Download Ivabradine and the SIGNIFY conundrum

European Heart Journal Advance Access published August 11, 2015
EDITORIAL
European Heart Journal
doi:10.1093/eurheartj/ehv368
Ivabradine and the SIGNIFY conundrum
John F. Beltrame*
The Queen Elizabeth Hospital Discipline of Medicine, University of Adelaide, Cardiology Stream, Central Adelaide Local Health Network, Adelaide, Australia
This editorial refers to ‘Bradycardia and atrial fibrillation in
patients with stable coronary artery disease treated with
ivabradine: the SIGNIFY study’, by K.M. Fox et al., on
page doi:10.1093/eurheartj/XXX
Stable angina is a prevalent and disabling condition that occurs in
10–14% of those aged 65 –84 years,1 with population studies suggesting that almost a third of affected patients experience an angina
episode at least once a week.2 Treatment focuses upon the alleviation of angina symptoms and the prevention of cardiac events.
Although the development of cardioprotective agents has received
considerable attention in recent years, there has been less progress
with novel antianginal agents.
Unravelling the SIGNIFY
conundrum
Ivabradine: an effective antianginal
Statistical aberration
Ivabradine is a novel antianginal agent that inhibits the sinus node If
channel to produce a dose-dependent bradycardia and thus antiischaemic effects without significant direct effects on vasomotor
tone, blood pressure, or myocardial contractility. Previous studies
have shown it to be superior to placebo and non-inferior to first-line
antianginal agents (beta-blockers and calcium channel blockers).1
However like the first-line agents, its cardioprotective benefit in patients with stable angina has not been confirmed,3,4 although its
benefit in heart failure is well supported.5
The BEAUTIFUL3 and SIGNIFY4 studies evaluated the cardioprotective effects of ivabradine in patients with coronary artery disease
with3 and without4 left ventricular systolic dysfunction, who had
resting sinus rhythm rates ≥70 b.p.m. Although neither study reported an overall cardioprotective benefit, a post-hoc analysis of
the BEAUTIFUL study observed a 42% reduction in myocardial infarct hospitalizations amongst patients with symptom-limiting angina.6 Consequently a pre-specified subgroup analysis of patients
with Canadian Cardiovascular Society Class II –IV angina was undertaken in the SIGNIFY study [hereafter referred to as the ‘SIGNIFY
Angina(II – IV) Subgroup’].
Astonishingly, ivabradine was associated with an 18% increase in
the primary endpoint (cardiovascular death and non-fatal infarction)
in the SIGNIFY Angina(II – IV) Subgroup. Thus although ivabradine is
The surprising findings in the SIGNIFY Angina(II – IV) Subgroup analysis raise the possibility of an invalid result or a Type I error. This
possibility is strengthened if no biological explanation for the
findings can be derived; hence this should be explored before the
statistical explanation is further considered.
The SIGNIFY Angina(II – IV) Subgroup analysis findings of increased
cardiac events in those treated with ivabradine may have several
potential explanations including: (i) statistical aberration; (ii) cardiac
arrhythmias; (iii) drug interactions; and/or (iv) dose titration.
Cardiac arrhythmias
Ivabradine use is associated with an increased frequency of emergent bradycardia and atrial fibrillation (see Figure 1). In this issue of
the journal, Fox et al. 7 compared the cardiac event primary endpoint
in the ivabradine- and placebo-treated SIGNIFY patients with/without emergent bradycardia (resting heart rate ,50 b.p.m., n ¼ 3572)
as well as those with/without emergent atrial fibrillation (n ¼ 754).
This subanalysis showed no difference in cardiac adverse events between placebo- and ivabradine-treated patients for both the overall
and the SIGNIFY Angina(II – IV) Subgroup. Similarly, there was no difference in adverse cardiac events between treatment groups for
those with emergent atrial fibrillation in both the overall and the
SIGNIFY Angina(II – IV) Subgroup. Thus, although emergent bradycardia and atrial fibrillation occur more often in the ivabradine-treated
patients, these arrhythmias do not appear to account for the increased cardiac events reported in the SIGNIFY Angina (II – IV)
Subgroup.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponidng author. The Queen Elizabeth Hospital Discipline of Medicine, c/o Ward 5B, 28 Woodville Rd, Woodville South, Adelaide, South Australia, 5011, Australia.
Tel: +61 8 8222 6740, Fax: +61 8 8222 6042, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
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an effective antianginal agent, at best it has neutral cardioprotective
effects but at worst it may increase major adverse cardiac events in
symptomatic stable angina patients without heart failure. Hence
those who would gain the most from its antianginal properties are
also those most at risk from its apparent adverse cardiac effects.
This conundrum warrants further investigation to explain these currently inexplicable findings.
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Editorial
angina (Canadian Cardiovascular Society Class II –IV) but without cardiac failure. CV, cardiovascular; MI, myocardial infarction.
Early clinical studies utilizing doses up to 10 mg b.i.d. concluded
that ivabradine prolongs the uncorrected QT interval by 18 –30 ms
in a dose-dependent fashion; however, when appropriately corrected for heart rate, this increase did not exceed 2 ms and thus
should not have direct torsadogenic potential.8 Accordingly, although QT prolongation was observed in 114 (1.9%) patients on
ivabradine and 42 (0.7%) patients on placebo in the SIGNIFY Angina(II – IV) Subgroup, this resulted in drug withdrawal in only three and
two patients, respectively.4 It is also noteworthy that serious ventricular arrhythmias resulting in drug withdrawal were uncommon
(4 vs. 1 patient, respectively) in this subgroup.4
Despite the apparent safety of ivabradine in relation to QT prolongation, patients with a propensity for torsades de pointes (i.e.
congenital or acquired long QT syndromes) have been excluded
in the clinical trials3,4 and listed as contraindications in the drug
product information. Recent clinical data has reinforced this concern with two case reports of ivabradine associated with torsades
de pointes when co-administered with potentially torsadogenic
medications.9,10 Furthermore a recent in vitro study has demonstrated that ivabradine at concentrations equivalent to the higher
clinical dosage spectrum prolongs ventricular repolarization and
alters electrical restitution, thereby potentially predisposing to
torsades de pointes.11
Drug interactions
Ivabradine has a plasma half-life of 2 h and a biological half-life of
11 h.12 It is extensively metabolized by the cytochrome P450
(CYP) enzyme, CYP-3A4, and although it does not influence the
metabolism of CYP-3A4 substrates, its own metabolism is influenced by potent CYP-3A4 inhibitors.12 Consequently, concurrent
use of strong CYP-3A4 inhibitors is contraindicated for ivabradine
and excluded from clinical trials.3,4 Moderate CYP-3A4 inhibitors
such as diltiazem or verapamil were discouraged in the earlier
ivabradine studies but could be utilized in the SIGNIFY trial.4 Thus
4.6% of patients randomized to ivabradine therapy were receiving
one of these agents.
Combining ivabradine with either verapamil or diltiazem not only
increases ivabradine plasma levels three-fold via the above
pharmacokinetic interaction, but also produces a pharmacodynamic
interaction via the negative chronotropic actions of these nondihydropyridine calcium channel blockers. The hazard of this interaction is exemplified by further analysis of the SIGNIFY Angina(II – IV)
Subgroup data, where concurrent use of verapamil/diltiazem or
other CYP-3A4 inhibitor with ivabradine was associated with a
62% increased trend in the primary endpoint (P ¼ 0.088) and a significant 88% increase in non-fatal myocardial infarction (P ¼ 0.026).
This observation has prompted the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency to list the
concurrent use of verapamil or diltiazem as a strong contraindication to initiating ivabradine therapy.
Dosage titration
In the SIGNIFY trial, ivabradine was initiated at a dose of 7.5 mg b.i.d.
(or 5 mg b.i.d. in those ≥75 years) and titrated to 10 mg b.i.d. in order to achieve a target heart rate of 55 – 60 b.p.m. Consequently,
47% of the ivabradine study patients who were ,75 years of age
were receiving the 10 mg b.i.d. dosage. This contrasts with contemporary clinical practice, where ivabradine is initiated at 2.5 –5.0 mg
b.i.d. and titrated to a maximum of 7.5 mg b.i.d. Moreover, the primary endpoint occurred on the 10 mg b.i.d. dosage in 58% of the
SIGNIFY Angina(II – IV) Subgroup patients.
Considering the higher dose of ivabradine and the potential interaction with the concurrent use of verapamil/diltiazem, it is possible
that the SIGNIFY trial may have inadvertently constructed the ‘perfect storm’, resulting in the disturbing findings in the SIGNIFY Angina(II – IV) Subgroup. Perhaps the high ivabradine levels unmasked a
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Figure 1 The SIGNIFY trial subanalysis findings. Cardiovascular endpoints in stable angina patients (n ¼ 12 049) with moderate to severe
Page 3 of 3
Editorial
biological effect (such as QT prolongation) that is not a problem at
the lower doses in routine clinical use.
The importance of resolving the
SIGNIFY conundrum
References
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Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK,
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artery disease without clinical heart failure. N Engl J Med 2014;371:1091 –1099.
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The plight of ivabradine is further exemplified by the author’s own
clinical experience in utilizing this agent for the treatment of angina
in patients with coronary microvascular disorders. Its antianginal effect in these patients was remarkable, with some achieving good
control despite failing to respond to proposed first-line treatments.1
However with the advent of the SIGNIFY Angina(II – IV) Subgroup
findings, a decision to withdraw the ivabradine therapy from these
patients was made on the basis of its ‘non-label use’ and an unclear
explanation for the cardiac events in the symptomatic patients. Two
of these patients with ivabradine-responsive angina subsequently
developed a myocardial infarct shortly after discontinuing this agent.
This appeared unrelated in one patient, since he experienced a periprocedural myocardial infarct during stenting of his obstructive coronary artery disease, which had developed on a long background
history of coronary microvascular dysfunction. However, the second patient experienced an unheralded myocardial infarct within
48 h of discontinuing ivabradine, despite a down-titration withdrawal over a week. These and several other microvascular angina patients in whom ivabradine was stopped are eager to recommence
this medication considering the symptomatic benefits they derived
from its use; however, their conservative physician remains reluctant until an adequate explanation for the SIGNIFY results is
established.
In conclusion, ivabradine can be used with confidence at the lower contemporary clinical doses (5– 7.5 mg b.i.d.) for the treatment
of angina, if it is believed to have neutral cardioprotective effects
(as for the first-line antianginal agents) and the SIGNIFY Angina(II –
IV) Subgroup adverse events can be attributed to a dose-dependent
effect resulting from the use of high dose ivabradine, potentially exacerbated by the concurrent use of verapamil/diltiazem. However,
the mechanisms for the SIGNIFY Angina(II – IV) Subgroup adverse
events require further clarification, since emergent bradycardia
and atrial fibrillation are not responsible and although QT prolongation at high doses may potentially be torsadogenic, it does not account for the reported increased myocardial infarcts. Hence the
search for the mechanism(s) responsible for the SIGNIFY Angina(II – IV) Subgroup findings must continue so that ivabradine can
be maintained as a useful tool in our very limited therapeutic antianginal armamentarium and avoid our previous errors of ‘throwing the
baby out with the bath water’.13
Conflict of interest: The author has previously received unrestricted research grants from Servier Laboratories for the study of
stable angina and the use of ivabradine in the treatment of refractory
angina. He has also been supported to attend meetings and provide
educational sessions.