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Ivabradine in clinical practice: benefits of If inhibition
Jean-Claude Tardif*
Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
* Corresponding author. Tel: +1 514 376 3330 ext. 3564; fax: +1 514 593 2500. E-mail address: jean-claude.tardif{at}icm-mhi.org
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Abstract
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Relieving the symptoms of angina and improving the quality of
life and functional status are important objectives in the management
of patients with chronic stable angina. A high heart rate induces
or exacerbates myocardial ischaemia and angina, because it both
increases oxygen demand and decreases myocardial perfusion,
the latter by shortening the duration of diastole. Moreover,
there is a large body of evidence about the relationship between
high resting heart rate and mortality, documented in different
population types. ß-Blockers are effective in reducing
angina largely by decreasing heart rate. Physician use and patient
compliance may be limited by the side effects of ß-blockers,
which include fatigue, depression, and sexual dysfunction. Heart
rate reduction can also be obtained by some calcium antagonists
and by the new agent ivabradine. Ivabradine (Procoralan) is
a selective and specific
If inhibitor, which acts on one of
the most important ionic currents for the regulation of the
pacemaker activity of sinoatrial node cells. Ivabradine has
demonstrated dose-dependent anti-ischaemic and anti-anginal
effects at dosages of 5, 7.5, and 10 mg bid in an extensive
programme of more than 5000 patients. The non-inferiority of
ivabradine was shown vs. the ß-blocker atenolol and
the calcium-channel blocker amlodipine. Unlike ß-blockers,
ivabradine is devoid of intrinsic negative inotropic effects
and does not affect coronary vasomotion. A whole range of patients
with angina may benefit from exclusive heart rate reduction
with ivabradine, including those with contraindications or intolerance
to the use of ß-blockers and patients who are insufficiently
controlled by ß-blockers or calcium-channel blockers.
Key Words: Angina • Heart rate • Pharmacology
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Introduction
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Chronic stable angina is a common and disabling condition, affecting
30 000–40 000 per 1 million people in Europe
and the United States. Angina results when myocardial perfusion
is insufficient to meet metabolic demand. Individuals with typical
chronic stable angina usually have significant narrowing of
at least one major epicardial vessel and experience pain, which
is related to an increase in physical activity or psychological
stress. Heart rate is one of the most important determinants
of myocardial oxygen demand. A high heart rate induces or exacerbates
myocardial ischaemia and subsequent angina, because it both
increases myocardial oxygen demand and decreases myocardial
perfusion, the latter by shortening the duration of diastole.
Relieving the symptoms of angina and improving the quality of life and functional status are an integral part of the management of patients with chronic stable angina.1 ß-Blockers are effective in reducing angina largely by decreasing the heart rate2 and they have been usually preferred as initial therapy in the absence of contraindications.3 Despite the demonstrated safety and effectiveness of ß-blockers, physician use and patient compliance may be somewhat limited by the side effects of this class of agents, which include fatigue, sexual dysfunction, depression, cold extremities, light-headedness, gastrointestinal disturbances, bronchospasm, and atrioventricular (AV) block.4,5 ß-Blockade can also increase coronary resistance and limit the exercise-induced increase in coronary arterial flow.6,7 In addition, ß-blockers can reduce left ventricular contractility and have negative lusitropic effects.8 Finally, this class of agents can have detrimental effects on carbohydrate and lipid metabolism.9,10
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Prognostic value of heart rate in patients with coronary artery disease
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Resting heart rate has been shown to be associated with mortality
in patients with hypertension as well as those with the metabolic
syndrome.
11 We have recently evaluated the relationship between
resting heart rate and future cardiovascular events in a population
of 25 000 patients with suspected or proven coronary artery
disease (CAD).
11 Over a median follow-up of 14.7 years, resting
heart rate was a predictor of overall and cardiovascular mortality,
independent of other known risk factors such as hypertension,
diabetes, and smoking. The size of the study also allowed adjustment
of the multivariable model for the extent of CAD and left ventricular
ejection fraction. Resting heart rate was an independent risk
factor for total and cardiovascular mortality, even after adjusting
for such covariates. A high resting heart rate [
83 beats per
minute (b.p.m.)] was indeed a strong predictor of total and
cardiovascular mortality (hazard ratios of 1.32 and 1.31, respectively).
In addition, resting heart rate was a risk factor for time to
cardiovascular rehospitalizations.
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Pharmacological properties of the If inhibitor ivabradine
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If, a mixed Na
+–K
+ inward current activated by hyperpolarization
and modulated by the autonomic nervous system, is one of the
most important ionic currents for regulating pacemaker activity
in the sinoatrial node. Ivabradine (Procoralan
®) is a novel,
specific heart rate-lowering agent, which acts in sinoatrial
node cells by selectively and specifically inhibiting the pacemaker
If current in a dose-dependent manner.
12,13 It slows the diastolic
depolarization slope of the action potential of sinoatrial node
cells
14 and reduces heart rate at rest and during exercise in
animals
14–17 and human volunteers.
18 Ivabradine has demonstrated
anti-ischaemic and anti-anginal activities at doses of 5 and
10 mg bid in a placebo-controlled study involving 360 patients
with stable angina.
19
Ivabradine is devoid of intrinsic inotropic effects and does not affect either the left ventricular systolic function or coronary vasomotion in experimental models at rest and during exercise.8,20 Ivabradine has no detectable effect on AV node cells, as evidenced by the absence of change in PR interval or any other intraventricular conduction parameters.21 An intravenous dose of ivabradine does not prolong the corrected QT interval or modify conductivity and refractoriness of the atria, AV node, His–Purkinje system, and ventricles.21 In addition, Manz et al.22 studied with echocardiography the impact of a single intravenous dose of ivabradine on left ventricular function in patients with systolic dysfunction. The left ventricular ejection fraction did not decrease significantly with ivabradine (0.2%) when compared with placebo (1.7%). Other echocardiographic parameters, such as fractional shortening and stroke volume, were also unchanged after the intravenous administration of ivabradine. Left ventricular relaxation is as crucial for optimal left ventricular function as is contractility. The negative lusitropic effect of ß-blockers could therefore be potentially deleterious. Colin et al.23 investigated the effects of ivabradine and atenolol on left ventricular isovolumetric relaxation at rest and during treadmill exercise in chronically instrumented dogs. For a similar reduction in heart rate at rest and during exercise, ivabradine, in contrast to atenolol, did not exert any negative lusitropic effect. In addition, in contrast to ß-blockers, ivabradine does not cause detrimental effects on coronary vasomotion.8
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Ivabradine vs. ß-blockers in stable angina
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In the INternatIonal TrIal of the AnTi-anginal effects of IVabradinE
compared to atenolol (INITIATIVE), a 4-month randomized, double-blind,
controlled multicentre study of 939 patients with stable angina,
the non-inferiority of ivabradine, 7.5 and 10 mg bid, compared
with atenolol, 100 mg once daily, in terms of their anti-anginal
and anti-ischaemic effects was demonstrated for all exercise
parameters.
24 Ivabradine increased total exercise duration by
1.5 min at the trough of drug activity, and times to limiting
angina and angina onset were also improved. The increase in
time to 1 mm ST-segment depression indicates that the improvement
in total exercise capacity is associated with a relevant anti-ischaemic
effect of ivabradine.
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Ivabradine vs. calcium-channel blockers in angina
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A large clinical trial was also conducted to demonstrate the
non-inferiority of ivabradine vs. the calcium-channel blocker
amlodipine. Ivabradine at doses of 7.5 and 10 mg bid was
compared with amlodipine 10 mg once daily during 3 months
of therapy in a randomized trial that involved 1195 patients
with chronic stable angina and documented CAD.
25 In that study,
ivabradine 7.5 mg bid was found to have efficacy indistinguishable
from that of amlodipine 10 mg once daily for all measured
bicycle exercise test parameters. Statistical testing also revealed
that ivabradine is non-inferior to amlodipine (
P<0.0001)
in preventing angina attacks.
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Combination anti-anginal therapy
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Considerable evidence suggests that combination therapy may
be more effective than monotherapy for the treatment of angina
pectoris.
1,3 The efficacy and safety of combination therapy
with ivabradine have been established over 1 year in 386 patients
with stable angina already treated by nitrates or dihydropyridine
calcium-channel blockers.
26 Two different dosages of ivabradine
were used: 5 and 7.5 mg bid. Ivabradine was shown to reduce
the heart rate of patients by 10 b.p.m. at 5 mg bid
and 12 b.p.m. at 7.5 mg bid. Ivabradine maintained this
heart rate reduction over the year of follow-up. The number
of angina attacks reported by patients was reduced significantly
by the addition of ivabradine.
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Tolerability of ivabradine
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Ivabradine has demonstrated a very good safety profile throughout
its large clinical development programme. More than 5000 patients
have been included in this clinical programme, with 3500 patients
treated with ivabradine and 1200 of these patients treated for
>1 year. The most frequent adverse drug reactions have been
visual symptoms, the majority being phosphenes that were transient
and non-serious in nature. These symptoms consisted of transient
enhanced brightness in limited areas of the visual field that
were commonly associated with abrupt changes in light intensity.
The visual symptoms were dose dependent and generally mild and
well tolerated, causing <1% of patients to withdraw from
treatment. They may be related to the action of ivabradine at
HCN (hyperpolarization-activated, cyclic nucleotide-gated cation
currents) channels known to be present in the retina. All visual
symptoms resolved spontaneously during therapy or after drug
discontinuation. Importantly, the abrupt discontinuation of
ivabradine has not resulted in a rebound angina phenomenon.
In summary, the clinical tolerability of ivabradine was documented
in a large population of patients with CAD and stable angina,
and drug-related adverse events had minimal impact on acceptability.
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Patient profiles
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Ivabradine shares with ß-blockers the property of
decreasing heart rate and oxygen demand from the ischaemic heart,
which is presumably fundamentally important in mediating anti-ischaemic
effects. In the light of the positive results obtained in clinical
trials, the place of ivabradine in the therapeutic armamentarium
must be considered (
Table 1). Given the absence of cardiac
effects other than exclusive heart rate lowering, ivabradine
is probably suitable for most patients with stable angina and
is of particular interest in patients in whom ß-blockers
should be avoided (those with AV block, peripheral vascular
disease, and obstructive pulmonary disease) and in those who
do not tolerate well ß-blockers or calcium antagonists.
Unlike ß-blockers, ivabradine may be used in vasospastic
angina because it does not increase coronary vasomotor tone.
In addition to the side effects of ß-blockers, which
include depression, fatigue, and cold extremities, erectile
dysfunction is a particularly important problem associated with
their use in middle-aged men. Ivabradine may therefore be very
useful in such patients. Although asthma or chronic obstructive
pulmonary disease (COPD) represents only relative contraindications
to ß-blockade, some patients clearly develop bronchospasm
and wheezing with ß-blockers, which require dose reduction
or abrupt withdrawal. Such patients who require heart rate reduction
would clearly benefit from the lack of this side effect with
ivabradine. Furthermore, some patients with both CAD and COPD
develop angina when treated with inhaled ß-adrenergic
agonists because of the resulting tachycardia. The heart rate
reduction obtained with ivabradine could also be very helpful
in this setting. Patients with CAD can have variable degrees
of AV block that develop or are exacerbated with ß-blockers.
The need for selective heart rate reduction in patients with
myocardial ischaemia and AV node conduction abnormalities represents
another excellent indication for ivabradine. This is particularly
relevant for older patients with a prolonged PR interval.
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Conclusion
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Heart rate slowing is an integral part of an optimal pharmacological
anti-anginal strategy. ß-Blockers have been considered
traditionally as a first-line therapy for stable angina, but
their use may be limited by side effects including fatigue,
depression, and sexual dysfunction. Bronchospasm and AV block
represent other limitations of ß-blockers. Ivabradine
is a selective and specific
If inhibitor with anti-anginal and
anti-ischaemic effects that have been shown to be non-inferior
to those of the ß-blocker atenolol and the calcium-channel
blocker amlodipine. Unlike ß-blockers, ivabradine
is devoid of intrinsic negative inotropic effects and does not
affect coronary vasomotion. A whole range of patients with angina
may benefit from exclusive heart rate reduction with ivabradine,
including those with contraindications or intolerance to the
use of ß-blockers and patients who are insufficiently
controlled by ß-blockers or calcium-channel blockers.
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M. Tendera
Editorial: If inhibition: from pure heart reduction to treatment of stable angina
Eur. Heart J. Suppl.,
September 1, 2005;
7(suppl_H):
H3 - H6.
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Abstract
Introduction