Download Safety and Efficacy of Ivabradine in the Management of Stable

REVIEW
Safety and Efficacy of Ivabradine in the Management
of Stable Angina Pectoris
Jean-Claude Tardif
Montreal Heart Institute, Université de Montreal, Montreal, Québec, Canada.
Abstract: The first selective If current inhibitor, ivabradine, lowers heart rate (HR) at rest and during exercise with no
vasomotor, negative inotropic, or negative lusitropic effects. Given that elevated resting HR is a key factor in the onset of
myocardial ischemia and a strong independent predictor of cardiovascular outcomes, ivabradine provides new therapeutic
prospects in coronary artery disease (CAD). Its selective HR-lowering action has proven anti-ischemic and anti-anginal
efficacy, and ivabradine is currently indicated for the symptomatic treatment of stable angina pectoris. Ivabradine can also
be safely combined with other anti-anginal agents, and addition of ivabradine to beta-blocker therapy further improves
anti-ischemic efficacy and exercise capacity of patients with stable angina. The recent BEAUTIFUL trial demonstrated that
although the primary endpoint was not met in the overall population, addition of ivabradine on top of standard preventive
treatments significantly reduced the risk of coronary events in stable CAD patients with left ventricular systolic dysfunction
among the subgroup of patients with a resting HR 70 bpm. This is in accordance with pre-clinical data showing that
long-term HR reduction improves endothelial function and reduces the progression of atherosclerosis. A significant proportion of patients with stable angina have elevated resting HR and ivabradine should therefore be considered as an important
therapy in these cases. In combination with other standard treatments, ivabradine can improve angina and could potentially
improve coronary outcomes. Ongoing and future clinical studies will evaluate the presence and magnitude of the cardioprotective benefits of HR lowering with ivabradine in patients with cardiovascular diseases.
Keywords: coronary artery disease, heart rate, ivabradine, stable angina pectoris, myocardial ischemia, clinical outcomes
Introduction
Coronary artery disease (CAD) is currently the leading cause of death and disability worldwide.1 The
presenting symptom in half of patients with CAD is stable angina pectoris, which significantly impairs
daily activities in most patients and often leads to premature retirement.2,3 Formal investigations using
validated questionnaires show that even mild angina symptoms seriously reduce the quality of life
(QoL) of patients in terms of physical functioning, sense of well-being, and perceived health.4 In agreement with these results, reduction in angina attacks through medical treatment or coronary revascularization is associated with marked improvement in QoL.5–8 In addition to the impact on QoL, the frequency
of anginal symptoms is also positively associated with higher rates of hospital admissions for coronary
events.9 Furthermore, recent data from a community cohort study indicate that CAD patients with
anginal symptoms alone have a similar prognosis to that of patients with a history of myocardial infarction (MI) or revascularization.10 These findings indicate that the importance of stable angina pectoris
cannot be underestimated, and it is crucial for the patient that this condition be optimally managed.
Although much progress has been made in the management of CAD and angina, many patients
remain poorly treated and there is a clear need for novel means of management. One established management strategy is heart rate (HR) reduction, which reduces myocardial oxygen demand and increases
diastolic perfusion time.11 This strategy is well-recognized as a beneficial therapeutic intervention for
the prevention of myocardial ischemia and angina. In addition, elevated resting HR is independently
associated with an increased long-term risk of cardiovascular outcomes, particularly among CAD
patients as demonstrated by retrospective clinical and epidemiological observations.12,13 Control of HR
Correspondence: Jean-Claude Tardif, MD, Montreal Heart Institute, Université de Montreal, 5000 Belanger
Street, Montreal, Québec, Canada H1T 1C8. Tel: +1 514 376 3330 Ext: 3612; Fax: +1 514 376 1355.
Email: [email protected]
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Clinical Medicine: Therapeutics 2009:1 571–581
571
Tardif
should therefore be regarded as a key therapeutic
target in CAD to improve symptoms and potentially long-term cardiovascular outcomes.
Consistent with this understanding of the central
importance of HR, ivabradine, the first clinically
available selective If current inhibitor, provides
new opportunities in the management of stable
angina pectoris. If is an inward mixed current of
Na+ and K+ ions carried through hyperpolarizationactivated cyclic nucleotide–activated channels
(f channels) and is crucial for regulating cardiac
pacemaker activity in the sinoatrial node. Ivabradine acts by selective and specific binding to f
channels to inhibit If in a dose-dependent manner,
with no effects on other cardiac channels. 14
Inhibition of If reduces the slope of diastolic depolarization in sinoatrial node cells, decreases the
frequency of action potential initiation (Fig. 1), and
thereby lowers HR at rest and during exercise.15,16
Unlike other pharmacological agents used to lower
HR, ivabradine can be considered as a selective
HR-reducing agent with no vasomotor, negative
inotropic, or negative lusitropic effects. In addition
to lowering myocardial oxygen demand, selective
HR reduction with ivabradine increases diastolic
perfusion time and improves oxygen supply,
while preserving cardiac stroke volume at rest and
40
Control
during exercise.17–19 In patients with CAD, these
actions have proven anti-ischemic and antianginal
efficacy,20 and ivabradine is currently indicated for
the symptomatic relief of stable angina pectoris. In
this article, we review preclinical and clinical
studies that demonstrate the anti-ischemic and antianginal effects of ivabradine and that give further
insights into its potential to modify disease progression in patients with stable angina.
Preclinical Studies Demonstrating
Beneficial Effects of Ivabradine
on Myocardial Ischemia, Endothelial
Function and Progression
of Atherosclerosis
Experimental animal models have clearly demonstrated that HR lowering with ivabradine reduces
myocardial oxygen consumption while improving
oxygen supply. In exercising dogs, graded HR
reduction with varying doses of ivabradine linearly
decreased myocardial oxygen consumption.21 In
the same study, ivabradine also increased diastolic
perfusion time in a dose-dependent manner.
Additional animal studies showed that HR
reduction with ivabradine increased coronary
blood flow during exercise.19 In contrast, for the
Ivabradine 0.3 µmol/I
Voltage (mV)
20
0
Time (seconds)
0.5
−20
−40
−60
Spontaneous diastolic depolarization slope
Figure 1. Spontaneous diastolic depolarization and action potential generation in rabbit sinoatrial node in the absence (control) and presence
of 0.3 μmol/L ivabradine. Reproduced with permission from DiFrancesco. Pharmacol Res. 2006;53(5):399–406.
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Clinical Medicine: Therapeutics 2009:1
Safety and efficacy of ivabradine in the management of stable angina pectoris
same HR reduction, β-blockers did not increase
diastolic perfusion time to the same degree
and also reduced coronary blood flow during
exercise.17,19 Unlike β-blockers which can lead to
vasoconstriction due to unmasked alpha-adrenergic
tone, ivabradine does not alter the balance between
α- and β-adrenergic tone. The cardioprotective
benefits of selective HR reduction with ivabradine
are in part due to reduced myocardial oxygen
consumption, together with improved oxygen
supply, through longer diastolic perfusion time
and preserved coronary artery dilation during
exercise.
The anti-ischemic effects of ivabradine were
initially investigated in a canine model of exerciseinduced myocardial ischemia and subsequent
stunning.22 In this model, dogs underwent surgical
coronary stenosis to suppress the normal increase
in coronary artery blood flow during exercise.
Under these experimental conditions, administration of ivabradine improved LV regional function
and perfusion in the ischemic zone during exercise
compared with saline.22 The anti-ischemic effect
of ivabradine also protected against myocardial
stunning during the recovery period after exercise.
Administration of ivabradine after exercise, when
the myocardium was stunned, also improved
LV regional contractility. None of these effects
occurred when dogs underwent atrial pacing,
indicating that the anti-ischemic effects of ivabradine are the result of selective HR reduction. In
contrast to treatment with ivabradine, administration of a beta-blocker during the stunning period
greatly impaired myocardial function as a result
of negative inotropic effects.23 Ivabradine also
reduced regional myocardial ischemia during
exercise by approximately 80% in pigs with surgical coronary artery stenosis.24 In the same study,
ivabradine preserved LV contractility at rest and
during exercise to a significantly greater degree
than the beta-blocker. Taken together, the findings
of these studies demonstrate that, under short-term
ischemic conditions, HR lowering with ivabradine maintains cardiac function by improving
myocardial perfusion and its relationship to myocardial oxygen demand and sustaining myocardial
contractility.
More recently, the protective effects of ivabradine against irreversible myocardial injury after a
prolonged period of myocardial ischemia have also
been investigated.25 While monitoring myocardial
regional blood flow and function, anesthetized
Clinical Medicine: Therapeutics 2009:1
pigs were subjected to 90 minutes of controlled
coronary hypoperfusion followed by 120 minutes
of reperfusion. At the end of the experimental
protocol, histological analysis was used to assess
myocardial infarct size. Compared with placebo,
treatment with ivabradine increased ischemic
regional blood flow and contractile function, and
reduced infarct size. Reduction in myocardial
infarct size was observed even when ivabradine
was administered only after the onset of ischemia
or just before the reperfusion period. These beneficial effects on infarct size were attenuated by
atrial pacing, suggesting that HR reduction per se
plays an important part in the cardioprotective
effects of ivabradine.25
Additional animal studies have examined the
long-term beneficial effects of HR lowering with
ivabradine on endothelial function and atherosclerosis. Apolipoprotein E–deficient (apoE−/−)
mice fed a high-cholesterol diet represent a wellcharacterized model of endothelial dysfunction.
In this model, administration of ivabradine for
6 weeks significantly improved aortic endothelium–
mediated vasodilation, without any effects on
blood pressure or lipid levels. Despite the severe
hypercholesterolemia, improvement of endothelial function with ivabradine was associated
with 40% and 70% reductions in atherosclerotic plaque size in the aortic root and ascending
aorta, respectively (both P 0.05; Fig. 2).26
Ivabradine also markedly inhibited vascular
oxidative stress; NADPH oxidase activity, superoxide production, and lipid peroxidation were all
reduced in the aortic wall of ApoE−/− mice receiving ivabradine.26 The authors found no direct
effects of ivabradine on the endothelium, implying
that these protective effects were mediated by the
observed 13.4% reduction in HR. In our study of
a transgenic model of dyslipidemia and endothelial
dysfunction, 3-month treatment with ivabradine
preserved endothelium-mediated vasodilation in
the renal and cerebral arteries of mice expressing
the human apoprotein B (apoB-100).27 In this
study, ivabradine also restored the contribution of
hydrogen peroxide to endothelium-dependent
vasodilation in cerebral vessels, implying a reduction in vascular oxidative stress. Treatment of
apoB-100 mice with the beta1 adrenoreceptor–
selective antagonist metoprolol did not restore
endothelial function to the same degree.27 This
was possibly because of inhibitory effects of
metoprolol on beta-adrenoreceptor–mediated
573
A
B
E
40
Plaque area
[% total]
Tardif
30
40%
20
*
10
0
Aortic sinus
D
F
Plaque area
[% total]
C
30
Vehicle
Ivabradine
20
70%
10
*
0
Vehicle
Ivabradine
Ascending aorta
Figure 2. Effect of ivabradine on atherogenesis in apolipoprotein E–deficient mice. Histological samples are shown from aortic sinus (A, B)
and ascending aorta (C, D), together with the respective histomorphometric analyses (E, F) (*P 0.05 versus vehicle). Reproduced with
permission from Custodis F, et al. Circulation. 2008;117:2377–87.
activation of endothelial nitric oxide synthase.
Overall, the findings of these two studies show
that long-term HR reduction with ivabradine
improves endothelial function and reduces progression of atherosclerosis in mice models of
dyslipidemia and atherosclerosis.
Clinical Data Demonstrating
Beneficial Effects of Ivabradine
on Myocardial Ischemia, Stable
Angina Pectoris and Coronary
Events in CAD Patients
As in animal studies, clinical trials have
demonstrated that ivabradine reduces HR at
rest and during exercise in a dose-dependent
manner.20,28,29 Exercise tolerance tests (ETTs) have
shown the anti-ischemic and anti-anginal efficacy
of ivabradine. During bicycle ETTs, time to 1-mm
ST-segment depression significantly increased after
2 weeks of treatment with ivabradine 5 mg b.i.d.
compared with placebo in patients with CAD and
stable angina (P 0.05).20 In the same study,
continuation of treatment with ivabradine for
3 months reduced the weekly number of angina
attacks more than fourfold compared with baseline
(P 0.001).
The clinical efficacy of ivabradine was also
confirmed when compared to that of other common classes of anti-anginal agents, including
574
beta-blockers and calcium channel blockers. The
INternatIonal TrIal of the AnTianginal effects of
IVabradinE compared with atenolol (INITIATIVE)
compared the anti-ischemic and anti-anginal
effects of ivabradine 7.5 mg and 10 mg b.i.d.
and of atenolol 100 mg o.d. in 939 stable angina
pectoris patients.29 After 4 months of treatment,
ivabradine had increased total treadmill exercise duration by 86.8 seconds compared with
78.8 seconds for atenolol (P 0.001 for noninferiority). Interestingly, HR reduction with
ivabradine resulted in a greater improvement in
exercise capacity than atenolol for a 1 bpm reduction in HR: 10.1 seconds with ivabradine vs.
5.6 seconds with atenolol (Fig. 3). This difference
may be due in part to the absence of any negative
inotropic or coronary vasoconstrictive effects of
ivabradine during exercise. In another comparative study, 1195 stable angina patients received
either ivabradine (7.5 mg b.i.d. or 10 mg b.i.d.)
or amlodipine 10 mg o.d. for 3 months.28 Results
of ETTs showed that time to 1-mm ST-segment
depression increased by 45 seconds with ivabradine
versus 40 seconds with amlodipine (P 0.001),
and both treatments decreased the frequency of
anginal attacks by two-thirds. Ivabradine was
superior to amlodipine in reducing myocardial
oxygen consumption as demonstrated by the
significantly greater effect on the rate-pressure
product.
Clinical Medicine: Therapeutics 2009:1
Safety and efficacy of ivabradine in the management of stable angina pectoris
Change in TED per unit reduction
Change
(s/bpm)
in HR (s/bpm)
Change in total exercise duration for every 1 bpm
reduction in heart rate
12
10.1s
10.1
10
8
6
5.6s
5.6
4
2
0
Atenolol100
100
od
Atenolol
mgmg
o.d.
(n = 300)
Ivabradine
Ivabradine7.5
7.5mg
mg bid
b.i.d.
(n = 315)
Figure 3. Change in total exercise duration per 1 bpm reduction in heart rate at peak exercise after 4 months of treatment with atenolol
100 mg o.d. (n = 300) or ivabradine 7.5 mg b.i.d. (n = 315) bpm, beats per minute.
Although beta-blockers are recommended as
the initial therapy for stable angina pectoris, they
are associated with a range of side effects and are
not always well tolerated. Therefore, a large
number of patients in clinical practice do not
receive sufficient doses to provide optimal HR
reduction and anti-ischemic protection.30 Combination therapy is recommended to improve the
symptomatic management of angina,2 and the
majority of stable angina patients receive two antianginal agents. However, most clinical studies
demonstrate only modestly improved ETT parameters with combination therapy compared with
monotherapy at the peak of drug activity, with no
significant benefit 6 hours after drug intake.31
Recently, the anti-ischemic efficacy of ivabradine in combination with beta-blocker therapy
was investigated in a 4-month study of 889
stable angina patients already receiving atenolol
50 mg/day.32 This dosage of atenolol is the most
commonly prescribed one in clinical practice.30
Patients were randomly assigned to treatment with
ivabradine 5 mg b.i.d. uptitrated to 7.5 mg b.i.d.
after 2 months (n = 449), or placebo (n = 440), on
top of beta-blockade. During the study, the addition
of ivabradine to the beta-blocker further reduced
Clinical Medicine: Therapeutics 2009:1
HR by 7 bpm after 2 months and by 9 bpm after
4 months compared with placebo (Fig. 4).
Accompanying these HR reductions, treadmill
ETT at trough of drug activity after 2 months and
4 months showed significant improvements in all
test parameters for patients receiving ivabradine
compared with placebo (Fig. 5). Furthermore,
combination therapy of ivabradine and betablocker was well tolerated, with only 1% of
patients receiving this treatment having to withdraw because of sinus bradycardia.32 Altogether,
the size of this study, the compliance with the
regulatory recommendations, and the consistency
of improvement across all ETT parameters constitute perhaps the best clinical evidence of benefit
of any combination of anti-anginal drugs published
to date.
The long-term antianginal efficacy and safety
of ivabradine have been investigated in a population of 386 stable angina patients in a double-blind,
randomized, parallel-group study over 12 months.33
At study entry, many of the patients were receiving
concomitant therapy for cardiovascular conditions,
including dihydropyridine calcium channel blockers and long-acting nitrates to manage anginal
symptoms. Patients were assigned to treatment
575
Tardif
68
67
66
66
Heart rate (bpm)
66
64
62
Placebo +
atenolol (n = 432)
Ivabradine
5 mg bid
Ivabradine +
atenolol (n = 431)
60
bpm)
60 60
(–7(-7
bpm)
58
58 (–9 bpm)
56
54
Baseline
2 months
4 months
Figure 4. Effect of 4 months of treatment with ivabradine (5 mg b.i.d. for two months increased to 7.5 mg b.i.d. for two months) in combination
with atenolol (50 mg/o.d.) on heart rate in patients with stable angina (n = 431), versus placebo and atenolol (50 mg/o.d.) (n = 432).
60
P < 0.001
P < 0.001
Ivabradine
Placebo
Change in ETT criteria (s)
50
P ≤ 0.001
P < 0.005
40
P < 0.001
30
P = 0.017
P < 0.001
P = 0.018
20
10
0
M2
M4
Total exercise
duration
M4
M2
Time to limiting
angina
M2
M4
Time to angina
onset
M2
M4
Time to 1 mm ST
depression
Figure 5. Changes in exercise tolerance test (ETT) criteria from baseline to month 2 (M2) and month 4 (M4) among stable angina patients
treated with the addition of either ivabradine (5 mg b.i.d. for two months increased to 7.5 mg b.i.d. for two months) (n = 449) or placebo
(n = 440) on top of beta-blocker therapy (atenolol 50 mg/o.d.). Reproduced with permission from Tardif JC, et al. Eur Heart J. 2009.
576
Clinical Medicine: Therapeutics 2009:1
Safety and efficacy of ivabradine in the management of stable angina pectoris
with either ivabradine 5 mg b.i.d. (n = 198) or
ivabradine 7.5 mg b.i.d. (n = 188). After 12 months,
mean HR was significantly reduced by 10 bpm
from baseline in the ivabradine 5 mg b.i.d. group
and by 12 bpm in the 7.5 mg group. These HR
reductions were achieved after 1 month of treatment and remained stable thereafter, with no evidence
of pharmacological tolerance. The HR-lowering
efficacy of ivabradine was associated with
significant anti-anginal efficacy: the mean number
of angina attacks per week decreased by 50% in
both treatment groups (P 0.001). Ivabradine also
significantly reduced the number of angina attacks
among the 259 patients receiving concomitant
anti-anginal treatment with dihydropyridine
calcium channel blockers or long-acting nitrates
in both treatment groups (P 0.001 for 5 mg b.i.d.;
P 0.05 for 7.5 mg b.i.d.). Throughout the study,
both doses of ivabradine were well tolerated: only
4 patients withdrew because of visual symptoms
(1 in the 5 mg group and 3 in the 7.5 mg group),
and only 0.8% of patients had to withdraw due to
bradycardia. These findings clearly demonstrate
the anti-anginal efficacy and safety of long-term
treatment with ivabradine 5 mg b.i.d. and 7.5 mg
b.i.d. on top of other widely used cardiovascular medications in patients with stable angina
pectoris.
The two goals of treating a patient with CAD
are to relieve anginal symptoms and to prevent
acute coronary complications. In addition to its
anti-ischemic and anti-anginal efficacy, recent
clinical trial evidence suggest that selective HR
lowering with ivabradine reduces the risk of coronary events. The BEAUTIFUL (morBidity-mortality
EvAlUaTion of the I f inhibitor ivabradine in
patients with left ventricULar dysfunction) trial
investigated the effects of ivabradine on top of
standard treatments in a population of 10,917
CAD patients with LV systolic dysfunction over
2 years.34 In addition to their standard cardiovascular treatments, patients in the BEAUTIFUL trial
were randomly assigned to treatment with either
ivabradine 5 mg b.i.d, with uptitration to 7.5 mg
b.i.d., or placebo for 24 months. The mean age of
the population at baseline was 65 years, and mean
resting HR was 72 bpm. The proportion of patients
receiving concomitant medications for cardiovascular disease was high: 94% of patients were
receiving aspirin or anticoagulants, 74% were
receiving statins, 90% were receiving angiotensinconverting enzyme (ACE) inhibitors or angiotensin II
Clinical Medicine: Therapeutics 2009:1
receptor blockers, and 87% of patients were
receiving β-blockers.
BEAUTIFUL addressed the important clinical
and pathophysiological relevance of HR reduction
for cardiovascular outcomes. The large placebo
population of the BEAUTIFUL trial (n = 5438)
provided an opportunity to examine the importance of HR for long-term coronary outcomes in a
well-treated CAD population with LV systolic
dysfunction. This was done by analyzing the effect
of elevated resting HR at baseline on outcomes in
the placebo population.35 Analyses of the adjusted
data for coronary outcomes in the placebo group
showed that elevated resting HR 70 bpm was a
strong risk factor for cardiovascular events in
patients with stable CAD and LV dysfunction.
Within the placebo group, HR 70 bpm was associated with a 34% increase in the risk of cardiovascular death (hazard ratio, 1.34; 95% confidence
interval [CI], 1.10–1.36; P 0.005) and a 53%
increase in the risk of hospitalization for new or
worsening heart failure (hazard ratio, 1.53;
95% CI, 1.25–1.88; P 0.0001) compared with
HR 70 bpm.35 Likewise, elevated HR was associated with a 46% increase in risk of fatal and
nonfatal MI (hazard ratio, 1.46; 95% CI, 1.11–1.91;
P 0.01) and a 38% increase in the risk of coronary revascularization (hazard ratio, 1.38; 95% CI,
1.02–1.86; P 0.05). These findings are the first
prospective demonstration that elevated resting HR
increases the risk of coronary events even in CAD
patients who are well treated in accordance with
current guidelines.
Ivabradine significantly improved coronary
outcomes in BEAUTIFUL among the subpopulation of patients with baseline resting HR 70 bpm
(n = 5392), although no effect was seen on the
primary composite end point (cardiovascular
death, hospitalization for acute MI, and hospitalization for new or worsening heart failure) in the
total study population.34 These differences are most
likely due to the greater HR reduction with ivabradine among patients with elevated baseline resting
HR. Within this subpopulation, ivabradine reduced
HR by 7.9 bpm after 12 months and 6.9 bpm after
24 months versus placebo. This was associated
with a relative risk reduction of 36% in hospitalization for fatal and nonfatal MI (hazard ratio, 0.64;
95% CI, 0.49–0.84; P = 0.001) and 30% in the
need for coronary revascularization (hazard ratio,
0.70; 95 CI, 0.52–0.93; P 0.05) (Fig. 6). In terms
of absolute benefits for stable CAD patients with
577
Tardif
A)
Proportion admitted to hospital with
myocardial infarction (%)
10
Placebo
Ivabradine
p = 0.001
5
0
0
Number at risk
Placebo group 2693
Ivabradine group 2699
0.5
1.0
1.5
2.0
1493
1503
617
632
Years
2548
2573
2347
2364
Proportion with coronary revascularization (%)
B)
Placebo
Ivabradine
p = 0.016
0
Number at risk
Placebo group 2693
Ivabradine group 2699
0.5
1.0
Years
1.5
2.0
2552
2571
2347
2356
1483
1495
624
629
Figure 6. Kaplan-Meier time-to-event plots by treatment group (ivabradine or placebo) in the subgroup of stable coronary artery disease patients
with an elevated resting heart rate 70 bpm, for hospitalization for myocardial infarction A) and coronary revascularization B) Reproduced
with permission from Fox K, et al. Lancet. 2008;372:807–16.
elevated HR (70 bpm) if confirmed in ongoing
and future trials, a 2-year treatment with ivabradine
would prevent one MI in every 56 patients, and
one revascularization in every 83 patients. These
data compare favorably with the number needed
to treat for other agents used to prevent coronary
events in stable CAD, including statins, ACE
inhibitors, and beta-blockers.36–38 Ivabradine also
578
resulted in a 22% relative risk reduction in the
composite outcome of hospitalization for fatal and
nonfatal MI and unstable angina pectoris (hazard
ratio, 0.78; 95% CI, 0.52–0.93; P 0.05). It is
noteworthy that 84% of the subpopulation of
patients with HR 70 bpm were already receiving
beta-blockers, and the addition of ivabradine was
safe and well-tolerated. Taken together, the findings
Clinical Medicine: Therapeutics 2009:1
Safety and efficacy of ivabradine in the management of stable angina pectoris
of the BEAUTIFUL trial reinforce the importance
of addressing elevated resting HR to potentially
improve cardiovascular outcomes in CAD.
Practical Implications in Light
of Recent Clinical Trial Results
The first aspect of management of stable angina
pectoris is the control of symptoms to improve
exercise capacity and QoL.2 Agents used to relieve
angina include beta-blockers, calcium channel
blockers, potassium channel openers, nitrates, and
metabolic agents.2 Although all these agents have
documented anti-anginal and anti-ischemic efficacy, they are also associated with problems
regarding tolerability and contraindications,
which can considerably compromise the benefits
of treatment.39 Another option for the management
of angina is surgical revascularization. However,
the Clinical Outcomes Utilizing Revascularization
and Aggressive Drug Evaluation (COURAGE)
trial demonstrated only relatively small benefits in
the QoL of patients after revascularization, which
only lasted up to 3 years.40 Furthermore, revascularization has not been shown to improve major
cardiovascular outcomes in stable patients.40 Thus,
many patients with angina still have unmet clinical
needs and require alternative therapies for symptomatic management.
The clinical data that we have reviewed demonstrate that ivabradine has further applications that
can considerably improve the management of
stable angina pectoris. Ivabradine is currently indicated for relief of anginal symptoms in CAD.3 The
anti-anginal and anti-ischemic efficacy of ivabradine apply to a wide range of patients irrespective
of their background treatment. Ivabradine can be
safely added on top of anti-anginal therapy with
dihydropyridine calcium channel blockers, longacting nitrates, or beta-blockers.32,33
In addition to controlling symptoms, the management of patients with stable angina pectoris requires
cardioprotective treatment to improve clinical
outcomes in the long term.2 The main classes of
agents used for cardioprotection in CAD include
statins, ACE inhibitors and antiplatelet agents.
Despite their anti-anginal efficacy, beta-blockers
have never been shown to improve long-term
outcomes in patients with stable CAD.2 In this
context, ivabradine is the first anti-anginal and
anti-ischemic agent that can potentially reduce
the risk of MI and revascularization in a stable
Clinical Medicine: Therapeutics 2009:1
CAD population with LV dysfunction and resting
HR 70 bpm.34 Furthermore, the BEAUTIFUL
trial showed that resting HR 70 bpm at baseline
increased the risk of cardiovascular outcomes, even
within a CAD population that was being well
treated with a combination of cardioprotective
agents, including beta-blockers.35 A large number
of stable angina patients in clinical practice have
resting HR above this threshold and this ought to
be considered as an important factor in risk stratification.41 Addition of ivabradine treatment to
lower HR in this population should be considered
as an important part of the long-term management
strategy to improve potentially cardiovascular
outcomes. Together with its anti-anginal efficacy,
ivabradine will potentially play an important role
in improving the long-term management of patients
with stable angina pectoris, although this will need
to be confirmed in new randomized trials.
Ongoing and Future Clinical
Studies with Ivabradine
The VIVIFY (Evaluation of Intravenous If Inhibitor
Ivabradine in Acute Coronary Syndrome) study is
currently investigating the safety and tolerability
of intravenous ivabradine (5 mg bolus followed by
an 8-hour infusion of 5 mg) versus placebo among
120 patients with acute MI and ST-segment depression on ECG. Follow-up of patients after 6 months
will also evaluate the cardioprotective effects of
intravenous ivabradine on infarct size as assessed
by magnetic resonance imaging. Support for the
VIVIFY study comes from the protective action
of ivabradine against irreversible myocardial injury
in pigs after prolonged ischemia.25
In patients with congestive heart failure,
HR-lowering with beta-blockade is associated with
a reduction in mortality.42 Furthermore, pilot studies
in patients with moderate LV dysfunction showed
that ivabradine reduced LV end-systolic and enddiastolic volumes, suggesting a preserving effect
on cardiac function.43 These results have formed
the basis of the SHIFT (Systolic Heart failure with
the If inhibitor ivabradine Trial) study, which is
currently investigating the effects of ivabradine
in congestive heart failure.44 This large-scale,
randomized, placebo-controlled trial has recruited
over 7000 patients with moderate to severe heart
failure and resting HR 70 bpm. Throughout the
study, all patients have continued their current
standard treatments for heart failure and any other
579
Tardif
cardiovascular conditions. The aim is to evaluate
the advantages of adding treatment with ivabradine
versus placebo in terms of reduction in cardiovascular events in patients with heart failure.
Conclusion
Management of stable angina pectoris requires
symptomatic treatment to improve patients’ QoL, as
well as cardioprotective treatment to reduce the risk
of cardiovascular events. The clinical studies that
we have reviewed show that HR lowering with the
If inhibitor ivabradine can play a role in both of these
management strategies. The selective HR-lowering
action of ivabradine reduces myocardial oxygen
demand while increasing oxygen supply by virtue
of a longer diastolic perfusion time. Ivabradine has
proven anti-ischemic and anti-anginal efficacy without many of the problems associated with commonly
used anti-anginal agents. Ivabradine is therefore
suitable for a wide range of stable angina patients
irrespective of their background treatment.
The BEAUTIFUL trial has shown that ivabradine is unique among anti-anginal agents, in light
of its potential effect on coronary outcomes in
stable CAD patients with elevated resting HR. This
is consistent with preclinical data showing that
long-term HR reduction with ivabradine protects
against endothelial dysfunction and progression of
atherosclerosis. Interestingly, the same preclinical
studies showed that HR reduction with betablockers provided less endothelial protection.
Selective HR reduction with ivabradine should
therefore be considered as an important approach
in the long-term management of stable angina
patients with elevated resting HR. Furthermore,
data from ongoing and future clinical studies will
help us to determine more precisely the role of HR
lowering with ivabradine as a new therapeutic
modality for the management of patients with
cardiovascular diseases.
Disclosure
The author reports no conflicts of interest.
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