Download Ivabradine in the management of coronary artery disease with or

European Heart Journal Supplements (2015) 17 (Supplement G), G24–G29
The Heart of the Matter
doi:10.1093/eurheartj/suv056
Ivabradine in the management of coronary artery
disease with or without left ventricular dysfunction
or heart failure
Roberto Ferrari1,2*
1
Department of Cardiology and LTTA Centre, University Hospital of Ferrara and Maria Cecilia Hospital,
GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy
2
Azienda Ospedaliero-Universitaria di Ferrara, Ospedale di Cona, Via Aldo Moro 8, 44124 (Cona) Ferrara, Italy
KEYWORDS
Left ventricular dysfunction;
Heart failure;
Coronary artery disease;
Ivabradine
Heart rate reduction is an integral part of antianginal therapy. In this article, we examine
currently available data related to the use of ivabradine in patients with angina pectoris
with and without left ventricular dysfunction (LVD) or heart failure (HF). We explore
results from large morbidity–mortality trials of ivabradine in stable coronary artery
disease (CAD) without HF (SIGNIfY), stable CAD with LVD (BEAUTIfUL), and systolic HF
(SHIfT). While ivabradine did not improve outcomes in the main population in SIGNIfY,
analyses of the antianginal effect of ivabradine in a pre-specified angina subgroup
(n ¼ 12 049) were in line with knowledge of the antianginal properties of ivabradine,
with improvements in angina class vs. placebo (P ¼ 0.01) and a trend towards less elective coronary revascularization (P ¼ 0.058). A post hoc analysis in a subgroup of 1507
BEAUTIfUL patients with limiting angina at baseline showed that risk reduction in
favour of ivabradine, which was nominally statistically significant for hospitalization
for myocardial infarction; the results were even better in patients with heart rate
≥70 b.p.m. Similarly, a post hoc analysis in 2220 SHIfT patients with angina at baseline
indicated that the beneficial prognostic effects of ivabradine were maintained. The
main differences between the three studies are LVD and ivabradine dosage (which was
higher in SIGNIfY than in the other two trials). We conclude that heart rate reduction
has a different role according to LVD. Provided that it is used at the recommended
dose, ivabradine has been proved to be an effective, useful antianginal agent in patients
with and without LVD.
Introduction
Heart rate reduction is an integral part of optimal antianginal therapy. The efficacy of heart rate reduction with the If
inhibitor ivabradine in reducing the symptoms of angina
pectoris in patients with stable coronary artery disease
(CAD) with normal left ventricular (LV) function either
alone or on top of beta-blockers is well documented1–3
and recognized by the European Guidelines.4,5 The recent
* Corresponding author. Tel: +39 0532 239882, Fax: +39 0532 237841,
Email: [email protected]
Study assessInG the morbidity-mortality beNefits of the If
inhibitor ivabradine in patients with coronarY artery
disease (SIGNIfY) reported that the use of ivabradine in
patients with normal LV function appeared to be associated
with an increase in the incidence for primary composite
endpoint in a pre-specified subgroup of 12 049 patients
with Canadian Cardiovascular Society (CCS) class II or
higher angina at baseline.6 Whatever the explanation for
the results of SIGNIfY in terms of outcomes, analyses of
the antianginal effect of ivabradine in the same angina subgroup were in line with the symptomatic use of ivabradine
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015.
For permissions please email: [email protected]
Ivabradine in the management of CAD with or without LVD or HF
in patients with stable angina pectoris. There were
improvements in CCS angina vs. placebo (P ¼ 0.01) and a
trend towards lower incidence of elective coronary revascularization (P ¼ 0.058).6 A substudy of SIGNifY evaluated
the effects of ivabradine on angina-related quality of life
in 4187 patients. The results indicate that ivabradine produces consistent improvements of self-reported quality
of life parameters related to angina pectoris, notably in
terms of angina frequency and disease perception.7 Thus,
the antianginal effect of ivabradine in CAD patients with
normal LV function is unquestionable. The scope of the
present article is to examine currently available data
related to the use of ivabradine in patients with angina
and LV dysfunction or heart failure (HF), because, in
these patients, ivabradine could provide symptomatic
and prognostic benefits. To achieve this, we also need to
examine data from the MorBidity-mortality EvAlUaTion of
the If inhibitor ivabradine in patients with coronary
disease and left ventricULar dysfunction (BEAUTIfUL) and
Systolic Heart failure treatment with the If inhibitor ivabradine (SHIfT) trials.8,9
Patients with angina in BEAUTIfUL
BEAUTifUL was an international, multicentre, randomized,
double-blind, placebo-controlled, phase 3 study designed
to evaluate cardiovascular (CV) outcomes in subjects
with CAD and LV systolic dysfunction [LV ejection fraction
(EF) ,40%] and heart rate ≥60 b.p.m.8 Subjects received
ivabradine in combination with optimal, stable conventional CV medication, deemed appropriate for CAD or specific aspects of their presentations, as background therapy,
e.g. beta-blockers (86.9%), aspirin (84.8%), angiotensinconverting enzyme (ACE) inhibitors (79.9%), statins (74.2%),
diuretics (mineralocorticoid receptor antagonists, 27.1%;
other agents, 58.9%), organic nitrates (43.4%), dihydropyridine (10.2%), and diltiazem or verapamil (2.3%). The study
was designed to accrue 950 events of the primary composite endpoint, which was defined as the first event among
G25
CV death, hospitalization of acute myocardial infarction
(MI), or hospitalization for new or worsening HF.
The main results of the BEAUTIfUL trial were neutral.
There was no impact of ivabradine on outcomes: in the
primary analysis in the randomized set of 10 917 subjects,
ivabradine had no effect on the primary composite endpoint. However, in a pre-specified subgroup of subjects
with baseline resting heart rate ≥70 b.p.m., there was a
trend in the primary composite endpoint in favour of ivabradine. The opposite trend was observed in the subgroup or
subjects with heart rate ,70 b.p.m. at baseline. In the subgroup with heart rate ≥70 b.p.m., ivabradine’s main impact
was on coronary endpoints with the observation of a 36%
relative risk reduction for hospitalization for fatal or nonfatal MI and a 30% relative risk reduction for coronary revascularization. These findings were attributed to differential
effects of increased heart rate of CV outcomes with a
direct effect on coronary outcomes, i.e. ischaemia or MI.8
Considering the value of ivabradine in the management
of angina, a post hoc analysis was performed in a subgroup
of BEAUTIfUL subjects with anginal pain as the limiting
factor for physical activity at baseline (n ¼ 1507).10 The
presence of angina at baseline was determined by
New York Heart Association (NYHA) class II or III, whether
they reported symptoms limiting activity, and whether
those symptoms were noted as angina-related. This definition of limited angina was considered to be equivalent to
CCS classes II and III angina. In this subgroup, the hazard
ratios of the primary composite endpoint, all component
endpoints, and all-cause mortality all favoured ivabradine,
and the reduction in risk for hospitalization for acute MI was
nominally statistically significant (Table 1, Figure 1A).
Compared with placebo, the ivabradine group also had a
lower incidence of all-cause mortality than placebo (8.7
vs. 10.0%, respectively), CV death (7.4 vs. 8.3%), and
death due to acute MI (0.3 vs. 1.2%). In patients with limiting angina and heart rate ≥70 b.p.m., there was an even
greater effect on coronary outcomes and treatment was
associated with substantial reductions in hospitalization
for fatal and non-fatal MI and coronary revascularization
(Figure 1B).
Table 1 Incidence of primary composite endpoint [cardiovascular death, hospitalization for acute myocardial infarction (MI), or
hospitalization for new or worsening heart failure (HF)] and selected secondary endpoint in BEAUTIfUL subjects with angina pain at
baseline
Endpoint
Primary composite endpoint
Secondary endpoints
Cardiovascular death
Hospitalization for acute MI
Hospitalization for new or worsening HF
All-cause mortality
Event rate, n(%)
Hazard ratio
E (95% CI)a
P valueb
Ivabradine
N ¼ 734
Placebo
N ¼ 773
88 (12.0%)
120 (15.5%)
0.76 (0.58–1.00)
0.05
54 (7.4%)
33 (3.8%)
33 (4.5%)
64 (8.7%)
64 (8.3%)
50 (6.5%)
41 (5.3%)
77 (10.0%)
0.88 (0.62–1.27)
0.58 (0.37–0.92)
0.84 (0.53–1.33)
0.87 (0.62–1.21)
0.51
0.021
0.45
0.41
CI, confidence interval (two-sided).
a
Estimate (E) of hazard ratio using an adjusted Cox proportional hazards model with beta-blocker intake at baseline as a covariate.
b
Log-rank test stratified on beta-blocker intake at randomization.
G26
R. Ferrari
Figure 1 Event curves for the primary composite endpoint of cardiovascular death, hospitalization for acute myocardial infarction, or hospitalization for
new or worsening heart failure in patients with limiting angina (A) and in those with limiting angina and heart rate ≥70 b.p.m. (B) at baseline in the BEAUTIfUL
study. HR, hazard ratio; CI, confidence interval. Reproduced from reference (10) with permission.
We should consider these data in the light of the main
results of the BEAUTIfUL study,8 in which there was no
impact of ivabradine on the primary composite endpoint.
This unexpected result was attributed to the domination
of HF events in the primary composite endpoint. Patients
with angina would be expected to have proportionately
more coronary events—especially MI—and that would affect
the primary composite endpoint. The BEAUTIfUL placebo
group is informative on this point. Placebo patients with
angina had higher rates of hospitalization for fatal and nonfatal MI than placebo patients in the whole study (6.5 vs.
4.2%, respectively; 6.3 vs. 4.9% in patients with heart
rate ≥70 b.p.m.) and lower rates of hospitalization for
HF (5.3 vs. 7.9%; and 5.5 vs. 10.1%).
BEAUTIfUL was not designed to detect the symptomatic
effects of ivabradine, and so it was not possible to establish
whether treatment reduced the burden of angina pain,
which could have explained the reduction of CV risk. This
would have been in agreement with the literature reports
that patients with angina symptoms are at higher risk for
MI, whether they have stable angina, stable CAD, and independently of the presence of LV dysfunction.11–15 It remains
unclear by which mechanism limiting angina predicts coronary events. The most probable explanation is related
to the obstructive nature of coronary atherosclerosis.
Indeed, the pain associated with ischaemia usually indicates a fixed obstructive lesion,14 whereas the progression
of disease and acute coronary events are generally related
to overall plaque burden, as well as the vulnerability and instability of plaque. Ivabradine’s beneficial effect on endothelial function has been demonstrated in animal models,
which support the notion that it should attenuate the progression of atherosclerosis.16,17 While these mechanisms
are attractive, they now appear unlikely to be relevant in
humans since the SIGNIfY trial clearly demonstrated that
ivabradine has no effect on CV death or MI in CAD patients
with normal ventricular function, which implies no beneficial effect on atherosclerosis progression or plaque
rupture.6
There are a number of differences between BEAUTIfUL
and SIGNIfY. The most relevant to our discussion here is
probably LV function, which was reduced in BEAUTIfUL
and normal in SIGNIfY. This may explain—at least in part—
the beneficial prognostic effect found in the angina subgroup of BEAUTIfUL.10 To this end, it is interesting to
examine the patients enrolled in SHIfT with angina, since
they also had LV dysfunction as well as HF.9
Patients with angina in SHIfT
SHIfT included 6558 patients with chronic HF, resting heart
rate ≥70 b.p.m. and baseline EF 29.0 + 5.1%, who were
also receiving guideline-based background therapy.9 Treatment with ivabradine was associated with a highly significant effect on the primary composite outcome of CV
death and hospitalization for HF. The effect was found to
be mainly driven by HF hospitalization, the risk of which
was reduced by 26% (P , 0.0001). There was no difference
in the effect of ivabradine between ischaemic and nonischaemic HF, with a similar magnitude of risk reduction
whatever the origin of HF.
About a third of the SHIfT population (n ¼ 2220) had
angina at entry to the study.18 Preliminary data reported
at this year’s American College of Cardiology meeting
demonstrated that effect of ivabradine was similar in
patients in the whole SHIfT population and in the subgroup
of 2220 patients with angina: ivabradine reduced CV death
or hospitalization for worsening HF by 18% compared with
placebo in the whole population [hazard ratio (HR), 0.82;
95% confidence interval (CI), 0.75–0.90; P , 0.0001] and
by 15% in the patients with angina (HR, 0.85; 95% CI, 0.73–
1.00; P ¼ 0.0553). Ivabradine reduced CV death or non-fatal
MI by 11% vs. placebo in the whole population (HR, 0.89; 95%
CI, 0.79–1.01; P ¼ 0.0660) and by 8% (HR, 0.92; 95% CI,
0.75–1.12; P ¼ 0.3797) in the angina subgroup. Both
groups showed directionally consistent results for non-fatal
MI. Thus, it appears that SHIfT patients with angina and HF
receiving ivabradine had the same benefit in terms of the
primary composite endpoint as the overall SHIfT population.
How to interpret the data
The first point that needs to be made is that both of the evaluations in BEAUTIfUL and SHIfTon patients with angina are
Ivabradine in the management of CAD with or without LVD or HF
both post hoc, non-prespecified analyses. There is,
however, a difference: BEAUTIfUL was a neutral study
and so, from a purely statistical and procedural point of
view, any sub-analyses have no validity and, actually,
should not even be considered. This approach, although
correct, is a bit drastic and, in every large trial, there is
the temptation (and even a duty) to further dissect the
data in the hope of finding interesting hypotheses or explanations for the results. This was the case for the post hoc exploratory analyses performed in BEAUTIfUL, which was
subsequently tested in the SIGNIfY trial. The SIGNIfY
trial, however, was not a pure replica of BEAUTIfUL in
patients with heart rate ≥70 b.p.m., and ended up exploring the effect of a different regimen in quite a different
population. The main differences between the two trials
were the level of LV function (normal in SIGNIfY, reduced
in BEAUTIfUL) and the higher initiation and maintenance
dosage employed in SIGNIfY.6,8 It follows that the only argument that could be put forward for BEAUTIfUL angina10 is
that the sample size was relevant (1507 patients with
angina) and the results are plausible and in line with previous data for ivabradine in a pure angina population,2,3 but
not with those of SIGNIfY.6
On closer inspection, the BEAUTIfUL patients with angina
resemble more those enrolled in SHIfT, with a 32% EF in
BEAUTIfUL and 29% EF in SHIfT, and the two trials share
the same dose regimen. The results are also concordant
since there was a reduction in primary composite endpoints
with less hospitalization for HF in SHIfT vs. less hospitalization for MI in BEAUTIfUL. It would be interesting to make a
meta-analysis of the two angina subgroups.
Therefore, it seems that ivabradine improves prognosis
in patient with LV dysfunction, suggesting an important
role of heart rate reduction in relation to LV function.19
When ventricular function is reduced, the elevation of
heart rate is closely associated with stroke volume, and
its early increase could be considered as a compensatory
mechanism. However, this is true only in the initial
stages; prolonged neuroendocrine activation has deleterious effects on the myocytes resulting in ventricular
changes for the worse and remodelling of the ventricle, a
complex phenomenon whereby the ventricles progressively enlarge and EF reduces. Under these conditions, heart
rate per se impacts on LV dysfunction with an increase in
volumes and reduction in EF at higher rates, as shown in
paced patients.20,21 As HF progresses, the force–frequency
relationship by which the normal heart regulates cardiac
function becomes negative and the compensatory mechanism of increased heart rate is lost; myocardial contractility
no longer improves with increasing heart rate. On the contrary, it further deteriorates.22 The situation is further
aggravated by a heart rate-associated increase in energy
deprivation, inducing hypoxia, which stimulates local production of a range of cytokines, free radicals, and vasoconstrictors implicated in the development of LV remodelling.
Of course, all of the processes are further exaggerated by
the presence of angina causing short periods of ischaemia
with further negative consequences on the myocytes.
In stable CAD with maintained LV function, heart rate is a
well-established determinant of ischaemia. In line with experimental data, clinical results indicate that elevations of
G27
heart rate during physical or emotional stress induce ischaemia and angina.23 Consistent with this, heart rate reduction is a recognized strategy for the prevention of
ischaemia and therefore of angina symptoms in patients
with maintained24 or depressed LV function.25 Heart rate
reduction with ivabradine has been demonstrated to
improve angina symptoms since it reduces heart rate
both at rest and on exercise, which is when ischaemia is
most likely to occur. In line with this, a heart rate of 55 to
60 b.p.m. is currently recommended for optimal antianginal efficacy of beta-blockers and ivabradine in stable CAD.4
Furthermore, experimental and clinical data suggest that
heart rate may be involved in the progression of atherosclerosis and plaque rupture leading to MI.26,27 This was
the underlying rationale for the SIGNIfY study. The results
of SIGNIfY6 confirm the symptomatic benefit of ivabradine,
as shown by an improvement in angina class, but do not
show a prognostic benefit.
Conclusion
Provided that it is used at the recommended dose, ivabradine has been proved to be an effective, useful antianginal
agent in patients with preserved or reduced EF. The angina
substudy of BEAUTIfUL and an analysis of SHIfT patients
with angina at entry seem to support a prognostic
benefit, but these data should be considered with caution
as they are results of sub-studies, albeit in a relevant
number of patients.
The improvement of outcomes have never been shown
to improve with an antianginal treatment in patients
with stable angina pectoris. The effects of calcium
channel blockade on CV mortality and morbidity were
tested in CAMELOT (Comparison of AMlodipine vs. Enalapril to Limit the Occurrence of Thrombosis) and ACTION
(A Coronary disease Trial Investigating Outcome with Nifedipine),26,27 but neither trial demonstrated a significant
reduction in major CV events independently of LV dysfunction. The IONA (Impact Of Nicorandil in Angina) trial
showed a trend,28 but was not powered to show a benefit
on CAD mortality or non-fatal MI, and all-cause mortality
and therefore we are unable to draw conclusions regarding
effects on these endpoints. On the other hand, the benefits of beta-blockade in terms of reduction of mortality
are well known, but are limited to post-MI and HF
patients.29–32 Moreover, most of these post-MI trials with
beta-blockers were performed before the era of thrombolysis or primary angioplasty with extensive use of ACE
inhibitors and statins,4 which leaves uncertainty regarding
their efficacy on top of more recent management strategies. From these studies, it has been extrapolated that
beta-blockade may have an effect on prognosis in angina
pectoris, but this has never been evaluated in randomized
controlled trials.4 Actually, recent registry data demonstrate the opposite.33
In any case, in angina patients from both BEAUTIfUL and
SHIfT, ivabradine was given on top of beta-blockers. Certainly, it did not worsen the prognosis but most likely
improved it. Thus, it seems to be a logical to use ivabradine
when elevated heart rate remains high.
G28
Acknowledgements
We thank Sarah Novack, PhD, who provided editorial assistance on
behalf of Servier, France.
Funding
This work was supported by a grant from Fondazione Anna
Maria Sechi per il Cuore (FASC), Italy. The funders had no
role in the study design, data collection and analysis, decision to publish or the preparation of the manuscript.
Conflict of interest: R.F. reported that he received honorarium
from Servier for steering committee membership consulting and
speaking, and support for travel to study meetings from Servier.
In addition, he received personal fees from Boehringer-Ingelheim,
Novartis, Merck Serono, and Irbtech.
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