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Role of the Funny Current Inhibitor Ivabradine in Cardiac Pharmacotherapy: A Systematic Review

Petite, Sarah, E., PharmD, BCPS*; Bishop, Bryan, M., PharmD, BCPS; Mauro, Vincent, F., PharmD, FCCP

doi: 10.1097/MJT.0000000000000388
Systematic Review and Clinical Guidelines
Free

The pharmacology, pharmacokinetics, efficacy and safety of ivabradine are reviewed. Ivabradine is an oral medication that directly and selectively inhibits the hyperpolarization-activated cyclic-nucleotide gated funny (If) current in the sinoatrial node resulting in heart rate reduction. It has a plasma elimination half-life of 6 hours and is administered twice daily. Ivabradine is extensively metabolized by cytochrome P450 3A4, and its metabolism is affected by inducers and inhibitors of the 3A4 enzyme. Studies in patients with heart failure indicate that ivabradine improves surrogate markers such as exercise tolerance. The results of (1) phase III trial demonstrated ivabradine significantly reduced heart failure hospitalizations but had no effect on mortality. Ivabradine has been extensively evaluated for coronary artery disease wherein (2) large trials was shown to have no mortality benefit. Ivabradine has been associated with improved symptoms in stable chronic angina pectoris. Ivabradine has been evaluated for other cardiovascular conditions including tachycardias of various natures, arrhythmia prevention postcardiac surgery, in acute coronary syndrome, and for heart rate control during coronary computed tomography angiogram. The most common adverse events reported in clinical trials were bradycardia, new-onset atrial fibrillation, and phosphenes. Ivabradine, a novel cardiac medication, has been studied in numerous cardiac conditions. It is only currently approved in the United States to reduce hospitalizations for systolic heart failure. The role of this medication in other conditions has not been fully elucidated.

University of Toledo College of Pharmacy, Toledo, OH.

Address for correspondence: University of Toledo College of Pharmacy, 3000 Arlington Avenue, MS# 1013, Toledo, OH 43614. E-mail: sarah.petite@utoledo.edu

The authors have no conflicts of interest to declare.

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INTRODUCTION

Ivabradine is a novel cardiac medication approved by the Food and Drug Administration (FDA) in April 2015 to reduce hospitalizations in patients with stable, symptomatic chronic heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35% and a sinus rhythm of 70 beats per minute (bpm) or more at rest despite receiving maximum doses of beta-blockers or who are unable to receive beta-blocker therapy. It had previously been approved by the European Medicines Agency in April 2005 for use in select HF and stable coronary artery disease (CAD) patients. This review examines the current body of literature for FDA approved and nonapproved indications for ivabradine and evaluates the role of ivabradine in the current therapeutic landscape.

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DATA SOURCES

A literature search of the MEDLINE database was conducted from inception to June 1, 2015 to evaluate study data regarding the pharmacology, pharmacokinetics, and efficacy data for ivabradine in human subject trials for various cardiac indications. Ivabradine was the sole search term used. References from extracted sources were further searched for any relevant, missed data sources. All prospective, randomized clinical trial data are included in this review. Select other nonprospective or nonrandomized trial data are also reviewed when relevant (ie, elucidating the pharmacokinetic or drug–drug interaction profile for ivabradine).

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PHARMACODYNAMICS

Ivabradine is a direct, selective inhibitor of the hyperpolarization-activated cyclic-nucleotide gated funny (If) current, a mixed sodium–potassium inward channel in the sinoatrial node.1 The rate of sinoatrial generated impulses is dependent on spontaneous diastolic depolarization of myocytes in the sinoatrial node and the If current has a major inhibitory influence on this depolarization.2 Ivabradine preferentially binds to the If channel in the open state causing the medication to have the largest reduction in sinoatrial rate at a higher baseline heart rate (HR).1–3 Ivabradine has no negative inotropic effects and also reverses left ventricular remodeling.4 In other disease states in animal models, such as CAD with damaged myocardium from ischemia, the decrease in HR leads to a reduction in myocardial oxygen demand and improved myocardial perfusion.5,6

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PHARMACOKINETICS

In healthy volunteers, ivabradine displays a linear pharmacokinetic profile.7,8 On ingestion of a single oral dose during a fasting state, absorption is rapid with a time to peak of 1 hour. This time to peak is prolonged to 2 hours in the fed state. The bioavailability of ivabradine while fasting is approximately 40% and is increased by 20%–40% if taken in the fed state.8 The volume of distribution is approximately 100 L and the medication is 70% plasma protein bound. The distribution half-life is 2 hours with an elimination half-life of approximately 6 hours.

Ivabradine does not undergo significant renal clearance with only 4% of the medication excreted unchanged in the urine.8 The medication undergoes extensive cytochrome P450 (CYP) 3A4 metabolism in the liver and intestines.5 The major metabolite is a N-desmethylated derivative (S18982) and is equipotent to ivabradine with a plasma concentration that is 40% of ivabradine. S18982 is also metabolized by CYP3A4. The metabolites are equally eliminated through the feces and urine.8 Mild or moderate renal or hepatic impairment does not affect the clearance of ivabradine; however, the medication has not been studied in severe renal or hepatic dysfunction.9

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CLINICAL STUDIES

Heart Failure

It is estimated that more than 650,000 new cases of HF are diagnosed in the United States each year.10 There are 2 major types of HF: HF with reduced LVEF (HFrEF) (systolic dysfunction) and HF with preserved EF (HFpEF) (diastolic dysfunction). Regardless of the HF type, the mortality risk is 50% within 5 years of diagnosis and HF is responsible for more than 1 million hospitalizations every year. Standard medication therapy for HF with reduced LVEF typically includes a beta-blocker, a vasodilator (angiotensin-converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), and/or hydralazine/isosorbide dinitrate), and a mineralocorticoid receptor blocker. All these medications have been shown to improve HF morbidity and mortality. Other medications, such as digoxin or diuretics, are utilized for benefits on morbidity and symptom relief in HFrEF, respectively. Standard therapy for HFpEF has not been well established yet.

Elevated resting HR has been associated with worse cardiovascular outcomes in HF.11 This HR elevation may persist despite beta-blocker therapy or patients may be unable to tolerate recommended doses of beta-blocker therapy. Due to its propensity to decrease HR, the efficacy and safety of ivabradine in HF has been assessed in several clinical trials for both HFrEF and HFpEF patient populations.

Kosmala et al12 conducted a randomized, single-blinded, placebo-controlled study to evaluate change in exercise capacity with ivabradine that included 61 patients with HFpEF. Included patients had signs or symptoms of HF (dyspnea, fatigue, exercise intolerance, etc.) with LVEF ≥50%, HR >60 bpm, and evidence of HFpEF. Beta-blocker use was not reported in this study. Patients were randomized to receive either ivabradine 5 mg twice daily or placebo for 7 treatment days. The primary efficacy endpoint was change in exercise capacity from baseline assessed by metabolic equivalents and maximal oxygen consumption (VO2). The increase in metabolic equivalents with ivabradine and placebo was 1.5 ± 1.2 versus 0.4 ± 1.2 (P = 0.001) and increase in peak VO2 was 3 ± 3.6 versus 0.4 ± 2.7 mL−1·kg−1·min−1 (P = 0.003), respectively. Baseline HR was 72 ± 7 bpm in the ivabradine group and 70 ± 6 bpm in the placebo group and follow-up HR was 62 ± 8 and 70 ± 7 bpm, respectively. The investigators concluded ivabradine was associated with an improvement in exercise capacity for patients with HFpEF.

Cocco and Jerie13 assessed the impact of ivabradine compared with digoxin in patients with ischemic diastolic HFpEF. This was a single-center, open-label randomized study that included 42 patients on maximally tolerated renin antagonists, diuretics, and beta-blockers. The included patients had a diagnosis of HFpEF and stable CAD with previous revascularization and were randomized to ivabradine 7.5 mg twice daily or digoxin to a target serum drug concentration of 0.5–0.9 ng/mL for a total of 3 months. No baseline HR requirements were specified. Study endpoints included New York Heart Association (NYHA) class, HR, and duration of 6-minute walk test. NYHA class before treatment in both groups was 3 and decreased to 2.6 ± 0.5 in ivabradine-treated patients and 2.2 ± 0.4 in digoxin-treated patients (P < 0.0001 in both groups). Comparison between ivabradine and digoxin demonstrated a greater decrease in NYHA with digoxin (P < 0.0001). Pretreatment HR was 85 ± 5 bpm in both groups and decreased to 81 ± 5 bpm with ivabradine (P = NS) and 76 ± 4 bpm with digoxin (P < 0.0001); comparison of the ivabradine and digoxin groups found a significantly greater reduction in HR in digoxin-treated patients (P < 0.003). The 6-minute walk test was also significantly improved in both ivabradine-treated and digoxin-treated groups compared with pretreatment tests (P < 0.0001), and comparison between ivabradine and digoxin patients demonstrated a more significant improvement with digoxin (P < 0.0001). This study demonstrated mixed outcomes for ivabradine in HFpEF compared with digoxin with greater improvements in NYHA class, HR, and 6-minute walk test duration with digoxin therapy. However, it is important to note that the role of digoxin in HFpEF has not been established.

The CARVIVA HF trial was a randomized, multicenter open-label study evaluating the effect of ivabradine on clinical function in HFrEF. A total of 121 patients with NYHA functional class II or III HF on either no beta-blocker or beta-blocker with suboptimally dosed ACE-I.14 There was a 3-week run-in period for beta-blocker discontinuation and uptitration of ACE-I to optimal doses. Patients were randomized to 3 study groups: carvedilol titrated up to 25 mg twice daily, ivabradine titrated up to 7.5 mg twice daily, and combination carvedilol/ivabradine titrated up to 12.5/5 mg twice daily for a total of 3 months of therapy. Baseline HR was 76.7, 79.6, and 76.7 bpm in the carvedilol, ivabradine, and combination therapy groups, respectively. Significantly more patients achieved target doses of study medication in the ivabradine group versus carvedilol group (88% vs. 47%; P < 0.001) and in combination-therapy patients compared with carvedilol-treated patients (76% vs. 47%; P < 0.003). The primary endpoint (distance covered in the 6-minute walk test and VO2) was more improved in the ivabradine and combination therapy groups at 3 months (P < 0.01 for both groups compared with baseline), but not in the carvedilol group. This improvement was also significant compared with carvedilol for both ivabradine-treated and combination-treated groups (P < 0.02). HR at 12-week follow-up in the per protocol analysis was 64.8 bpm in the carvedilol therapy group, 62.4 bpm in the ivabradine therapy group, and 57.2 bpm in the combination therapy group (P < 0.05 vs. carvedilol). This trial demonstrated that a greater number of patients with systolic HF could reach target doses of ivabradine compared with carvedilol and this led to greater improvements in study outcomes for patients treated with both ivabradine monotherapy and carvedilol/ivabradine combination therapy.

Sixty patients with ischemic systolic HF were assessed for the impact of ivabradine on exercise capacity, gas exchange, functional class, quality of life, and neurohormonal modulation.15 The included patients had documented signs and symptoms of HF, LVEF ≤40%, and baseline HR >70 bpm and were classified as NYHA class II or III. Patients were randomized to ivabradine 5 mg twice daily to a maximal dose of 7.5 mg twice daily or placebo for a treatment duration of 3 months. All study endpoints were significantly improved with ivabradine therapy, and there were no significant changes in studied endpoints for placebo-treated patients. Exercise capacity improved from 14.8 ± 2.5 minutes to 28.2 ± 3.5 minutes (P < 0.001). Peak oxygen consumption increased from 13.5 ± 1.3 to 17.9 ± 2.4 mL−1·kg−1·min−1 (P < 0.001). NYHA functional class decreased from 2.5 ± 0.1 to 1.6 ± 0.1 (P < 0.0001). Quality of life (measured with the Minnesota Living with Heart Failure Questionnaire) scores improved from 30.9 ± 2.3 to 37.5 ± 1.9 (P < 0.0001). N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels decreased from 2356 ± 2113 pg/mL to 1434 ± 1273 pg/mL (P = 0.045). Resting HR improved from 76 ± 5 to 63 ± 3 bpm (P < 0.001). For patients with systolic HF, this study demonstrated improvement in several endpoints that was similar to the previous study.

The largest study in the HF population was the systolic HF treatment with the If inhibitor ivabradine trial (SHIFT), a multicenter, randomized, double-blind, placebo-controlled study in 6505 patients with moderate to severe HF and LV systolic dysfunction (LVSD).16 Patients were included if at the time of study screening they were in sinus rhythm, had a resting HR ≥70 bpm on 2 consecutive visits before randomization, stable symptomatic HF for ≥4 weeks, prior hospital admission because of worsening HF within the previous 12 months, and LVEF ≤35%.17 The major exclusion criteria were a myocardial infarction (MI) within the past 2 months, a requirement of ventricular or atrioventricular pacing for ≥40% of the day, presence of atrial fibrillation or flutter, or symptomatic hypotension. Patients were randomized to ivabradine 5 mg twice daily (N = 3241) or matched placebo (N = 3264) in addition to stable background HF treatment.16 Doses were adjusted after 14 days to 7.5 mg twice daily but no adjustment was made if resting HR was less than 60 bpm. If resting HR was less than 50 bpm or patient had symptoms of bradycardia, ivabradine was decreased to 2.5 mg twice daily. These adjustments were also made at follow-up appointments that occurred every 4 months.

Baseline characteristics were similar between groups with a mean age of 60.7 ± 11.2 versus 60.1 ± 11.5 years in the ivabradine-treated and placebo-treated patients, respectively.16 The most prevalent NYHA classes were class II in 1585 (49%) of ivabradine-treated and 1585 (49%) of placebo-treated patients and class III in 1605 (50%) versus 1618 (50%) of the ivabradine and placebo groups, respectively. At the time of randomization, most patients were on an optimal HF medication regimen with 2897 (89%) of ivabradine-treated and 2923 (90%) of placebo-treated patients on a beta-blocker. A total of 3020 (93%) of patients in the ivabradine group and 3023 (92%) of patients receiving placebo were on ACE-I or ARB medications.

The median duration of follow-up was 22.9 months (interquartile range, 18–28 months).16 The primary endpoint (composite of cardiovascular death or hospital admission for worsening HF) occurred significantly less frequently in the ivabradine-treatment group compared with placebo (24% vs. 29%; hazard ratio, 0.82; 95% CI, 0.75–0.9; P < 0.0001). The incidence of cardiovascular death was similar between ivabradine-treated and placebo-treated patients (14% vs. 15%; hazard ratio, 0.91; 95% CI, 0.8–1.03; P = 0.128). Significantly greater hospitalizations for worsening HF occurred in the placebo group (21%) compared with the ivabradine group (16%) (hazard ratio, 0.89; 95% CI, 0.82–0.96; P < 0.0001). Severe HF, defined as NYHA class IV or NYHA class II or III with LVEF ≤20%, was examined in an additional analysis to assess efficacy and safety with no difference found between severe and nonsevere HF and treatment effect with ivabradine.18

A predefined subgroup in the SHIFT study were patients who received at least 50% of the evidence-based target daily dose of beta-blocker to evaluate the benefit of ivabradine therapy on the primary composite endpoint.16 There was no significant difference between ivabradine and placebo in this subgroup; however, hospital admissions for worsening HF were still reduced by 19% (P = 0.021). Further analyses were also conducted evaluating the impact of achieving target beta-blocker dose on the study endpoints.19 Ivabradine had a significant difference from placebo in patients who achieved <50% of target beta-blocker dose; however, this effect was nonsignificant after adjusting for HR, suggesting HR is the major determinant for impact on the study endpoints. Baseline HR was further evaluated in 2 studies demonstrating the increased risk of the study endpoints in patients with higher baseline HR compared with the lowest HR.20,21 A summary of all additional analyses that were conducted from the SHIFT population is provided in Table 1.18–28

Table 1

Table 1

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Table 1

Several prespecified substudies were conducted from the SHIFT population. These included an evaluation of health-related quality of life, a Holter substudy, and an echocardiography substudy. A 24-hour Holter monitoring substudy was conducted in 602 patients from the SHIFT population; 298 received ivabradine and 304 receiving matched placebo.29 Holter monitoring was performed at baseline and 8 months into the study to assess heart rhythm safety of ivabradine throughout the day compared with resting office HR. Baseline mean 24-hour HR was similar in the ivabradine-treated and placebo-treated groups at 75.4 ± 10.3 versus 74.8 ± 9.7 bpm, respectively. At 8 months, mean 24-hour HR decreased by 9.5 ± 10 bpm for ivabradine-treated patients compared with 1.2 ± 8.9 bpm for placebo-treated patients (P < 0.0001). In terms of safety, 21.3% in the ivabradine group compared with 8.5% in the placebo group had a bradycardic episode of HR <40 bpm at the 8 months 24-hour Holter (P < 0.0001). Episodes of symptomatic bradycardia were not reported in this analysis. Additionally, no episodes of sustained ventricular tachycardia were found in this patient population.

Health-related quality of life was assessed in 1944 patients; 968 treated with ivabradine and 976 treated with placebo, using the validated Kansas City Cardiomyopathy Questionnaire (KCCQ).30 The questionnaire was given at baseline, and at 4, 12, and 24 months after study entrance in addition to the last study visit; however, the reported analysis focused on follow-up to 12 months. Both overall summary score (OSS), the mean of physical limitation, total symptom, quality of life and social limitation scores, and clinical summary score (CSS), the mean of the physical limitation and the total symptom domain, were reported. The change in KCCQ CSS from baseline to 12 months was a mean of 5 ± 17.5 in ivabradine-treated and 3.3 ± 16.5 in placebo-treated patients (P = 0.018). Similar significant differences were found with KCCQ OSS from baseline to 12 months with a mean change of 6.7 ± 17.3 versus 4.3 ± 16.7 in ivabradine-treated and placebo-treated patients, respectively (P < 0.001). The changes in KCCQ scores were inversely correlated with changes in HR with ivabradine reducing HR by 10.1 bpm (placebo-corrected P < 0.0001) and improving CSS by 1.8 (P = 0.018) and OSS by 2.4 (P < 0.001).

An echocardiography substudy enrolled 411 patients from the SHIFT study; 208 in the ivabradine group and 203 in the placebo group.31 Echocardiograms were performed at baseline and 8 months for the included patients. The primary substudy endpoint was the change in left ventricular end-systolic volume index (LVESI) and a secondary endpoint was the change in LVEF. LVESI decreased by 7 ± 16.3 versus 0.9 ± 17.1 mL/m2 in ivabradine-treated and placebo-treated patients, respectively (P < 0.001). LVEF improved by 2.4 ± 7.7% and decreased by 0.1 ± 8% in patients receiving ivabradine and placebo, respectively (P < 0.001). A further analysis of the patients in this substudy was conducted including 275 (132 receiving ivabradine and 143 receiving placebo) of the 411 patients who had both HR and stroke volume measurement on each echocardiogram assessment. The purpose of this analysis was to assess the afterload reduction associated with HR reduction by evaluating stroke volume, Ea (a marker of arterial vascular load on the heart), total arterial compliance (a measure of pulsatile load of the heart), and left ventricular end-systolic elastance (a representation of LV contractility). At 8 months, Ea (P < 0.0001) and total arterial compliance (P = 0.004) were significantly improved in ivabradine-treated patients compared with placebo-treated patients. Change in left ventricular end-systolic elastance was similar in both the ivabradine and placebo groups. However, there was a significant improvement in stroke volume from baseline to 8 months in the ivabradine compared with the placebo-treated patients (P < 0.0001).

Overall, the SHIFT study series demonstrated an improvement in the primary efficacy endpoint that was driven by reduced HF hospitalizations in patients treated with ivabradine compared with placebo. This improvement was no longer significant for patients receiving greater than 50% of recommended beta-blocker doses.

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Coronary Artery Disease/Angina Pectoris

Stable angina pectoris affects 20,000–40,000 per 1 million in the United States and Europe and is associated with serious morbidity as it often restricts every day activities.32 Medical therapy, either alone or in combination with revascularization therapy, usually consists of low dose aspirin, short-acting nitroglycerin for acute symptomatic relief, a beta-blocker titrated to full dose (or, if beta-blocker cannot be used or optimally dosed, a calcium channel blocker or long acting nitrate), and potentially ranolazine.

Ivabradine has been evaluated in numerous controlled trials for the prevention of cardiac events in patients with CAD and/or angina. In an initial dose ranging, randomized, placebo-controlled trial conducted in 360 patients, patients were randomized into 1 of 4 groups: ivabradine 2.5, 5, or 10 mg twice daily or placebo.33 After 2–3 months of therapy, ivabradine demonstrated a dose-dependent improvement in exercise tolerance and time to 1-mm ST-segment depression. Exercise tolerance, which was measured as time to exercise-limiting angina, deteriorated in patients who received placebo but not in those receiving ivabradine (P < 0.02 for all groups). The results for exercise tolerance were significantly different when measured at trough of drug activity compared with the peak of drug activity. However, this study was relatively small, was of a short duration, and did not use an active control.

The INITIATIVE study was a randomized, double-blind, parallel-group, active-control, noninferiority trial that compared the efficacy and safety of ivabradine with atenolol in patients with stable angina pectoris.34 In this trial, 939 patients were enrolled in 144 centers across 21 countries. Inclusion criteria included evidence of CAD with at least a 3-month history of stable angina pectoris plus 2 positive exercise tolerance tests (ETT). Exclusion criteria included any significant heart disease other than CAD (ie, HF, uncontrolled hypertension, and atrial fibrillation), recent treatment with amiodarone (<3 months), electrolyte disorders, renal dysfunction, and uncontrolled thyroid disorders. After a 7-day washout of all antianginal medications, patients were randomized to 1 of 3 groups: ivabradine 5 mg twice daily for 4 weeks increasing to 7.5 mg twice daily for 12 weeks, ivabradine 5 mg twice daily for 4 weeks increasing to 10 mg twice daily for 12 weeks, or atenolol 50 mg once daily for 4 weeks increased to 100 mg once daily for 12 weeks. The primary efficacy endpoint was change in total exercise duration (TED) at time of expected trough drug concentrations. TED increased by 86.8 ± 129.0 seconds with ivabradine 7.5 mg twice daily, 91.7 ± 118.8 seconds with ivabradine 10 mg twice daily, and 78.8 ± 133.4 seconds with atenolol 100 mg once daily. When compared with atenolol, the change in TED was 10.3 ± 9.4 seconds and 15.7 ± 9.5 seconds for ivabradine 7.5 and 10 mg, respectively (P < 0.001 for noninferiority). All 3 intervention groups demonstrated decreased number of weekly angina attacks and weekly consumption of short-acting nitrates. The rate of sinus bradycardia was similar to that usually reported with beta-blockers.35 This trial demonstrated that ivabradine is noninferior to a first-line antianginal medication using a primary endpoint recommended for use in angina trials.

A similar trial comparing ivabradine with atenolol was conducted in Chinese patients with stable angina pectoris.36 This randomized, double-blind, double-dummy, active-control, multicenter, noninferiority trial enrolled patients with chronic stable angina pectoris with CAD, positive ETT, and LVEF ≥50%. Patients were randomized to either ivabradine 5 mg twice daily or atenolol 12.5 mg twice daily. After 4 weeks, the dose of ivabradine and atenolol could be increased to 7.5 and 25 mg twice daily, respectively, depending on HR. The primary endpoint was change in TED after 12 weeks of treatment. In the ivabradine group, TED improved by 84.1 ± 130.5 versus 77.8 ± 126.6 seconds in the atenolol group (P = 0.6495). Both ivabradine and atenolol were efficacious in reducing the frequency of angina attacks with no difference between the 2 groups.

The ASSOCIATE trial was designed to evaluate the efficacy and safety of ivabradine when used in combination with a beta-blocker in patients with stable angina pectoris.37 A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial compared atenolol with atenolol plus ivabradine for the treatment of stable angina pectoris. This trial, which involved 219 centers across 20 countries, enrolled 889 patients. Inclusion criteria included a history of chronic angina, evidence of CAD, sinus rhythm, currently being treated with atenolol 50 mg daily or equivalent, and with 3 positive ETTs. There was a 6- to 8-week single-blind run-in where all patients received atenolol 50 mg once daily and placebo twice daily. Patients were subsequently randomized to either continue placebo or start ivabradine 5 mg twice daily with a forced uptitration at 2 months to 7.5 mg twice daily. The primary endpoint was change in TED after 4 months of treatment. TED increased by 24.3 ± 65.3 seconds in the ivabradine group compared with 7.7 ± 63.8 seconds in the placebo group (P < 0.001). Frequency of angina attacks decreased from 1.8 ± 3.3 to 0.9 ± 2.1 per week in the ivabradine group and from 1.6 ± 2.4 to 0.9 ± 2.1 in the placebo group (between-group difference not significant). In a subgroup analysis that evaluated study endpoints by baseline HR (>65 or ≤65 bpm), improvement in exercise capacity was seen regardless of the baseline HR.38 Overall, this study demonstrated a positive effect for ivabradine when added to a beta-blocker for the treatment of stable angina pectoris.

Calcium channel blockers are usually thought of as second-line or add-on therapy for stable angina pectoris. A randomized, double-blind, 3-arm parallel-group, multicenter, noninferiority trial was conducted to compare the efficacy of ivabradine with amlodipine in stable angina pectoris.39 The trial, involving 133 centers across 10 countries, enrolled 1195 patients with a ≥3-month history of chronic stable angina pectoris, CAD, and a positive bicycle ETT. After a 14-day washout and single-blind placebo run-in, patients were randomized to 1 of the 3 groups: ivabradine 7.5 mg twice daily, ivabradine 10 mg twice daily, or amlodipine 10 mg once daily. The primary endpoint was change in TED after 3 months of treatment. When measured at trough medication concentrations, ivabradine 7.5 and 10 mg twice daily resulted in improvements in TED of 27.6 ± 91.7 and 21.7 ± 94.5 seconds, respectively, compared with 31.2 ± 92.0 seconds for amlodipine (P < 0.001 for noninferiority for both groups). Both ivabradine groups were noninferior to amlodipine for other ETT parameters including change in time to angina onset, time to exercise limiting angina, and time to ST-segment depression.

In a randomized, double-blind, parallel-group, multicenter trial, researchers evaluated the long-term safety and efficacy of ivabradine in 386 patients with chronic stable angina pectoris.40 Assessing the long-term safety of ivabradine in this patient population was the primary objective of this study and long-term efficacy was a secondary objective. Patients were randomized to receive either ivabradine 5 mg twice daily or 7.5 mg twice daily for 12 months. Ivabradine was generally well tolerated. Visual symptoms were the most common adverse event reported (23 and 43 patients in the ivabradine 5 and 7.5 mg twice daily groups, respectively). In the 5 mg twice daily group, 31 patients (15.6%) experienced serious nonfatal adverse events and 18 (9.1%) withdrew from the study. In the 7.5 mg twice daily group, 21 patients (16.5%) experienced serious nonfatal adverse events and 22 patients (11.7%) withdrew from the study. Seven patients died during the study, 6 were classified as cardiovascular deaths. Overall, 19.4% of patients reported an emergent cardiac adverse event during the study; although, only a few of these events were serious enough to warrant withdrawal. Serious cardiac events (angina aggravation, unstable angina, MI, supraventricular tachycardia, atrial fibrillation, ventricular tachycardia, and cardiac failure) occurred in 25 patients in the total study population (6.5%). Sinus bradycardia was reported in only 5 patients (1.3%). This study is the first long-term study to demonstrate the safety of ivabradine in patients with chronic stable angina.

The first truly large trial evaluating the efficacy and safety of ivabradine in CAD was the BEAUTIFUL trial.41 This randomized, double-blind, placebo-controlled, parallel-group, multicenter trial enrolled 10,917 patients with stable CAD and LVEF <40%. After a 14-day run-in of no study treatment, patients were randomized to either ivabradine 5 mg twice daily (uptitrated to 7.5 mg twice daily after 2 weeks) or matching placebo. Concomitant cardiovascular therapies included beta-blockers, ACE-Is or ARBs, lipid-lowering agents, and aspirin (or other antiplatelet or antithrombotic). The primary endpoint was the composite of cardiovascular death, admission to hospital for acute MI, and admission to hospital for new-onset or worsening HF. The primary endpoint occurred in 844 patients (15.4%) in the ivabradine group and in 832 patients (15.3%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.91–1.1; P = 0.94). The effect of ivabradine was similar in all prespecified subgroup analyses. There was no difference between ivabradine and placebo for any individual components of the composite endpoint. The mean placebo-adjusted HR reduction for ivabradine in this trial was 6 bpm at 12 months and 5 bpm at 24 months. A total of 1528 patients (28%) in the ivabradine group and 856 patients (16%) in the placebo group discontinued study medication. The authors note that the lack of effect seen in this trial could be attributed to the relatively small decrease in HR seen in the ivabradine group, which could be secondary to appropriate beta-blocker use or low baseline HR. An effect was seen for the endpoint of fatal and nonfatal MIs (relative reduction, 36%; P = 0.001) consistent with previous CAD studies evaluating the role of HR. The authors suggest that the HR lowering effect of ivabradine is more likely to be beneficial in CAD patients on coronary endpoints and in patients with a high baseline HR.42

A post hoc subgroup analysis of the BEAUTIFUL trial evaluated the relationship between ivabradine treatment and cardiovascular endpoints in patients with CAD, LVSD, and limiting angina.43 Of the entire study population in the BEAUTIFUL trial, 13.8% presented with limiting angina (734 in the ivabradine group and 773 in the placebo group). In this patient population, there was a nonsignificant reduction in the primary endpoint in the ivabradine group (hazard ratio, 0.76; 95% CI, 0.58–1.00) and a 42% reduction in fatal and nonfatal MIs (hazard ratio, 0.58; 95% CI, 0.37–0.92). Among patients with a baseline HR ≥70 bpm, there was a 73% reduction in hospitalization for MI (hazard ratio, 0.27; 95% CI, 0.11–0.66) and a 59% reduction in coronary revascularization (hazard ratio, 0.41; 95% CI, 0.17–0.99).

There were 2 substudies in the BEAUTIFUL trial.44,45 In the echocardiographic substudy, enrolled patients (n = 590) had 2-dimensional echocardiography performed at baseline, 3 months, and 12 months.44 The primary endpoint was to demonstrate the superiority of ivabradine over placebo on change in LVESI. The effect of ivabradine on LVEF and NT-proBNP were secondary endpoints. LVESI decreased in the ivabradine group by 1.48 ± 13.00 mL/m2 and increased in the placebo group by 1.85 ± 10.54 mL/m2 (P = 0.018). There was an increased in LVEF in the ivabradine group (2.00 ± 7.02%) versus virtually no change in the placebo group (0.01 ± 6.20%) (P = 0.009). Additionally, no difference existed between the 2 groups with respect to NT-proBNP. This substudy provides additional evidence regarding the beneficial effect of ivabradine on left ventricle remodeling (as evidenced by positive changes in LVESI and LVEF) compared with placebo. In the Holter substudy, enrolled patients (n = 840) underwent 24-hour ambulatory Holter monitoring at baseline, 1 month, and 6 months.45 This was an exploratory substudy to evaluate any potential cardiac rhythm abnormalities in patients taking ivabradine. The fact that no difference was present between the 2 groups with respect to conduction or rhythm abnormalities suggests that ivabradine is safe from a cardiac conduction standpoint when used in combination with beta-blockers in patients with CAD and LVSD.

A pooled analysis was conducted for the 2 largest studies with ivabradine to date, BEAUTIFUL and SHIFT, to evaluate the impact of ivabradine in a broad patient population with LV dysfunction with either HF or CAD as the primary diagnosis. All patients from the SHIFT study were included (N = 6505) and all patients from the BEAUTIFUL study with a baseline HR ≥70 bpm [5392 of the 10,917 patients (49%)] were included in this analysis for a total patient population of 11,897; 5940 patients received ivabradine and 5957 received placebo. The primary composite endpoints from SHIFT (cardiovascular mortality or hospital admission for worsening HF) and BEAUTIFUL (cardiovascular mortality, hospital admission for new or worsening HF or MI) were analyzed. Cardiovascular mortality or hospitalization for HF (the primary composite endpoint in SHIFT) occurred in 1229 (21%) ivabradine-treated and 1379 (23%) placebo-treated patients (P < 0.001). Similar to the SHIFT study, this endpoint was driven by hospitalizations for worsening HF. Cardiovascular mortality, hospitalization for HF, or hospitalization for MI was significant for 1288 patients (22%) who received ivabradine versus 1477 patients (25%) who received placebo (P < 0.001). All these endpoints were significantly better for ivabradine-treated patients when analyzed separately. The study investigators concluded that ivabradine is effective for the improvement of clinical endpoints for patients with LVSD with a baseline HR ≥70 bpm, regardless of the concomitant disease state.

A small single-center, prospective, randomized, placebo-controlled, proof-of-concept trial was conducted to further elucidate the role of ivabradine in CAD.46 This trial enrolled 46 patients with chronic, stable CAD to receive either ivabradine 5 mg/d (goal HR = 60 bpm; maximum ivabradine dose was 7.5 mg twice daily) or matching placebo for 6 months. Percutaneous coronary intervention was performed at baseline and after study treatment. The primary endpoint was collateral flow index (ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure) a measure of coronary collateral perfusion. In the ivabradine group, collateral flow index increased from 0.111 ± 0.078 to 0.156 ± 0.089 (P = 0.0461) after 6 months of therapy, whereas in the placebo group it decreased from 0.140 ± 0.097 to 0.109 ± 0.067 (P = 0.12).

The BEAUTIFUL trial ultimately had negative results, but subgroup analyses did suggest potential benefit in patients with a baseline HR ≥70 bpm and CAD. The SIGNIFY trial was conducted to evaluate ivabradine in patients with stable CAD and no clinical HF.47 In this randomized, double-blind, placebo-controlled, parallel-group, event-driven, multicenter trial, 19,102 patients were enrolled if they had documented CAD with no clinical evidence of HF, and sinus rhythm with a HR ≥70 bpm. Patients were excluded if they had a LVEF ≤40% or any unstable cardiovascular condition. After a 2- to 4-week placebo run-in to confirm eligibility and clinical stability, patients were randomized to 1 of the 2 groups; ivabradine 7.5 mg twice daily (5 mg twice daily in patients aged ≥75 years) or matching placebo. All patients were on stable, guideline recommended background cardiovascular disease therapy (aspirin, statins, ACE-I or ARB, and beta-blocker) at appropriate doses as indicated. During follow-up study, medication could be adjusted to 5, 7.5, or 10 mg twice daily according to HR (target HR, 55–60 bpm). The primary endpoint was the composite of death from cardiovascular causes or nonfatal MI. No significant difference was seen between the 2 groups with respect to the primary endpoint in the ivabradine and placebo groups (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% CI, 0.96–1.20; P = 0.20) and in either of the components of the primary endpoint as well. No difference was seen between the groups for any of the secondary efficacy endpoints including death from any cause, coronary revascularization, admission to the hospital for HF, and MI. In a subgroup analysis, there was a significant negative interaction between ivabradine and the presence of angina at baseline (hazard ratio, 1.18; 95% CI, 1.03–1.35; P = 0.02). This effect seemed to be consistent in both components of the composite endpoint. Overall, ivabradine was associated with no benefit in this large trial conducted in patients with stable CAD with no clinical HF. The authors concluded that HR is a risk factor for cardiovascular outcomes in CAD, but potentially not a modifiable one.

One trial has evaluated the role of ivabradine in microvascular angina pectoris, which is defined as typical angina pain on exertion, evidence of myocardial ischemia, and absence of CAD.48 This randomized, single-center study enrolled patients with stable primary microvascular angina with suboptimal symptom control with traditional antiischemic therapy who have not received either ivabradine or ranolazine before. Patients in this 4-week study were randomized to receive 1 of the 3 regimens: ivabradine 5 mg twice daily, ranolazine 375 mg twice daily, or placebo twice daily. The primary endpoint was a quality of life questionnaire. The questionnaire results were significantly improved in the ivabradine and ranolazine group across all domains (physical, angina stability, angina frequency, treatment satisfaction, and disease perception). This small study demonstrates the potential for ivabradine as a second-line or third-line agent for microvascular angina.

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Cardiac Surgery

Ivabradine was compared with beta-blocker therapy in patients with conduction abnormalities or LVSD undergoing cardiac surgery in a randomized, open-label, single-center trial, which enrolled 527 patients.49 Inclusion criteria included patients having cardiac surgery (CABG, valve replacement, or combined) with conduction abnormalities, LVSD, or both. Two days before surgery, patients were randomized into 1 of the 3 groups: metoprolol 100 mg once daily (study does not specify metoprolol salt form), metoprolol 50 mg once daily plus ivabradine 5 mg twice daily, or ivabradine 5 mg twice daily. Treatment occurred for 2 preoperative days and at least 10 postoperative days. Efficacy endpoints were 30-day mortality, in-hospital occurrence of atrial fibrillation/arrhythmias, in-hospital occurrence of third degree atrioventricular block, in-hospital worsening of HF, and duration of hospitalization. In-hospital atrial fibrillation occurred less frequently in the metoprolol plus ivabradine group (8.94% of patients) compared with either drug alone (9.66% and 19.77% for metoprolol and ivabradine, respectively) (P < 0.001). In-hospital third degree atrioventricular block occurred in 2.91% of patients in the ivabradine group compared with 12.50% and 6.15% of patients in the metoprolol and metoprolol plus ivabradine groups (P < 0.001). The combined endpoint of 30-day mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital third degree atrioventricular block, or in-hospital HF worsening) was lower in the metoprolol plus ivabradine group (23.46% of patients) compared with either the metoprolol group (34.09%) or the ivabradine group (29.07%) alone (P < 0.001). Mean duration of hospital stay was decreased in the ivabradine group (8.2 ± 6.4 days) and ivabradine plus metoprolol group (8.5 ± 6.8 days) versus the metoprolol group (10.2 ± 6.3 days). This study demonstrates that ivabradine in combination with a beta-blocker may decrease the incidence of postoperative atrial fibrillation/arrhythmias, although the mechanism is unknown. However, this needs to be confirmed in a more robust trial.

Ivabradine has been evaluated in post-CABG patients as a part of cardiac rehabilitation program.50 This prospective, randomized trial occurred in a cardiac rehabilitation unit in Italy and enrolled 81 patients. Eligibility criteria were post-CABG patients, LVEF ≥50%, in stable clinical condition, on standard cardiovascular background therapy, in sinus rhythm, and have a HR >70 bpm. All patients were on bisoprolol 1.25 mg daily at baseline and were randomized to either ivabradine 5 mg twice daily or to an increased bisoprolol dose (2.5 or 3.75 mg once daily). The primary endpoint was improvement in 6-minute walking test after 3 months of therapy. At 3 months, there was no difference between the groups in the 6-minute walking test (ivabradine plus bisoprolol, 370 ± 55 vs. 347 ± 42 m; P = not significant). Both groups had similar LVEF at admission (57 ± 3% in both groups), but the ivabradine plus bisoprolol group had a significantly higher LVEF at 3 months follow-up (66 ± 3 vs. 59 ± 3%; P < 0.05). This study has several limitations including using only low doses of bisoprolol in addition to its small, single-center design. However, the improvement in LVEF is a promising result but requires confirmation in a larger, better designed trial.

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Coronary Computed Tomography Angiography

A unique indication that ivabradine has been evaluated for is as a premedication for coronary computed tomography angiography (CCTA) to improve image quality, which is directly associated with HR. CCTA is an emerging, noninvasive diagnostic tool for the evaluation of CAD. To achieve optimal diagnostic accuracy image quality control is imperative. Increased HR is associated with reduced image quality in an almost linear manner.51 Multiple studies have been performed to evaluate the efficacy of ivabradine in reducing HR to achieve optimum image quality in CCTA. A summary of these studies and the various dosing strategies are given in Table 2.52–58

Table 2

Table 2

Table 2

Table 2

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Tachycardias

Ivabradine, because of its unique mechanism of action, has been evaluated for a variety of tachycardias. One is inappropriate sinus tachycardia, which is defined as a sinus HR >100 bpm while resting (with a mean 24-hour HR >90 bpm) associated with palpitations.59 Beta-blocker therapy is generally not effective and can cause adverse effects. Efficacy of ivabradine has been reported in numerous case reports, case series, and uncontrolled trials for inappropriate sinus tachycardia.60–65

The efficacy of ivabradine for treating patients with inappropriate sinus tachycardia syndrome has been evaluated by 1 prospective, randomized, placebo-controlled, double-blind, crossover trial enrolling 21 patients.66 Inclusion criteria included a resting HR during daytime ≥95 bpm on a 24-hour Holter monitor and/or a rapid stable symptomatic increase in HR (>25 bpm) when moving from a supine position to a standing position or in response to physiological stress. Patients were randomized to either ivabradine 5 mg twice daily (could be titrated up or down depending on HR and tolerability after 3 weeks) or matching placebo for two 6-week trial phases. The primary endpoint was resolution of symptoms associated with inappropriate sinus tachycardia (palpitations, presyncope/syncope, orthostatic intolerance, chest pain, dyspnea, fatigue, and anxiety). Overall, >70% of symptoms were relieved with ivabradine compared with placebo (relative risk, 0.25; 95% CI, 0.18–0.34; P < 0.001). Ivabradine was also associated with significantly decreased HR compared with placebo. Overall, this study demonstrated the potential for ivabradine to reduce HR and improve symptoms in patients with inappropriate sinus tachycardia.

Successful reports of using ivabradine to treat other tachycardias exist as well, although none were in randomized controlled trials. Case series have reported the use of ivabradine for treating sinus tachycardia associated with clozapine therapy, sinus tachycardia–mediated vasovagal syncope, catecholamine-induced tachycardia following cardiac surgery, and in postural orthostatic tachycardia syndrome.67–70

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DRUG–DRUG INTERACTIONS

Ivabradine has no effect on the pharmacokinetics of lansoprazole, omeprazole, digoxin, warfarin, sildenafil, simvastatin, or metformin.5,71 Ivabradine is a weak inhibitor of CYP3A4 and has not been demonstrated to have a major impact on the metabolism or plasma concentrations of other CYP3A4 substrates. Steady-state area under the curve (AUC) and Cmax of ivabradine are decreased by more than 50% when administered with strong inducers of CYP3A4, such as hypericum perforatum (St. John's wort), carbamazepine, and phenytoin; therefore, concomitant use of ivabradine is recommended to be avoided.5,72–74 Concomitant administration with strong CYP3A4 inhibitors, including ketoconazole, results in a greater than 2-fold increase in steady-state AUC and Cmax of ivabradine. Coadministration of strong inhibitors is contraindicated per the package labeling. An approximate 2-fold increase in steady-state AUC and Cmax of ivabradine is seen with concomitant administration of moderate CYP3A4 inhibitors and their use with ivabradine is recommended to be avoided.

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ADVERSE EFFECTS

The most common adverse events reported in the SHIFT and BEAUTIFUL studies were bradycardia (symptomatic and asymptomatic), atrial fibrillation, and phosphenes.16,41 Symptomatic bradycardia occurred more in ivabradine patients (5%–11%) versus placebo patients (1%–1.2%) (P < 0.001 in both studies) and a similar trend was observed with asymptomatic bradycardia (6%–11% vs. 1%–1.3%; P < 0.0001 in both studies). Both studies had a greater incidence of new-onset atrial fibrillation developing in 5.3%–9% of patients in the ivabradine group versus 3.8%–8% in the placebo group. The mechanism for the increased risk of atrial fibrillation is unknown. Additionally, phosphenes, defined as transient enhanced brightness in a restricted area of the visual field, developed in 3%–5.4% compared with 0.5%–1% of ivabradine and placebo-treated patients, respectively (P < 0.001 in both studies). The mechanism of this adverse event relates to the interaction of ivabradine with a hyperpolarization current in the retina.75 In healthy adults, a single intravenous dose of ivabradine has no effect on the QTc interval.76

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DOSAGE RECOMMENDATIONS

Ivabradine is available as 5 and 7.5 mg tablets.5 The FDA-approved starting dose in systolic HF for ivabradine is 5 mg given orally twice daily with meals. The dose can be adjusted after 2 weeks with a goal resting HR between 50 and 60 bpm; the same titration schedule that was studied in the SHIFT trial.5,16,17 The maximum dose is 7.5 mg twice daily and the dose can be decreased to 2.5 mg twice daily for patients unable to tolerate 5 mg twice daily (HR <50 bpm or symptomatic bradycardia). No dose adjustment is recommended for age, renal impairment, or mild or moderate hepatic impairment. No dosage recommendations are available for patients with a creatinine clearance below 15 mL/min or severe hepatic impairment (Child–Pugh C).

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PLACE IN THERAPY

Because of the high morbidity and mortality associated with HF, novel medication therapies are highly appealing.10 The SHIFT study and the subsequent subgroup analyses demonstrated a reduction in HF hospitalizations in patients treated with ivabradine; however, this benefit was not significant for patients receiving more than 50% of the recommended beta-blocker dose in HF.16 Patients on optimal HF medication management do not obtain any additional benefit based on currently available evidence. One may be tempted to try this therapy if a beta-blocker cannot be used, but no evidence exists to support this practice. The select patients that can benefit from this medication along with the high cost of ivabradine, estimated at $4500–$5500 per year, limit its routine use for HF in current practice.77 Ivabradine may have a role in other cardiovascular conditions where HR plays a significant role pathophysiologically, that is, CAD or tachycardias, but is currently only approved in the United States for HF.

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CONCLUSIONS

Ivabradine is an If channel inhibitor, the first in this class, approved for HF in the United States and HF and CAD in Europe. It provides no mortality benefit but may decrease the number of hospitalizations experienced by patients with HF and an elevated HR. The role of ivabradine in treating HF has yet to be addressed by HF guideline-issuing professional organizations, but the medication has only been recently approved by the FDA.

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Keywords:

ivabradine; systematic review; heart failure; coronary artery disease

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