Ivabradine for the Treatment of Cardiovascular Diseases

Abstract

Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the I_f current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of I_f inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.

Increased heart rate (HR) is an independent risk factor for cardiovascular mortality and morbidity both in subjects without and with various cardiovascular diseases (CVDs), including hypertension, coronary artery disease (CAD), and heart failure (HF).¹ Lowering HR by β-blocker is related to the drug’s beneficial effects such as improvement of myocardial oxygen demand, energy depletion, atherosclerosis, and plaque rupture.^2–5 Beta-blockers have numerous actions on the heart, including a decrease in myocardial contractility and in blood pressure (BP), and anti-arrhythmic effects, which may contribute not only to the anti-anginal effect, but also to the improvement of long-term outcomes in HF with reduced ejection fraction (HFrEF).⁶

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels expressed in the sinoatrial node (SAN) play an important role in the regulation of HR.^7,8 HCN channels open in response to hyperpolarization voltage, which allows permeation of sodium ions, and generation of an inward I_f current (f for “funny” because of its unusual electrophysiological properties).⁹ The 4 HCN isoforms, HCN1–4, have different biophysical properties, including time course of activation and deactivation, and sensitivity to cyclic adenosine monophosphate (cAMP).¹⁰ HCN4 is the principal isoform and contributes to the generation of the I_f current in the SAN.

Ivabradine is a novel and currently the only HCN4 inhibitor used clinically for chronic stable angina and chronic HF. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of ivabradine in I_f inhibition, and the pharmacological and clinical effects of ivabradine in CVDs.

Pharmacological Studies

I_f (HCN4 Channel) in Cardiac Pacemaking

HR is determined by spontaneous electrical activity in pacemaker cells in the SAN, which is located in the right atrium. Automatic slow diastolic depolarization (DD) of SAN cells occurs via ion channels that are mainly responsible for the I_f.¹¹ The most interesting feature of the I_f is its voltage dependence, because it is activated by hyperpolarization with a threshold of approximately −40/−50 mV with low conductance (Figure 1). The molecular identity of the “funny” channel is considered to be HCN4, based on the physiological characteristics of the channel and evidence from genetic manipulation in mice.^12,13

Figure 1.

Schematic diagram of the mechanism of action of ivabradine. Pacemaker sinoatrial node (SAN) cells are primarily responsible for initiation of electrical impulses, and the frequency of spontaneous action potential firing determines heart rate (HR). SAN cells cause slow diastolic depolarization (DD) generated by inward ionic currents (I_f) from the orchestrated work of ionic channels; the so-called membrane clock. Ivabradine inhibits I_f to decrease the rate of slow DD, which leads to reduced HR. (Inset) Schematic illustration of a subunit of HCN4, composed of 6 transmembrane α-helices (S1–S6, S4: positively charged voltage sensor, S5–S6: pore domain) and a cyclic nucleotide-binding domain (CNBD) motif. Ivabradine accesses the inner cavity of HCN4 when the channel is open.

The HCN4 channel is organized as a tetramer of 4 identical subunits arranged around a centrally located channel pore.¹⁴ Monomeric HCN4 has 6 transmembrane α-helices, which form the voltage-sensing domain (S1–S4) and the pore domain (S5–S6), and an intracellular carboxy-terminal cyclic nucleotide-binding domain (CNBD) motif (Figure 1). Beta-adrenergic stimulus increases HR by increasing intracellular cAMP in the SAN, and cAMP binds to the CNBD motif and elicits a positive shift in the voltage dependence of activation of the HCN4 channel.¹³ The expression of HCN4 is SAN selective and controlled by transcriptional mechanisms.¹⁵ Increased expression of HCN4 and HCN2 has been reported in the hypertrophic heart, which is considered to be one of the mechanisms responsible for atrial and ventricular arrhythmias in HF.¹⁶

Mechanism of HCN4 Channel Inhibition by Ivabradine

Ivabradine has a unique pharmacological profile for HCN4 inhibition; dose, time, and current frequency (use)-dependent inhibition (Figure 2).^17–19 Ivabradine requires several hours to achieve stable reduction in the spontaneous action potential (AP) firing rate of isolated SAN because it binds to intercellular sites of the HCN4 channel with an open channel configuration. Ivabradine also shows current frequency-dependent inhibition, and this is associated with the characteristic of ivabradine; that is, more effective in HR reduction at higher HR. The reduced pacemaker rate is thought to be based on slowing the rate of DD, but not for prolonged AP repolarization, reducing the maximal diastolic potential, and shifting the threshold potential.

Figure 2.

Time and dose-dependent effects of ivabradine on the spontaneous firing rate of the rabbit isolated sinoatrial node. (A) Demonstrable traces of action potential (AP) showing reduction of the pacemaker firing rate by 3 µmol/L ivabradine (0, 5, 10, 15, and 20 min). (B) Time-dependent effects of different doses (0.1, 0.3, and 1 µmol/L) of ivabradine. Data are expressed as mean±SEM (n=5). The AP rate is shown as the % change from baseline. Reproduced with permission from Thollon C, et al¹⁸ and Thollon C, et al.¹⁹

Regarding ion channel selectivity, ivabradine inhibits HCN1–4 with similar IC₅₀ values.²⁰ Ivabradine has good selectivity for pacemaker I_f, mainly HCN4, over other ion-channel (I_CaL, I_CaT, and I_Kr) currents in the SAN.²¹ Ivabradine has no effect on cardiac repolarization, as indicated by the absence of an effect on QTc upon repeated administration to dogs.²² Therefore, ivabradine is a specific HCN inhibitor that can lead to “pure” HR reduction.

In Vivo Pharmacological Studies of Ivabradine

The “pure” HR reduction by ivabradine without other hemodynamic and electrophysiological effects has been extensively investigated in normal animals. In conscious rats, a single oral administration of ivabradine reduced HR with maximal reduction (maximal 22% reduction from pre-value) without affecting mean BP.²³ Ivabradine reduced HR with increased stroke index and therefore showed minimal effect on the cardiac index.²⁴ In anaesthetized pigs, ivabradine reduced myocardial oxygen consumption, in parallel with HR reduction, without affecting the ratio of oxygen delivery to oxygen consumption in hemodynamic experiments.²¹ Similar to β-blockers, intravenous administration of ivabradine reduced HR at rest and during treadmill exercise in dogs.²⁵ Ivabradine did not decrease myocardial contractility (LVdP/dt) at rest and only slightly decreased LVdP/dt during exercise by HR reduction, whereas propranolol reduced myocardial contractility at rest and during exercise (Figure 3). In contrast to propranolol, ivabradine did not decrease coronary vascular resistance and only slightly decreased the coronary artery diameter. Furthermore, ivabradine prolonged diastolic perfusion time, simultaneously preserved coronary blood flow, coronary vascular resistance, and cardiac output, and had no negative effects on peripheral vascular resistance.²⁶

Figure 3.

Effects of ivabradine on hemodynamics in conscious dogs at rest and during treadmill exercise. Data are shown for % change from baseline for heart rate, left ventricular peak dP/dt, mean coronary resistance, and mean coronary artery diameter at rest and during treadmill exercise at 5, 10, and 12 km/h after intravenous administration of saline (open circles), 0.5 mg/kg ivabradine (full circles), and 1 mg/kg propranolol (open squares). Data are expressed as mean±SEM (n=7). *P<0.05; **P<0.01 vs. baseline; ^†P<0.01 vs. saline; ^‡P<0.01 vs. propranolol. Reproduced with permission from Simon L, et al.²⁵

Ivabradine prevented myocardial injury, as indicated by the attenuation of ST-segment elevation and the preservation of regional contractility in the myocardial area perfused by the stenotic artery in an exercise-induced myocardial ischemia model in pigs.²⁷ Systolic shortening was preserved to a greater extent by ivabradine compared with β-blockers. Ivabradine reduced HR and improved cardiac function, cardiac energy metabolism, and structural and electrophysiological cardiac remodeling in a rat model of HF induced by myocardial ischemia.¹⁸ Ivabradine reduced HR and improved left ventricular ejection fraction (LVEF) in a dog model of HF, in association with the changes in plasma biochemical markers including N-terminal pro-B-type natriuretic peptide (NT-proBNP), norepinephrine, angiotensin-II, and cytokines.²⁸ Recently, we reported that mechanochronotropic unloading using the combination of a transvascular LV assist device (Impella) and ivabradine could reduce the infarct size via suppression of myocardial oxygen consumption in a dog model of ischemia-reperfusion (Figure 4).²⁹

Figure 4.

Effect of ivabradine (IVA) combination with a transvascular left ventricular (LV) assist device (Impella) on reduction of infarct size in a dog model of ischemia-reperfusion. (A) Representative mid-level slices of the LV in control, Impella, and Impella+IVA groups (n=6). Scale bar=1 cm. (B–D) Comparison of infarct size in 3 groups. Risk (area in red, B) and infarct area (area in white, C) were traced and measured using an image analyzer. Normalized infarct size (infarct size normalized by risk area in %, D) was smaller in the Impella+IVA group than in the control and Impella groups. Data are expressed as mean±SD. *P<0.05 vs. control, **P<0.001 vs. control, ^†P<0.05 vs. Impella. Reproduced with permission from Sunagawa G, et al.²⁹

Clinical Studies

The efficacy and safety of ivabradine are summarized and discussed based on clinical studies mainly of chronic HF and CAD. Table 1 shows the 3 main clinical studies of ivabradine.

Table 1. Main Clinical Studies of Ivabradine for HF and CAD

Study name	Patients	No. of patients	Dosage and administration	Primary endpoint	Hazard ratio (P value)
SHIFT31	HF -NYHA II–IV -LVEF ≤35% -Resting HR ≥70 beats/min in sinus rhythm -Under standard therapy	Total 6,505 -Ivabradine: 3,241 -Placebo: 3,264	Initial: 5 mg BID Adjustment: 2.5–7.5 mg BID based on the resting HR and tolerance	CV death or hospital admission for worsening HF	0.82 (P<0.0001)
BEAUTIFUL67	CAD -LVEF <40% -Resting HR ≥60 beats/min in sinus rhythm -Under standard therapy	Total 10,917 -Ivabradine: 5,479 -Placebo: 5,438	Initial: 5 mg BID Adjustment: 2.5–7.5 mg BID based on the resting HR and tolerance	CV death, admission to hospital for MI or admission to hospital for new-onset or worsening HF	1.00 (P=0.94)
SIGNIFY69	CAD -Non-clinical HF -Resting HR ≥70 beats/min in sinus rhythm -Under standard therapy	Total 19,102 -Ivabradine: 9,550 -Placebo: 9,552	Initial: 7.5 mg BID Adjustment: 5–10 mg BID based on the resting HR and tolerance	CV death or non-fatal MI	1.08 (P=0.20)

BID, twice daily; CAD, coronary artery disease; CV, cardiovascular; HF, heart failure; HR, heart rate; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York heart association.

HFrEF

The hemodynamic effects of ivabradine was evaluated in 10 advanced HF patients with LVEF <35% and New York Heart Association (NYHA) III.³⁰ Intravenous infusion of ivabradine significantly reduced HR while stroke volume and LV systolic work were increased, preserving the cardiac index or cardiac output.

The long-term efficacy and safety of ivabradine in HFrEF were reported in the SHIFT study, which was a placebo-controlled randomized study of 6,505 patients with stable chronic HF in NYHA II–IV, LVEF ≤35%, and resting HR ≥70 beats/min in sinus rhythm under standard therapy (Table 2).³¹ The study showed a clinically significant relative risk reduction of 18% for a primary composite endpoint of CV death or hospital admission for worsening HF over a median follow-up period of 22.9 months (hazard ratio 0.82, P<0.0001). The results for this endpoint were mainly driven by hospital admission for worsening HF (hazard ratio 0.74, P<0.0001). Cardiovascular deaths were not significantly reduced in the ivabradine group (hazard ratio 0.91, P=0.128). All-cause mortality tended to be lower in the ivabradine group, which, however, did not reach statistical significance (hazard ratio 0.90, P=0.092). During treatment, resting HR was continuously and stably lower with ivabradine compared with placebo; mean change from placebo was −10.9 at 28 days, −9.1 at 1 year, and −8.1 beats/min at the end of the study.

Table 2. Main Outcomes From the SHIFT Study

	Ivabradine group (n=3,241)	Placebo group (n=3,264)	Hazard ratio (95% CI)	P value
Primary endpoint
CV death or hospital admission for worsening HF	793 (24)	937 (29)	0.82 (0.75–0.90)	<0.0001
Mortality endpoints
All-cause mortality	503 (16)	552 (17)	0.90 (0.80–1.02)	0.092
Cardiovascular mortality	449 (14)	491 (15)	0.91 (0.80–1.03)	0.128
Death from HF	113 (3)	151 (5)	0.74 (0.58–0.94)	0.014
Other endpoints
All-cause hospital admission	1,231 (38)	1,356 (42)	0.89 (0.82–0.96)	0.003
Hospital admission for worsening HF	514 (16)	672 (21)	0.74 (0.66–0.83)	<0.0001
Any CV hospital admission	977 (30)	1,122 (34)	0.85 (0.78–0.92)	0.0002
CV death, or hospital admission for worsening HF, or hospital admission for non-fatal myocardial infarction	825 (25)	979 (30)	0.82 (0.74–0.89)	<0.0001

Data are number of first events (%), hazard ratio (95% confidence interval [CI]), and P values. CV, cardiovascular; HF, heart failure. Reproduced with permission from Swedberg K, et al.³¹

Symptomatic bradycardia occurred in 5% of the ivabradine group and significantly higher than that in the placebo group (1%) (P<0.0001). Phosphenes were reported to be 3% in the ivabradine and 1% in the placebo group (P<0.0001). Visual side effects, curtailing response to bright light stimuli, are considered to be caused by inhibition of HCN channels in the retina.³² However, these adverse events rarely led to treatment withdrawal (≤1%). Atrial fibrillation (AF) was also more frequent with ivabradine (9%) than with placebo (8%) (P=0.012), but there was no significant difference in the treatment withdrawal rate (4% and 3%, respectively; P=0.137).

The effects of ivabradine on cardiac remodeling were evaluated in the SHIFT echocardiography substudy (Table 3).³³ Ivabradine significantly reduced the LV end-systolic volume index at 8 months compared with placebo (−5.8 mL/m², P<0.001). It also significantly improved LVEF (+2.7%, P<0.001). In other SHIFT substudies, ivabradine improved health-related quality of life assessed by the Kansas City Cardiomyopathy Questionnaire during an 8-month period.³⁴ It also improved HR variability without inducing significant bradycardia, ventricular arrhythmias, or supraventricular arrhythmias assessed by 24-hour Holter ECG.³⁵

Table 3. Effects of Ivabradine on LV Remodeling and Function in the SHIFT Echocardiographic Substudy

Variable	Ivabradine				Placebo				Treatment effect
	n	Baseline	8 months	Change	n	Baseline	8 months	Change	E (SE), 95% CI	P value
Primary endpoint
LVESVI (mL/m2)	208	65.2±29.1	58.2±28.3	−7.0±16.3	203	63.6±30.1	62.8±28.7	−0.9±17.1	−5.8 (1.6), −8.8 to −2.7	<0.001
Secondary endpoints
LVESV (mL)	208	123.8±55.6	110.8±54.6	−13.0±31.6	203	122.2±59.8	120.9±56.4	−1.3±32.8	−11.2 (3.0), −17.1 to −5.4	<0.001
LVEDVI (mL/m2)	204	93.9±32.8	85.9±30.9	−7.9±18.9	199	90.8±33.1	89.0±31.6	−1.8±19.0	−5.5 (1.8), −8.9 to −2.0	0.002
LVEDV (mL)	204	178.4±63.4	163.7±60.6	−14.7±36.4	199	174.7±67.6	171.7±63.8	−2.9±36.8	−10.9 (3.4), −17.6 to −4.2	0.001
LVEF (%)	204	32.3±9.1	34.7±10.2	2.4±7.7	199	31.6±9.3	31.5±10.0	−0.1±8.0	2.7 (0.8), 1.3 to 4.2	<0.001

Data are number of patients (%) or mean±SD. Parametric approach with adjustment for country, β-blocker intake at randomization, and baseline value. CI, confidence interval; E (SE), estimate (standard error of treatment effect); LVEDV, left ventricular end-diastolic volume; LVEDVI, LVEDV index; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVESVI, LVESV index. Reproduced with permission from Tardif JC, et al.³³

Post-hoc subgroup analyses of the SHIFT study demonstrated that ivabradine was effective and safe in various patient subgroups (Table 4). The prespecified subgroup analysis for median baseline resting HR of 77 beats/min showed significant treatment effects on the primary composite endpoint, and post-hoc analysis revealed that the threshold for beneficial effects on cardiovascular death was baseline resting HR ≥75 beats/min.³⁶ Ivabradine significantly reduced both the risk of the primary composite endpoint and other clinical events, including all-cause death in a subgroup of patients with a baseline resting HR ≥75 beats/min.³⁶ Regarding the background β-blocker dose, there was no significant interaction between the primary composite endpoint and β-blocker dose (P interaction=0.135).³⁷ The magnitude of the HR reduction by β-blocker plus ivabradine primarily determined the subsequent effects on outcomes.³⁷ In patients with or without chronic obstructive pulmonary disease (COPD), the primary composite endpoint was more frequent in patients with COPD (hazard ratio 1.22, P=0.006), however, relative risk was reduced similarly by ivabradine in either COPD (14%) or non-COPD (18%) patients (interaction P=0.82).³⁸ In patients divided by quartiles of age (<53, 53–<60, 60–<69, and ≥69 years), the relative risk in the primary composite endpoint was reduced by ivabradine, ranging from 38% (hazard ratio 0.62, P<0.001) in the youngest group to 16% (hazard ratio 0.84, P=0.035) in the oldest group.³⁹ Bradycardia and phosphenes occurred more frequently with ivabradine at a similar rate according to age group.³⁹ In patients divided by tertiles of systolic BP (<115, 115–<130, and ≥130 mmHg), ivabradine was associated with a similar relative risk reduction of the primary composite endpoint (hazard ratio 0.84, 0.86, and 0.77, respectively; P interaction=0.68).⁴⁰ There was no difference in the safety profile according to systolic BP group.⁴⁰

Table 4. Post-Hoc Subgroup Analyses of the SHIFT Study

Objective/population	Main results	Ref.
Resting HR at baseline and day 28	Effect of ivabradine on outcomes greater in patients with HR ≥75 beats/min, with achieved HR <60 beats/min or HR reduction >10 beats/min predicting the greatest risk reduction	36
Dose of BB	Magnitude of HR reduction by a BB plus ivabradine, rather than the background BB dose, primarily determined the subsequent effect on outcomes	37
COPD	Ivabradine similarly effective and safe in patients with chronic HF with or without COPD, and was safe in combination with BBs	38
Age	Safety and efficacy of ivabradine comparable across all quartiled-age groups	39
Blood pressure	Efficacy and safety of ivabradine independent of systolic blood pressure	40
BB type (carvedilol, bisoprolol, metoprolol or nebivolol)	Improvements in cardiovascular outcomes when co-prescribed with ivabradine, especially with the most prescribed BB, carvedilol	41
Comorbidities	Effect of HR reduction with ivabradine was maintained at all comorbidity loads	42
Concomitant chronic HF therapies (ACEI or ARB, BB, and MRA)	Ivabradine improved outcomes in patients with HR ≥70 beats/min receiving multiple neurohormonal modulation treatments	43
Duration of HF	Duration of HF predicts outcome independently of risk indicators such as higher age, greater severity and more comorbidities. HR reduction with ivabradine improved outcomes independently of HF duration	44
Recurrent hospitalization	Ivabradine reduced the incidence of all-cause hospitalization during the vulnerable phase within 3 months after hospitalization for HF and recurrent hospitalization for worsening HF	45–47
Severe HF	HR reduction with ivabradine was safe in severe HF and may improve clinical outcomes independently of disease severity	48
Angina	Ivabradine showed consistent reduction of cardiovascular outcomes in patients with chronic HF. Similar results were seen in a subgroup of patients with angina	49
Diabetes mellitus	Ivabradine was effective and safe irrespective of diabetic status	50
Renal dysfunction	Reduction in HR by ivabradine had a neutral effect on renal function during 2-year follow-up. Beneficial cardiovascular effects and safety of ivabradine were similar in patients with and without renal dysfunction	51
LBBB	Ivabradine was safe in LBBB. Its effect was directionally similar to that in patients without LBBB	52

Severe CHF defined as left ventricular ejection fraction ≤20% and/or New York Heart Association class IV. Renal dysfunction defined as estimated glomerular filtration rate <60 mL/min/1.73 mm². ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BB, β-blocker; COPD, chronic obstructive pulmonary disease; HF, heart failure; HR, heart rate; LBBB, left bundle branch block; MRA, mineralocorticoid-receptor antagonist.

In addition, ivabradine was effective and safe irrespective of the β-blocker type,⁴¹ cardiac and non-cardiac comorbidities,⁴² treatment with neurohormonal modulation treatments, including mineralocorticoid-receptor antagonist,⁴³ HF duration,⁴⁴ recurrent hospitalization,^45–47 severe HF (LVEF ≤20% and/or NYHA IV),⁴⁸ angina,⁴⁹ diabetes mellitus,⁵⁰ renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 mm²),⁵¹ and left bundle branch block.⁵²

The SHIFT study included Asian patients, but not Japanese patients. Resting HR reduction by ivabradine in Japanese HFrEF patients was demonstrated in a randomized, double-blind, placebo-controlled phase II study.⁵³ The J-SHIFT study, a randomized, double-blind, placebo-controlled Phase III study, is currently being conducted to evaluate the effects of ivabradine on long-term outcomes in Japanese HFrEF patients.

HFpEF (HF With Preserved Ejection Fraction)

Previous pharmacological and clinical studies have suggested the efficacy of ivabradine for HFpEF.^54,55 However, EDIFY, an 8-month randomized, double-blind, placebo-controlled clinical trial in HFpEF patients, did not demonstrate efficacy of ivabradine in E/e’, 6-min walking distance test, or plasma NT-proBNP levels despite significant HR reduction.⁵⁶ There are several possible explanations for these results. First, the severity of target patients was too great to evaluate the clinical benefits. Second, HR reduction by ivabradine might facilitate an increase in filling time in a stiff ventricle. Third, factors other than elevated HR, such as systemic inflammation, might be involved in the myocardial remodeling seen in HFpEF.⁵⁷

AF

A recent meta-analysis of clinical studies suggested that ivabradine might increase the risk of AF.⁵⁸ In that meta-analysis, which included 8 randomized clinical trials and 40,437 patients, the incidence of AF was 5.34% in patients receiving ivabradine and 4.56% in those receiving placebo, with a 24% increase of relative risk (P=0.003). However, in non-clinical studies, ivabradine inhibited the I_f and Ca²⁺ transient in pulmonary vein (PV) sleeve cells, critical sources of AF origination and maintenance.⁵⁹ In addition, ivabradine has been reported to increase the effective refractory period of PV cells and the atrium, and decrease the AF rate in a dog model.⁶⁰ Ivabradine has been also shown to reduce HR without increasing the inducibility of AF, irrespective of underlying vagal activity in dogs.⁶¹ These findings suggest that ivabradine could suppress the enhanced cellular automaticity caused by increased I_f activity in PV cells and the left atrium and, as a result, may have beneficial effects on preventing AF. However, close monitoring may be required during ivabradine treatment at the present time.

CAD

The efficacy and safety of ivabradine in chronic stable angina have been shown in several clinical studies. Ivabradine reduced HR at rest and during exercise, and had anti-ischemic and anti-anginal effects as potent as β-blockers and calcium-channel blockers.^62–65 Ivabradine had additional efficacy in patients receiving β-blockers, with a significant improvement in exercise tolerance accompanied by HR reduction.⁶⁶

The large randomized, double-blind, placebo-controlled BEAUTIFUL study was performed in 10,917 patients with CAD, resting HR ≥60 beats/min in sinus rhythm, and LV dysfunction (LVEF <40%) on top of optimal background therapy.⁶⁷ This study showed no between-group difference in the primary composite endpoint of CV death, admission to hospital for acute myocardial infarction (MI), or admission to hospital for new-onset or worsening HF (hazard ratio 1.00, P=0.94). In a prespecified subgroup analysis of resting HR ≥70 beats/min, ivabradine did not affect the primary composite endpoint, but reduced admissions to hospital for fatal and non-fatal MI (hazard ratio 0.64, P=0.001) and coronary revascularization (hazard ratio 0.70, P=0.016). These results were also supported in patients with angina and resting HR ≥70 beats/min by the post-hoc analysis.⁶⁸ In contrast, the large randomized, double-blind, placebo-controlled SIGNIFY study conducted in 19,102 patients with CAD, resting HR ≥70 beats/min in sinus rhythm, under standard therapy and without clinical HF, reported no significant difference between treatments in the primary composite endpoint of CV death or non-fatal MI (hazard ratio 1.08, P=0.20) over a median follow-up period of 27.8 months.⁶⁹ The difference in the efficacy of ivabradine between the SIGNIFY and SHIFT studies is unclear; however, the effects of HR might differ among CVDs.⁷⁰ In HF, prolonged elevation of HR itself has detrimental effects, including impairment of LV systolic function, which in turn further increases HR as a vicious cycle. On the other hand, in stable CAD, HR is a well-established determinant of ischemia and HR reduction by ivabradine can ameliorate ischemic symptoms. Elevated HR in stable CAD may be required to maintain coronary perfusion and its reduction may not be beneficial for prognosis despite symptom improvement.

Conclusions

This review summarizes the latest knowledge of the HCN4 channel and its inhibitor, ivabradine. HR is an independent predictor for long-term outcomes in various cardiac diseases. The SHIFT study showed beneficial effects and proved that HR is a risk factor in patients with HFrEF. Ivabradine, a pure HR lowering agent, can provide novel insights into HR management in HF.

Acknowledgments

We are grateful to the Institut de Recherches Internationales Servier for helpful advice on this review.

Disclosures

T.I. and K.O. belong to a department endowed by Actelion Pharmaceuticals. T.H. has no conflict of interest. M.T. and Y.K. are employees of Ono Pharmaceutical Co., Ltd. H.T. has received speakers’ bureau/honorarium from Otsuka Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Bayer Yakuhin, and Pfizer, research funds from Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma, MSD, Daiichi-Sankyo, and Teijin Pharma, and consultation fees from Nippon Boehringer Ingelheim, Novartis Pharma K.K, Bayer Yakuhin, and Ono Pharmaceutical. H.T. is also a committee member of Phase II and III studies of ivabradine in Japanese patients with chronic HF.

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