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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

How does pure heart rate lowering impact on cardiac tolerability?

A. John Camm{dagger}

Division of Cardiac and Vascular Sciences, St George's University of London, Cranmer Terrace, London SW17 0RE, UK

Corresponding author. Tel: +44 20 8725 3554; fax: +44 20 8767 7141. E-mail address: jcamm{at}sgul.ac.uk


   Abstract
Top
 Abstract
Introduction
 Pure heart rate lowering...
 Sinus bradycardia
 Cardiac electrophysiology
 Myocardial contractility
 Haemodynamic parameters
 Conclusion
 References
 
By selectively and specifically inhibiting the cardiac pacemaker If current, the If inhibitors lower heart rate without compromising myocardial contractility, haemodynamic status, or the electrophysiological properties of the heart. The first agent in this class, ivabradine, has completed its large clinical development programme, for which the cardiac tolerability data cover nearly 5000 patients, about 3500 of whom received the agent. Examination of the data shows that If inhibition with ivabradine constitutes an effective anti-anginal and anti-ischaemic therapy; cardiac adverse events were reported at a rate that is acceptable for a population with stable angina. Among the other adverse events, the most frequently reported were visual symptoms, which are related to retinal Ih inhibition and often resolve during treatment. Ivabradine is associated with significant increases in sinus node recovery time and uncorrected QT interval, which are related to heart rate, but had no significant effect on any other electrophysiological parameter. Correction of the QT interval using a population correction formula confirmed that ivabradine has no significant effect on the duration of ventricular repolarization, i.e. no proarrhythmic effect. Ivabradine produced no negative inotropic effect even in the presence of left ventricular (LV) systolic dysfunction. Preliminary clinical data suggest that ivabradine has a beneficial effect on cardiac performance and LV geometry. These results are currently being tested in the ongoing morBidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study.

Key Words: Heart rate • If inhibition • Ivabradine • Cardiac tolerability • Sinus bradycardia • Cardiac electrophysiology • QT interval • Myocardial contractility


   Introduction
Top
 Abstract
 Introduction
Pure heart rate lowering...
 Sinus bradycardia
 Cardiac electrophysiology
 Myocardial contractility
 Haemodynamic parameters
 Conclusion
 References
 
A new class of agents that target the cardiac pacemaker If current is showing great promise for the treatment of a wide range of cardiovascular disorders such as stable angina and heart failure. By selectively and specifically inhibiting this current, these so-called If inhibitors lower heart rate without compromising myocardial contractility, haemodynamic status, or the electrophysiological properties of the heart. Agents with such a pure heart rate lowering effect can be expected to be devoid of cardiac side effects and have a good cardiac tolerability profile. This contrasts with existing agents that slow the heart rate, such as calcium channel blockers (CCBs) and beta-blockers, which also have hypotensive and negative inotropic effects.1

In this article, we will examine the cardiac tolerability of ivabradine, the first agent in this class to have completed its clinical development programme. Ivabradine has recently been licensed for use by the European Agency for the Evaluation of Medicinal Products.2 We will discuss the physiological rationale behind the safety profile of ivabradine according to the results obtained in the clinical development programme.


   Pure heart rate lowering via If inhibition
Top
 Abstract
 Introduction
 Pure heart rate lowering...
Sinus bradycardia
 Cardiac electrophysiology
 Myocardial contractility
 Haemodynamic parameters
 Conclusion
 References
 
Pacemaking activity occurs in many regions of the heart, including the sinoatrial node (SAN), the bundle of His, and the Purkinje fibres. However, the heart rate is primarily determined in the SAN because it is here that the fastest intrinsic rhythm is produced. At resting potential, the myocytes are hyperpolarized. The SAN pacemaker cells then generate a slow diastolic depolarization, driving the membrane potential towards a threshold level and triggering the next action potential. This action potential propagates through the heart and stimulates myocardial ventricular contraction.

The slow diastolic depolarization of the pacemaker cells in the SAN is regulated by four ionic currents: the outward potassium current IK, the inward If current, and two calcium currents ICaL (long-lasting) and ICaT (transient). The If current was first described in 19793 and is well recognized as the intrinsic pacemaker current of the heart. This mixed Na+/K+ current is slowly activated on hyperpolarization and determines the rate of the slow diastolic depolarization. Consequently, it also controls the time interval between successive action potentials and, therefore, the heart rate.

The ion channel responsible for the If current in the SAN, the f channel (Figure 1), is a member of the hyperpolarization-activated, cyclonucleotide-gated (HCN) family of channels, which are expressed in the heart, the retina, and the brain.4 Four isoforms of the HCN channel have been cloned in mammals. HCN1, HCN2, and HCN4 are all expressed in the human heart, but HCN4 is the major component of the f channels in the SAN.4


Figure 0191
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  		Figure 1 Pharmacological activity of the If inhibitors. Ivabradine binds to the hyperpolarization-activated, cyclonucleotide-gated (HCN) family of channels in the sinus node cells (f channels) and in the retina (h channels), which are responsible for the generation of the If and Ih currents, respectively. Inhibition of the If current leads to heart rate reduction, whereas inhibition of the Ih current leads to visual symptoms.

 
The idea of inhibiting the pacemaker current is by no means new, and a number of If inhibitors have been investigated in the last two decades.4 Alinidine was the first member of the class. Although alinidine is a derivative of clonidine, the anti-hypertensive agent, it has very different pharmacological actions, including analgesic and heart rate lowering properties. Alinidine was not developed clinically because its selectivity in the SAN was not restricted to the f channel. A second group of If inhibitors, including zatebradine and cilobradine, is benzazepinone derivatives. Zatebradine selectively inhibits the If current, reducing resting and exercise heart rate, but failed to have a clinically significant effect on myocardial ischaemia or the occurrence of angina.4,5 The only agent in the If inhibitor class to have been developed for clinical use is ivabradine.

Ivabradine and its main circulating active metabolite, S 18982, inhibit the If current by binding to the HCN4 channels from the intracellular side of the cell membrane. IC50 for the inhibition of the If current carried by HCN4 channels is in the range of 1.5–3 µM.6 At these concentrations, ivabradine also inhibits the Ih current in the retinal HCN1 channels, which accounts for the visual symptoms reported with ivabradine in some patients (Figure 1).2 If inhibition in the SAN prolongs the spontaneous slow diastolic depolarization of the pacemaker cells, thereby increasing the time interval between action potentials and lowering the heart rate. This is the primary mechanism of the action of ivabradine.

Ivabradine has been evaluated in a clinical development programme involving nearly 5000 patients2 in 36 countries from all continents. Nearly 3500 patients have been administered ivabradine, and 1200 of these patients have received it for more than 1 year. The anti-anginal and anti-ischaemic efficacy of ivabradine has been demonstrated in large-scale, double-blind, randomized trials against placebo,7 beta-blocker (atenolol),8 and CCB (amlodipine).9

If inhibition with ivabradine appears to be free of cardiac safety problems, according to the pooled data from the clinical development programme (Table 1).2 Cardiac adverse events were reported at a rate that is acceptable and predictable for a population with stable angina.10 The most frequent cardiac adverse events were bradycardia, ventricular extrasystoles, and coronary artery disorders. The incidence of myocardial infarction was lower than the predicted incidence of 2–3% in such a population.10


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  		Table 1 Emergent cardiac and eye adverse events reported by at least 0.5% of patients receiving ivabradine in the overall safety set compared with the rates for placebo, atenolol, and amlodipine in the same clinical programme2

 
In the overall clinical programme, the death rates for ivabradine (0.9%) were slightly higher than those for atenolol (0.2%), although atenolol was associated with lower all-cause mortality, which was not statistically significant.2 The rates for ivabradine and amlodipine (0.5%) are similar to those given in the European Society of Cardiology Guideline on stable angina, at ~2–3% mortality per annum.10

The incidence of visual adverse events was higher with ivabradine than in the other patient groups (Table 1) and the rate was dose-dependent.2 These effects are a direct consequence of the inhibition of the Ih current in the retina and have also been reported for other If inhibitors, such as zatebradine.5 For ivabradine, most of these symptoms were phosphene-like events (luminous phenomena). These were reported as mild to moderate and as having a low impact on patients' daily life. The frequency of patients changing their daily routine or discontinuing ivabradine treatment as a result of visual symptoms was <1%. A large proportion (76%) of these symptoms resolved during treatment,2 and all cases resolved spontaneously upon withdrawal of treatment. Ophthalmic investigations did not indicate any clinically significant persisting treatment-related deleterious effects.2


   Sinus bradycardia
Top
 Abstract
 Introduction
 Pure heart rate lowering...
 Sinus bradycardia
Cardiac electrophysiology
 Myocardial contractility
 Haemodynamic parameters
 Conclusion
 References
 
Excessive sinus bradycardia can lead to hypotension and reduce the perfusion of organs and tissues, with the attendant symptoms of dizziness, syncope, fatigue, and dyspnoea. The rate of sinus bradycardia (heart rate <55 bpm) in the clinical development programme was 3.2% for 5–7.5 mg bid ivabradine,2 compared with 5.1% for atenolol and 1.7% for amlodipine (Table 1). Only 0.5% of the patients receiving ivabradine experienced severe bradycardia (<40 bpm).2

The rate of sinus bradycardia with ivabradine is dose-dependent, rising to 7.1% for the dosage of 10 mg bid, with a tendency towards a plateau for dosages up to 20 mg bid.2,7 This plateau is consistent with the results of pre-clinical studies in which the rate of If inhibition increased with ivabradine concentration, also with a tendency towards a plateau.6 In the clinical development programme, this translates into a dose-dependent decrease in heart rate, a trend that has been recorded in patients with stable angina pectoris for dosages up to 20 mg bid (Figure 2).2


Figure 0192
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  		Figure 2 Dose dependency of heart rate lowering with the If inhibitor ivabradine for dosages up to 20 mg bid over 3 weeks' treatment.2

 
Experimental studies in rabbit cardiac SAN cells demonstrated that the binding of ivabradine to the f channels is restricted to the open channel state.11 Ivabradine binds to the f channel when it deactivates upon depolarization, and this binding is relieved by long hyperpolarizing steps. This means that the binding is use-dependent,11,12 and in the clinical setting, it has been demonstrated to be related with the resting heart rate, which explains why the rates of sinus bradycardia are so low with ivabradine. The same property may be of advantage in clinical settings by enhancing the If inhibition at higher heart rates.

Complete inhibition of the If current at 30 µM and above has been reported to lead to a 30–40% reduction in the SAN discharge rate.13 We should recall here that cardiac pacemaker activity is modulated by a number of different ion channels, including the potassium and T-type and L-type calcium channels, which are not affected by ivabradine at therapeutic concentrations.6

Although the incidence of sinus bradycardia with ivabradine is similar to or lower than that with atenolol, the consequences of a low heart rate may be less serious in patients receiving the If inhibitor because it does not compromise myocardial contractility or haemodynamic parameters. This hypothesis is supported by the observation of a lower rate of withdrawals from the clinical programme because of bradycardia with ivabradine than with atenolol.2


   Cardiac electrophysiology
Top
 Abstract
 Introduction
 Pure heart rate lowering...
 Sinus bradycardia
 Cardiac electrophysiology
Myocardial contractility
 Haemodynamic parameters
 Conclusion
 References
 
The effect of ivabradine on the main ionic mechanisms of the cardiac pacemaker cells has been investigated in rabbit SAN using the patch-clamp technique.6 At the mean Cmax~0.1 µM associated with a dose of 10 mg bid, i.e. at a dose higher than that recommended in humans, ivabradine is highly selective for the If current, with no effect on the calcium currents ICaL and ICaT, or the potassium current IK. Ivabradine slightly decreased IK at extremely high therapeutic concentrations (10 µM), which corresponds to about 75 times the mean Cmax observed in patients receiving a therapeutic dose of ivabradine. This is well above the widely accepted 30-fold safety margin. In contrast, zatebradine reduced IK by ~20% at 3 µM, implying that it could play a role in prolonging the duration of the action potential.6 This could translate clinically into early after-depolarizations and ventricular tachyarrhythmias with zatebradine, but not with ivabradine.

The electrophysiological effects of ivabradine have been investigated in patients aged 18–75 years, who required cardiac electrophysiological investigation or catheter ablation for supraventricular arrhythmias, but who had normal electrophysiology at baseline.14 The patients received a single intravenous dose of ivabradine (0.2 mg/kg, corresponding to ~10 mg bid). The electrophysiological parameters measured at baseline and at 30 and 60 min after administration are presented in Table 2.14 Ivabradine reduced the resting heart rate by ~14 bpm. It was associated with a significant increase in the sinus node recovery time (SNRT) and the uncorrected QT interval. Ivabradine had no significant effect on any of the other electrophysiological parameters.


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  		Table 2 Selected electrophysiological parameters in 13 patients receiving a single intravenous (IV) dose of ivabradine (0.2 mg/kg)14

 
SNRT and sinoatrial conduction time
SNRT was increased by 122.9 ms at 60 min after drug administration (P=0.028 vs. baseline). There was also a non-significant trend towards an increase in sinoatrial conduction time (SACT) with ivabradine (20.3 ms after 60 min). SACT represents the time taken for the conduction of the paced atrial beat through the perinodal tissue into the SAN, the subsequent resetting of the SAN, and the conduction of the spontaneous impulse that follows through the perinodal tissue into the atrium. The If current plays an important role in SAN cell depolarization, and so ivabradine, which inhibits this current, increases the time taken for pacemaker cells to reach the depolarization threshold to initiate the action potential and activate the adjacent cells. Therefore, the prolongation of SNRT and SACT is most likely a direct consequence of the mechanism of action of the If inhibitor and is of no clinical concern.14

QT interval
Any drug that prolongs the heart rate would be expected to increase the QT interval, and ivabradine is no exception. The mean QT interval increased with ivabradine by 28.6 ms after 30 min and 37.5 ms after 1 h (P<0.001 vs. baseline for both values) (Table 2).14 However, a prolonged QT interval may indicate a delay in ventricular repolarization, which would increase the risk of arrhythmias and possibly torsade de pointes, and, for this reason, should be investigated very carefully.15

When the QT interval was corrected for heart rate using the Bazett method (QTcB), there was no change (Table 2), suggesting that ivabradine does not significantly affect ventricular repolarization.14 Although Bazett's is the most widely recognized formula for correcting QT, it may mask a QT interval prolongation.15 Similarly, the Fridericia formula (QTcF) may overestimate the QTc interval. For this reason, a population correction formula (QTcP) has been developed and validated in 1216 drug-free subjects, using a total of 23 997 paired QT/RR values.16 The QTcP values fell between the QTcB and QTcF values, indicating that the population correction formula neither under- nor overestimates QTc. The QTcP formula was then applied to electrophysiological data from 995 patients treated with ivabradine 10 mg bid for 3 months. Although the uncorrected QT interval was prolonged, there was no significant effect on QTcP, strongly supporting the conclusion that ivabradine has no significant direct effect on the duration of ventricular repolarization.16

Electrophysiological data for ivabradine are also available from the safety set of the clinical development programme.2 The mean changes in QTcP never exceeded ±1.4 ms with ivabradine and never attained statistical significance.2 There was a single case of QTcP ≥500 ms (0.1%) out of the 1140 patients receiving ivabradine and one case (1.1%) out of the 91 patients receiving atenolol. In the long-term, the proportion of patients with QTcP ≥500 ms was 1%, which was mainly due to four patients in the group receiving 7.5 mg bid. Notably, there was no report of any patient with the combination of a QTcP ≥500 ms and a change in QTcP ≥60 ms in the entire clinical programme.2

These observations have recently been confirmed clinically in the Noninvasive Electrophysiological Study of Ivabradine (NESI), which was a prospective, randomized, double-blind, placebo-controlled study in 25 patients with dual chamber pacemakers.17 Measurement of the QT interval during atrial pacing at fixed rates allows for direct comparison of the QT interval at the same heart rate, without the need for correction. The NESI patients received either 5 or 10 mg bid ivabradine, and electrophysiological parameters were recorded before and after 3.5 days of treatment. The results showed that ivabradine did not increase the QT interval during atrial pacing in comparison with placebo.17

According to the electrophysiological results for the QT interval with ivabradine,14,16,17 we can safely assume that this agent has no effect on ventricular repolarization and does not increase the risk of malignant arrhythmias. The failure of ivabradine to increase the ventricular effective refractory period at fixed heart rate in two of the electrophysiological studies14,17 strengthens the impact of these results. Moreover, there was no evidence of proarrhythmic effects with ivabradine in the clinical development programme, even in patients at higher risk for such events, such as female patients, elderly patients (>70 years), or those with a history of left ventricular (LV) hypertrophy, heart failure, atrial fibrillation, or hypokalaemia.2

Intra-atrial conduction time
Ivabradine does not affect intra-atrial conduction time or atrial refractoriness (Table 2).14 The incidence of atrial fibrillation was similar with ivabradine, atenolol, and amlodipine (Table 1).2 The functional status of HCN channels in fibrillating atria is unclear at present, but the If current is probably not fully operational under such conditions, which would render ivabradine ineffective at reducing heart rate in patients with permanent atrial fibrillation.

Atrioventricular conduction
Ivabradine does not appear to have an effect on atrioventricular conduction time in the clinical setting, as indicated by the lack of any change in the PR interval (Table 2).2,14 This is also supported by the results of animal studies, in which no change in PR interval was detected with ivabradine.18 This is in stark contrast with beta-blockers and CCBs, which have negative dromotrophic effects.


   Myocardial contractility
Top
 Abstract
 Introduction
 Pure heart rate lowering...
 Sinus bradycardia
 Cardiac electrophysiology
 Myocardial contractility
Haemodynamic parameters
 Conclusion
 References
 
One of the advantages of pure heart rate lowering is the absence of the changes in myocardial contractility, particularly in the cases of LV dysfunction, e.g. during myocardial stunning.

The effects of ivabradine and propranolol on global myocardial contractility have been tested in resting and exercising conscious dogs.19 In contrast to propranolol and for similar reductions in heart rate, ivabradine was devoid of any intrinsic negative inotropic effect at rest or during exercise. This was demonstrated to be due to the reduction in heart rate because it was abolished upon atrial pacing.

The effect of ivabradine on regional myocardial contractility has also been evaluated in an elegant series of experiments, in which ischaemia was provoked in dogs by a combination of treadmill exercise and coronary artery stenosis.20,21 The effects of administration of a heart rate lowering agent (ivabradine or atenolol) were recorded either before ischaemia or during the recovery period (i.e. during myocardial stunning) with or without atrial pacing. The results provided evidence that selective heart rate reduction with an If inhibitor has an anti-ischaemic action and simultaneously improves the contractility of the stunned myocardium.21 The additional negative inotropic effect of the beta-blocker was shown to be deleterious during stunning.

The absence of a negative inotropic effect with ivabradine has been confirmed in a placebo-controlled study, in which intravenous ivabradine (0.25 mg/kg) was administered to 31 patients with ischaemic cardiomyopathy.22 Resting heart rate was reduced by 17.6±4.7%, but there was no change in LV ejection fraction (0.2 vs. 1.7% in the placebo group), fractional shortening (0.7 vs. 1.7%), or stroke volume (2.4 vs. 12.2 mL).22 This is consistent with studies in animals,23 which, in addition, reported treatment-related improvement in the extracellular matrix and myocyte functioning. Ivabradine produced no negative inotropic effect irrespective of the presence of global or regional impairment of LV systolic function.

Preliminary clinical data suggest that ivabradine may have a beneficial effect on cardiac performance and LV geometry. The benefits of ivabradine have been investigated in a 3-month, double-blind, placebo-controlled trial in patients with coronary artery disease and moderate LV systolic dysfunction, all of whom were classified as having New York Heart Association class II heart failure.24 The patients received either ivabradine (10 mg bid) (n=53) or placebo (n=12). Ivabradine therapy appeared to reduce end-diastolic and end-systolic volumes after 3 months (Table 3).24 The effect of ivabradine increased as the LV ejection fraction decreased and was particularly pronounced in patients with values <35%. These results are currently being tested in the ongoing morBidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study in over 10 000 patients with coronary artery disease and LV dysfunction (LV ejection fraction ≤39%).25


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  		Table 3 Effects of 3 months' treatment with ivabradine 10 mg bid or placebo in patients with coronary artery disease and moderate LV systolic dysfunction24

 

   Haemodynamic parameters
Top
 Abstract
 Introduction
 Pure heart rate lowering...
 Sinus bradycardia
 Cardiac electrophysiology
 Myocardial contractility
 Haemodynamic parameters
Conclusion
 References
 
The effect of ivabradine on coronary artery dynamics has been tested in animals.18,19,23 Ivabradine selectively reduced heart rate at rest without modifying mean arterial pressure or global rate of change in LV pressure.18,23 In contrast to propranolol, ivabradine preserves mean coronary blood flow velocity and adaptation to exercise and decreases coronary vascular resistance during exercise.19 Moreover, ivabradine had no effect on resting epicardial coronary artery diameter and attenuated its increase during exercise. This contrasts with the effects of propranolol, which reduced this diameter at rest and maintained constriction during exercise. In the clinical setting, this translates into the preservation of cardiac adaptation to exercise with ivabradine.


   Conclusion
Top
 Abstract
 Introduction
 Pure heart rate lowering...
 Sinus bradycardia
 Cardiac electrophysiology
 Myocardial contractility
 Haemodynamic parameters
 Conclusion
References
 
Pure heart rate lowering via selective and specific If inhibition offers the exceptional opportunity to prevent angina without affecting other cardiac parameters. The results available for ivabradine indicate that, at therapeutic dosages, selective If inhibition can reduce heart rate without compromising myocardial contractility or haemodynamic status or affecting the electrophysiological properties of the heart, other than those directly related to heart rate, such as the uncorrected QT interval and SNRT. Correction of the QT interval for heart rate confirms the absence of any effect of this agent on ventricular repolarization.

Clinically, this translates into a good general safety profile, which is supported by the reports from the clinical development programme of this agent.2 The rates of adverse events were similar to those of the other anti-anginal treatment groups. The visual symptoms reported are in line with the mode of action involving binding to the retinal HCN channels and rarely led to the withdrawal of treatment. There appears to be a very low risk of sinus bradycardia. Moreover, the consequences of bradycardia in ivabradine-treated patients may be less serious because of the preservation of myocardial contractility and haemodynamic parameters.

Raised resting heart rate is itself associated with increased cardiovascular and total mortality. The ongoing BEAUTIFUL study has been designed to investigate the morbidity and mortality benefits of pure heart rate lowering with ivabradine in patients with coronary artery disease and LV dysfunction.25

Conflict of interest: A.J.C. is the chairman of the BEAUTIFUL Trial Data and Safety Monitoring Board and is a consultant to Servier.


   Footnotes
 
{dagger} Professor Camm is supported by the British Heart Foundation. Back


   References
Top
 Abstract
 Introduction
 Pure heart rate lowering...
 Sinus bradycardia
 Cardiac electrophysiology
 Myocardial contractility
 Haemodynamic parameters
 Conclusion
 References
 

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