rec-ommended dose. All females of childbearing poten-tial should use an effective method of contraception while taking ivabradine. Ivabradine was tested in pregnant rabbits and resulted in fetal toxicity and teratogenicity. Also, there is an increase in cardiac output in pregnant patients, especially during the first trimester, and patients with an injection fraction below 35% and receiving a maximal tolerated dose of a beta-blocker may be particularly sensitive to the effects of ivabradine. All pregnant patients started on ivabradine should be monitored, especially during the first trimester.1

Currently there are no data regarding the use of ivabradine in lactating females, but animal stud-ies demonstrate ivabradine is present in rat milk; due to the potential risk to breast-feeding infants, use in breast-feeding mothers is not recommended.1

There is an increased risk of atrial fibrillation associated with the use of ivabradine. In clinical tri-als, the rate was 5% per patient-year in those admin-istered ivabradine, but only 3.9% per patient-year in the placebo group. Cardiac rhythm should be regu-larly monitored.1

Bradycardia occurred at a rate of 6% per patient-year in those treated with ivabradine (2.7% symp-tomatic; 3.4% asymptomatic) compared with 1.3% per patient-year in the placebo group. Risk factors for bradycardia include sinus node dysfunction, conduction defects (eg, first- or second-degree atrio-ventricular block, bundle branch block), ventricular dyssynchrony, and use of negative chronotropes (eg, digoxin, diltiazem, verapamil, amiodarone). There have also been reports of sinus arrest and heart block in patients taking ivabradine.1

Ivabradine should not be used with a CYP3A4 inducer (eg, St. John’s wort, rifampicin, barbiturates, phenytoin).1

Verapamil or diltiazem used concurrently with ivabradine can increase patient exposure to ivabradine, may themselves contribute to heart rate lowering, and should be avoided.1

Ivabradine should be avoided in patients with second-degree atrioventricular block unless there is a functioning pacemaker present.1

ADVERSE REACTIONSIn ivabradine clinical trials for the treatment

of heart failure, the most common adverse reac-

tions were bradycardia (10%), hypertension (8.9%), atrial fibrillation (8.3%), and luminous phenom-ena (ie, shines or glows [like a ring or spot of light]; 2.8%).1 Since the approval of ivabradine, there have been reports of cardiovascular problems (such as syncope and hypotension), angioedema, skin reac-tions (including erythema, rash, pruritus, and urti-caria), vertigo, diplopia, and other types of visual impairment.1

Data from a 1-year safety and efficacy trial sug-gest that overall ivabradine is well tolerated, with changes in vision, infections, and aggravation of previous cardiac disease reported most commonly.40 Visual changes, the most commonly reported adverse reaction, were described as phosphene in nature and were generally transient, with 80% of cases resolv-ing while the patient was still under treatment and the other 20% resolving after ivabradine cessation.40 Serious cardiac events, including angina aggrava-tion, unstable angina, MI, rhythm disturbances, and cardiac failure, were reported by 13 patients in the 5 mg twice-daily group and in 12 patients in the 7.5 mg twice-daily group, with 3 and 2 patients, respectively, experiencing nonfatal MI.40 Heart rate was slowed in both treatment groups, with excessive sinus bradycardia and heart rate less than 40 bpm reportedly occurring in 2 patients in the 7.5 mg twice-daily group.40 There was a mean increase in QT interval, but when corrected with the Bazett formula, the QTc interval numerically decreased.40

In a pooled analysis of the BEAUTIFUL and SHIFT trials, adverse reactions occurring more com-monly than with placebo included symptomatic and asymptomatic bradycardia (4% each), atrial fibril-lation (8%), phosphenes (3%), and blurred vision (0.8%).32 These adverse events were similar to those reported in the largest randomized controlled trial.41

In a SHIFT trial substudy, there were no addi-tional adverse reaction concerns when ivabradine was administered to patients with heart failure and concurrent left bundle branch block, although patients with these conditions were more likely to experience hospitalization due to heart failure (P < .001), cardiovascular death (P < .001), a composite outcome of one or the other (P < .001), or death by any cause (P < .001), regardless of ivabradine use.30 In another substudy of the SHIFT trial examining the effects of ivabradine on patients with severe heart failure (NYHA class IV) and/or LVEF of 20% or less, there were no unexpected adverse events observed in the at-risk population.31

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There is the possibility of overdose leading to severe and prolonged toxicity, which should be treated with supportive care (such as IV fluids), atro-pine, and IV beta-stimulating agents (such as isopro-terenol). In the event of bradycardia with poor hemo-dynamic tolerance, temporary cardiac pacing may be required.1,42

DRUG INTERACTIONS Nondihydropyridine calcium channel blockers,

such as verapamil and diltiazem, should not be used in combination with ivabradine, although there have been no safety issues when ivabradine was used with the dihydropyridine calcium channel blockers amlodipine and lacidipine.1 Other CYP3A4 medications were tested concurrently with ivabradine. Based on the pharmaco-kinetic changes to the Cmax and AUC of ivabradine, con-current use of ketoconazole is contraindicated, grape-fruit juice and St. John’s wort should be avoided, and no changes are required when used with sildenafil, simvas-tatin, lansoprazole or omeprazole, and warfarin.1

Medications that inhibit or induce CYP3A4 should be avoided in patients currently taking ivabradine. CYP3A4 inhibitors may lead to suprath-erapeutic levels and increase the risk of toxic adverse effects (such as excessive bradycardia), and CYP3A4 inducers may result in subtherapeutic, ineffective lev-els of ivabradine.1

Most patients taking ivabradine are also treated with a beta-blocker. The risk of bradycardia increases with concurrent use of other medications that slow heart rate (eg, digoxin, amiodarone, beta-blockers).1

There were no changes to digoxin exposure when tested with ivabradine, and no dosage adjustment is required for ivabradine when used concurrently with digoxin.1 Ivabradine dosed at 10 mg twice daily until steady state was reached did not affect the pharmaco-kinetics of metformin (OCT2 sensitive substrate). No dosage adjustment is required for metformin when administered with ivabradine.1

Patients that rely on a pacemaker set to above 60 bpm have a difficult time achieving a goal heart rate between 50 and 60 bpm. These patients were excluded from clinical trials and ivabradine use is not recommended in this population.1

RECOMMENDED MONITORINGDue to the heart rate reduction effects of

ivabradine, regular heart rate and blood pressure checks are recommended. Patients taking ivabradine should be regularly monitored for the presence of

atrial fibrillation, which includes regular monitoring of cardiac rhythm.1

There are also indications that ivabradine leads to decreased levels of N-terminal pro b-type natriuretic peptide, carbohydrate antigen-125, and cystatin-C, but the significance of measuring these laboratory values in association with ivabradine is unknown at this time.6

DOSINGThe recommended starting dosage for the treat-

ment of chronic heart failure is 5 mg orally twice daily with meals. Patients should be assessed after 2 weeks of therapy and the dose adjusted to reach a resting heart rate between 50 and 60 bpm (see Table 1).1 After the initial treatment and assessment period, the dose should be adjusted according to resting heart rate and tolerability.1 In patients with a history of conduction defects or in those in whom bradycardia could cause hemodynamic compromise, treatment with ivabradine should be started at 2.5 mg orally twice daily before increasing the daily dosage based on heart rate.1

No dosage adjustment is required in patients with a CrCl greater than 15 mL/min; there are currently no data in patients with a CrCl below that threshold. No dosage adjustments are required for patients with mild to moderate hepatic impairment (Child-Pugh class A and B); there are no data on ivabradine use in patients with severe hepatic impairment.1

Oral dosages of ivabradine in clinical trials of chronic heart failure ranged from 2.5 to 7.5 mg twice daily.26 Ivabradine 2.5 to 10 mg twice daily was used in clinical trials of coronary artery disease and stable chronic angina.40,43-46

There were no pharmacokinetic differences observed in patients 65 years and older or patients 75 years and older.1 There are no data regarding the use of ivabradine in patients younger than 18 years.1

PRODUCT AVAILABILITYIvabradine was approved in April 20151 and is

available as 5 and 7.5 mg tablets. The 5 mg tablet is scored and can be cut in half to provide the 2.5 mg dose.1,2 Ivabradine tablets should be stored at room temperature (25°C [77°F]); excursions are permitted between 15°C and 30°C (59°F and 86°F).1

DRUG SAFETY/RISK EVALUATION AND MITIGATION STRATEGY (REMS)

No REMS is required for ivabradine.1,2

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CONCLUSION Ivabradine is approved in Europe for use in the

treatment of chronic heart failure and stable coronary artery disease; in the United States, ivabradine is only approved for use in chronic heart failure. Data from the SIGNIFY trial indicated there was an increased risk of cardiovascular death in patients randomized to ivabradine with Canadian Cardiovascular Soci-ety class II or higher angina, which prompted the European Medicines Agency to revisit the approval status of this medication, but this increased risk of death was not seen in patients without angina and diagnosed solely with heart failure. Overall, a limited number of randomized controlled trials supporting use of ivabradine in the treatment of chronic heart failure exist. Since the SHIFT study results were released, several smaller studies have confirmed a possible benefit in the unique population of patients with heart failure, left ejection fraction of 35% or less, and heart rate of at least 70 bpm. With the dem-onstrated benefit of ivabradine in the SHIFT trial and its overall safety profile in patients with heart failure, ivabradine may have found a treatment niche in indi-viduals already receiving a maximum beta-blocker dosage or in patients unable to tolerate a guideline-based beta-blocker and who have a heart rate above 70 bpm. Ivabradine is not included in current treat-ment guidelines but may be a viable treatment option in the select group of patients (patients with stable, symptomatic chronic heart failure with LVEF of <35%, who are in sinus rhythm with a resting heart rate of at least 70 bpm, and who are receiving the maximum tolerated dose of beta-blockers or have a contraindication to beta-blocker use).

REFERENCES 1. Corlanor (ivabradine) [prescribing information]. Thou-sand Oaks, CA: Amgen Inc; April 2015.

2. Unger EF. FDA approval letter: Corlanor (ivabradine NDA 206143). US Food and Drug Administration Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist. Pub-lished April 15, 2015. Accessed May 12, 2015.

3. Procoralan (ivabradine) [prescribing information]. Suresnes cedex, France: Les Laboratories Servier; October 2010.

4. Amgen presents analyses of phase 3 ivabradine data for the treatment of chronic heart failure [news release]. Thou-sand Oaks, CA: Amgen; September 15, 2014. http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1967698. Accessed May 11, 2015.

5. Review of Corlentor/Procoralan started. European Medi-cines Agency. http://www.ema.europa.eu/docs/en_GB/docu-ment_library/Press_release/2014/05/WC500166318.pdf. Pub-lished May 8, 2014. Accessed September 4, 2014.

6. Ordu S, Yildiz BS, Alihanoglu YI, et al. Effects of ıvabradine therapy on heart failure biomarkers [published online ahead of print March 3, 2015]. Cardiol J.

7. Abdel-Salam Z, Rayan M, Saleh A, Abdel-Barr MG, Hus-sain M, Nammas W. If current inhibitor ivabradine in patients with idiopathic dilated cardiomyopathy: Impact on the exercise tolerance and quality of life. Cardiol J. 2015;22(2):227-232.

8. Nar G, Inci S, Aksan G, et al. Ivabradine on aortic stiffness in patients with heart failure. J Investig Med. 2015;63(4):620-625.

9. Kurtoglu E, Balta S, Karakus Y, et al. Ivabradine improves heart rate variability in patients with nonischemic dilated car-diomyopathy. Arq Bras Cardiol. 2014;103(4):308-314.

10. Zugck C, Martinka P, Stöckl G. Ivabradine treatment in a chronic heart failure patient cohort: Symptom reduction and improvement in quality of life in clinical practice. Adv Ther. 2014;31(9):961-974.

11. Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to β-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther. 2015;32(2):108-119.

Table 1. Dosage adjustments of ivabradine based on heart rate1

Measured heart rate Recommended dosage adjustment

>60 bpm The dose should be increased by 5 mg per day divided twice daily (2.5 mg administered twice daily) to the maximum dose of 7.5 mg orally twice daily.

50 to 60 bpm The current dose should be maintained.

<50 bpm or clinical signs or symptoms of bradycardia

The dose should be decreased by 5 mg per day divided twice daily (2.5 mg administered twice daily); if patient is currently receiving 2.5 mg orally twice daily, ivabradine should be discontinued.

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12. Cappato R, Castelvecchio S, Ricci C, et al. Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: A prospective, randomized, placebo-controlled, double-blind, cross-over evaluation. J Am Coll Cardiol. 2012;60(15):1323-1329.

13. Benezet-Mazuecos J, Rubio JM, Farré J, Quiñones MÀ, Sanchez-Borque P, Macía E. Long-term outcomes of ivabradine in inappropriate sinus tachycardia patients: Appropriate effi-cacy or inappropriate patients. Pacing Clin Electrophysiol. 2013;36(7):830-836.

14. Zhang R, Bobylev D, Stiefel P, Haverich A, Bara C. Last-ing reduction of heart transplant tachycardia with ivabradine is effective and well tolerated: Results of 48-month study. Clin Res Cardiol. 2012;101(8):631-636.

15. Gerbaud E, Montaudon M, Chasseriaud W, et al. Effect of ivabradine on left ventricular remodeling after reperfused myocardial infarction: A pilot study. Arch Cardiovasc Dis. 2014;107(1):33-41.

16. Bonadei I, Sciatti E, Vizzardi E, D’Aloia A, Metra M. Ivabradine during cardiogenic shock: A clinical case and review of the literature. Heart Lung. 2015;44(1):57-58.

17. Meles E, Carbone C, Maggiolini S, et al. A case of atrial tachycardia treated with ivabradine as bridge to ablation [published online ahead of print March 18, 2015]. J Cardio-vasc Electrophysiol.

18. Kumar Goyal V, Godara S, Chandra Sadasukhi T, Lal Gupta H. Management of inappropriate sinus tachycardia with ivabradine in a renal transplant recipient. Drug Discov Ther. 2014;8(3):132-133.

19. Cavusoglu Y, Mert U, Nadir A, Mutlu F, Morrad B, Ulus T. Ivabradine treatment prevents dobutamine-induced increase in heart rate in patients with acute decompensated heart failure [published online ahead of print June 11, 2014]. J Cardiovasc Med (Hagerstown).

20. Sarullo FM, Vitale G, Di Franco A, et al. Nemaline myop-athy and heart failure: Role of ivabradine; a case report. BMC Cardiovasc Disord. 2015;15:5.

21. de Gregorio C, Potenza G, Ferraro G. Effectiveness of the combination therapy with lisinopril, ivabradine and multivita-min supplementation in anthracycline-induced severe cardio-toxicity. Int J Cardiol. 2014;176(3):1374-1376.

22. Borer JS, Tardif JC. Efficacy of ivabradine, a selective I(f) inhibitor, in patients with chronic stable angina pectoris and diabetes mellitus. Am J Cardiol. 2010;105(1):29-35.

23. Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs R D. 2003;4(2):83-89.

24. Yancy CW, Jessup M, Bozkurt B, et al; American Col-lege of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guide-line for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart

Association Task Force on Practice Guidelines. J Am Coll Car-diol. 2013;62(16):e147-e239.

25. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: The Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail. 2010;12(1):75-81.

26. Swedberg K, Komajda M, Böhm M, et al; SHIFT Inves-tigators. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study [published correction appears in Lancet. 2010;376(9757):1988]. Lancet. 2010;376(9744):875-885.

27. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: Results from the SHIFT study. Eur Heart J. 2011;32(19):2395-2404.

28. Tardif JC, O’Meara E, Komajda M, et al; SHIFT Investi-gators. Effects of selective heart rate reduction with ivabradine on left ventricular remodeling and function: Results from the SHIFT echocardiography substudy. Eur Heart J. 2011;32(20):2507-2515.

29. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investiga-tors. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: Is there an influence of beta-blocker dose?: Findings from the SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) study. J Am Coll Cardiol. 2012;59(22):1938-1945.

30. Reil JC, Robertson M, Ford I, et al. Impact of left bundle branch block on heart rate and its relationship to treatment with ivabradine in chronic heart failure. Eur J Heart Fail. 2013;15(9):1044-1052.

31. Borer JS, Böhm M, Ford I, et al; SHIFT Investigators. Effi-cacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study). Am J Cardiol. 2014;113(3):497-503.

32. Fox K, Komajda M, Ford I, et al. Effect of ivabradine in patients with left-ventricular systolic dysfunction: A pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials. Eur Heart J. 2013;34(29):2263-2270.

33. Böhm M, Borer J, Ford I, et al. Heart rate at baseline influ-ences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: Analysis from the SHIFT study. Clin Res Cardiol. 2013;102(1):11-22.

34. Komajda M, Böhm M, Borer JS, et al; SHIFT Investiga-tors. Efficacy and safety of ivabradine in patients with chronic systolic heart failure according to blood pressure level in SHIFT. Eur J Heart Fail. 2014;16(7):810-816.

35. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investi-gators. Efficacy and safety of ivabradine in chronic heart fail-ure across the age spectrum: Insights from the SHIFT study. Eur J Heart Fail. 2013;15(11):1296-1303.

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36. Voors AA, van Veldhuisen DJ, Robertson M, et al; SHIFT Investigators. The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: An analysis from SHIFT. Eur J Heart Fail. 2014;16(4):426-434.

37. Böhm M, Borer JS, Camm J, et al. Twenty-four-hour heart rate lowering with ivabradine in chronic heart failure: Insights from the SHIFT Holter substudy. Eur J Heart Fail. 2015;17(5):518-526.

38. Gallet R, Ternacle J, Damy T, et al, Hemodynamic effects of ivabradine in addition to dobutamine in patients with severe systolic dysfunction. Int J Cardiol. 2014;176(2):450-455.

39. Sargento L, Satendra M, Longo S, Lousada N, dos Reis RP. Heart rate reduction with ivabradine in patients with acute decompensated systolic heart failure. Am J Cardiovasc Drugs. 2014;14(3):229-235.

40. López-Bescós L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108(4):387-396.

41. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371(12):1091-1099.

42. Mathiaux F, Dulaurent S, Julia F, Gaulier JM. Case report of ivabradine intoxication. J Anal Toxicol. 2014;38(4):231-232.

43. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAU-TIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunc-tion (BEAUTIFUL): A randomised, double-blind, placebo- controlled trial. Lancet. 2008;372(9641):807-816.

44. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the study assessing the morbidity-mortality benefits of the If inhibitor ivabradine in patients with coronary artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease with-out clinical heart failure. Am Heart J. 2013;166(4):654-661.

45. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodip-ine in patients with stable effort angina pectoris: A 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67(3):393-405.

46. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INI-TIATIVE Investigators. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26(23):2529-2536.

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Continuing Education Case Study Quiz

Goal—The goal of this activity is to educate pharmacists about the use of ivabradine in the treatment of patients with chronic heart failure.

Objectives— At the completion of this activity, the reader will be able to:1. Describe the pharmacology and pharmacokinetics of ivabradine.2. Discuss the risks associated with the use of ivabradine.3. Discuss the potential benefit of ivabradine for an individual patient.4. Apply the information on the use of ivabradine to a case study.

Key Words—ivabradine, chronic heart failure, new drugs

This CE activity is jointly provided by ProCE, Inc. and Hospital Pharmacy. ProCE, Inc. is accredited by the Accredi-tation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number 0221-9999-15-226-H01-P has been assigned to this knowledge-based home-study CE activity (initial release

date 10-01-2015). This CE activity is approved for 1.5 contact hours (0.15 CEUs) in states that recog-nize ACPE providers. This CE activity is provided at no cost to participants. Completion of the evaluation and the post-test with a score of 70% or higher are required to receive CE credit. No partial credit will be given.

Faculty: Dennis J. Cada, Pharm.D., FASHP, FASCP (Editor), Founder and Contributing Editor, The Formulary; Ross Bindler, PharmD, Drug Infor-mation Resident, College of Pharmacy, Washing-ton State University, and Danial E. Baker, PharmD, FASHP, FASCP, Director, Drug Information Cen-ter, and Professor of Pharmacy Practice, College of Pharmacy, Washington State University. The authors indicate no relationships that could be perceived as a conflict of interest. This activity is self-funded by Hospital Pharmacy.

Release Date: October 1, 2015 Expiration Date: October 1, 2017Continuing Education for this activity is pro-

cessed through the ProCE online CE Center. To receive CE credit, please go to:

• www.ProCE.com/HPJFDR• Click to access the activity page to enroll and complete the Post-Test and Evaluation

For questions related to register-ing for and obtaining CE credit, contact ProCE at 630-540-2848 or [email protected].

1. Ivabradine was approved by the US Food and Drug Administration (FDA) to reduce the risk of hospitalization due to worsening heart failure in which types of patients with chronic heart fail-ure?A. Individuals with a heart rate of less than 65

beats per minute (bpm)B. Patients initiating beta-blocker therapyC. Those individuals who have a resting heart

rate above 70 bpm D. Patients who have a left ventricular ejection

fraction (LVEF) of greater than 40%

Hosp Pharm 2015;50(9):818–8202015 © Thomas Land Publishers, Inc.www.hospital-pharmacy.comdoi: 10.1310/hpj5009-818

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2. Ivabradine is an inhibitor of which of the follow-ing ion channels located within the cardiac con-duction system?A. IhB. IfC. ICa-TD. ICa-L

3. Which one of the following compounds is the active metabolite of ivabradine?A. S-18982B. X-16257688C. N-methyl-ivabradine D. N-oxydesmethyl-ivabradine

4. What is the most common adverse reaction asso-ciated with the use of ivabradine?A. Visual phenomenaB. Atrial fibrillation C. HypotensionD. Bradycardia

5. Which of the following calcium channel antago-nists should be avoided while using ivabradine?A. AmlodipineB. FelodipineC. VerapamilD. Nifedipine

6. All of the following are a recognized risk associ-ated with the use of ivabradine during pregnancy or lactation except:A. Embryofetal toxicity.B. Teratogenicity. C. Reduced cardiac output.D. Infant sedation.

7. The 2014 SIGNIFY trial of ivabradine prompted the European Medicines Agency to review the use of ivabradine in which of the following indi-cations? A. The treatment of stable anginaB. The treatment of atrial fibrillation C. The treatment of pulmonary hypertensionD. The treatment of chronic stable tachycardia

Case HistoryJ.W. is an 84-year-old male weighing 87.9 kg

with New York Heart Association (NYHA) class III (class C) chronic heart failure with a normal sinus rhythm, a resting heart rate of 84 bpm, and a resting

left ventricular ejection fraction (LVEF) of 30%. In addition to the chronic heart failure, J.W. has also been diagnosed with hypertension and gastroesoph-ageal reflux disease (GERD). J.W.’s current medica-tions include lisinopril, carvedilol, and eplerenone plus over-the-counter lansoprazole occasionally for GERD flare-ups. After J.W. experienced multiple hospitalizations for exacerbations of chronic heart failure in the past year, his cardiologist has added ivabradine to J.W.’s chronic heart failure medication regimen.

8. What is the recommended starting dose and schedule for initiating ivabradine therapy in J.W.?A. One 5 mg tablet by mouth once daily with

mealsB. One 5 mg tablet by mouth once daily with-

out mealsC. One 5 mg tablet by mouth twice daily with

mealsD. One 5 mg tablet by mouth twice daily with-

out meals

9. J.W. is nervous about starting another medica-tion for his chronic heart failure and would like to know what monitoring is going to be neces-sary while taking ivabradine. Which is the best response?A. There are no necessary monitoring param-

eters. B. J.W. should have his b-type natriuretic pep-

tide levels checked every week. C. J.W. should have monthly electrocardio-

grams to check his cardiac rhythm.D. J.W. should have regular checks of his heart

rate and blood pressure.

10. Due to J.W.’s older age, he is worried about how the medication will affect his body. How do the pharmacokinetics of ivabradine differ between the elderly and a person younger than 65 years? A. The area under the curve of ivabradine

will be higher in J.W. than in a younger patient.

B. The maximum concentration of ivabradine will be higher in J.W.

C. The time to maximum concentration of ivabradine will be longer in J.W.

D. There were no age-related differences in the pharmacokinetics of ivabradine.

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11. J.W. eats half a grapefruit every morning with his breakfast. If he continues to do this each morning, what pharmacokinetic changes may occur with the newly prescribed ivabradine?A. Increased levels of ivabradine, which may

lead to possible toxic effects.B. Decreased levels of ivabradine, which may

lead to subtherapeutic effects.C. Eating a grapefruit will have no impact on

the pharmacokinetics of ivabradine. D. Grapefruit has variable effects on different

patients, so the effects cannot be predicted.

12. After 2 weeks of taking ivabradine, J.W.’s resting heart rate has been reduced to 74 bpm. What is the recommended dosage adjustment at this time?A. There are no dosage adjustments needed at

this time.B. Ivabradine should be discontinued. C. The dose should be increased to 7.5 mg

orally twice daily.D. The dose should be decreased to 2.5 mg

orally twice daily.

13. Several months later, J.W. reports he has been frequently feeling light-headed and has had a decrease in his exercise tolerance while taking ivabradine 7.5 mg twice daily. Upon evaluation by the cardiologist his resting heart rate is 42 bpm. What changes in the dose of ivabradine should be made, if any?A. The dose should be decreased to 2.5 mg

orally twice daily.B. The dose should be decreased to 5 mg orally

once daily.C. The dose should be decreased to 5 mg orally

twice daily.D. The medication should be discontinued.

14. J.W. has experienced a flare-up of his GERD and want to know if he can use his over-the-coun-ter lansoprazole. Which of the following best describes the pharmacokinetic interaction that may occur with lansoprazole and ivabradine?A. Concurrent lansoprazole has been associ-

ated with clinically significant increased ivabradine levels requiring a change in the ivabradine dose.

B. Concurrent lansoprazole has been associ-ated with clinically significant decreased ivabradine levels requiring a change in the ivabradine dose.

C. Concurrent lansoprazole substantially reduced ivabradine absorption and must not be used concurrently.

D. No pharmacokinetic interaction was ob-served with lansoprazole and ivabradine that necessitates a change in therapy.

15. J.W. is now responding to ivabradine with a heart rate between 50 to 60 bpm at every check-up, but he has developed what he describes as little light flashes that occur quite often. Which is the recom-mended course of action since his ophthalmolo-gist had no appointment openings for several weeks?A. Discontinue ivabradine immediately, so that

the effects do not become permanent. B. Wait a short while to see if it goes away,

as the effects often resolve with continued therapy.

C. Reduce the ivabradine dose, because this type of adverse reaction tends to be dose related.

D. Continue ivabradine therapy, because the visual effects are permanent and discontinu-ation will not help.

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Documents

Ivadradine - ProCEs3.proce.com/res/pdf/hpjfdr/2015Oct.pdfthe maximum tolerated dose of beta-blockers or have a contraindication to beta-blocker use.1,2 Ivabradine was approved by the