Anticancer Section / Short Communication

Chemotherapy 2018;63:315–320 Received: August 24, 2018

Accepted: November 19, 2018
DOI: 10.1159/000495576 Published online: March 6, 2019

Ivabradine in Cancer Treatment-Related

Left Ventricular Dysfunction
Matteo Sarocchi a, b Eleonora Arboscello c Giorgio Ghigliotti a, b
     

Roberto Murialdo d Claudia Bighin e Francesca Gualandi f Vera Sicbaldi d

       

Manrico Balbi a, b Claudio Brunelli a, b Paolo Spallarossa a

     

a Cardiovascular Disease Unit, San Martino Policlinic Hospital, Genoa, Italy; b Department of Internal Medicine,
 

University of Genoa, Genoa, Italy; c Emergency Medicine Unit, San Martino Policlinic Hospital, Genoa, Italy; d Internal
   

Medicine Unit, San Martino Policlinic Hospital, Genoa, Italy; e Medical Oncology Unit, San Martino Policlinic Hospital,
 

Genoa, Italy; f Haematology Unit, San Martino Policlinic Hospital, Genoa, Italy
 

Keywords carefully titrated. Hypotension (70%) and fatigue (77%)

Ivabradine · Cardiotoxicity · Cardio-oncology · Heart failure ·
Cancer · Adverse drug reaction · Hypotension
Abstract
Background: Patients developing cancer treatment-relat-
ed left ventricular dysfunction (CTrLVD) require a prompt
therapy. Hypotension, dizziness, and fatigue often limit the
use of angiotensin-converting enzyme inhibitors (ACEi), an-
giotensin receptor blockers (ARB), and β-blockers (BB) in
cancer patients who may already be afflicted by these
symptoms. Ivabradine is a heart rate-lowering drug that
does not cause hypotension and may be used in heart fail-
ure with reduced left ventricular ejection fraction (LVEF).
Objective: The aim of this paper was to investigate the role
of ivabradine to treat CTrLVD. Methods: A retrospective
analysis in a cohort of 30 patients with CTrLVD (LVEF <50%)
receiving ivabradine on top of the maximal tolerated dose
of ACEi/ARB and BB was performed. We evaluated cardio-
vascular treatment, oncologic treatment, LVEF, functional
class (New York Heart Association [NYHA]), and fatigue dur-
ing the study period. Results: Ivabradine was initially start-
ed at the dose of 2.5 mg/b.i.d. in most patients and then
were the main causes limiting the treatment with ACEi/ARB
and BB. After a mean follow-up of 6.5 months, LVEF in-
creased from 45.1% (SD = 6.4) to 53.2% (SD = 3.9; p < 0.001).
When patients were analyzed according to the type of can-
cer therapy, no difference in LVEF changes across the
groups was found. NYHA class ameliorated in 11 patients,
while fatigue improved in 8 patients. No serious cardiovas-
cular side effects were reported. Conclusions: The ability to
improve symptoms and LVEF in unfit cancer patients makes
ivabradine a reasonable pharmacological tool for treating
CTrLVD. © 2019 S. Karger AG, Basel
Introduction
Left-ventricular dysfunction (LVD) related to can-
cer treatment (CTrLVD) is a threatening cardiovascu-
lar complication of many chemotherapeutic agents
and molecular-targeted therapies [1, 2] that should be
treated as soon as possible [3]. Patients who develop
this complication are likely to benefit from angioten-
sin-converting enzyme inhibitors (ACEi), angiotensin
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© 2019 S. Karger AG, Basel Paolo Spallarossa, MD

Cardiovascular Disease Unit, Policlinic Hospital San Martino
Largo Rosanna Benzi 10
E-Mail karger@karger.com
IT–16132 Genoa (Italy)
www.karger.com/che
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E-Mail paolo.spallarossa @ unige.it

 Functional class HR SBP
20
140 180
**

15 p < 0.01 120 160

Patients, n
100 140
10

mm Hg
bpm
80 120
5
60 100

0
40 80
NYHA 1 NYHA 2 NYHA 3

LVEF

60 ** ** ** * ** ** ** **

40
LVEF, %

20

0
Continued Discontinued ANT TRZ HSCT TnI− TnI+
Overall Cancer treatment Cancer treatment Troponin
discontinuation type alteration

■ Before ivabradine ■ After ivabradine

Fig. 1. New York Heart Association (NYHA) class, heart rate (HR), systolic blood pressure (SBP), and left ven-
tricular ejection fraction (LVEF) before and after ivabradine. Patients were grouped according to the type of an-
ticancer treatment (ANT, anthracyclines; TRZ, trastuzumab; HSCT, allogeneic stem cell transplantation), main-
tenance or interruption of treatment, and occurrence or absence of troponin abnormalities (TnI– or TnI+).
** p < 0.001, * p < 0.01.

receptor blockers (ARB), and β-blocker (BB) treatment
to a similar extent as in the general population [1].
There are, however, conflicting reports in this regard
[4], as well as concerns about the side effects of these
drugs in patients undergoing active cancer treatments
[5, 6]. Cancer and cancer treatment may induce varia-
tions in volume load, heart rate, and blood pressure.
Accordingly, it is not surprising that the use of vasoac-
tive medications in oncologic patients may exacerbate
dizziness, hypotension, and fatigue, which are likely to
influence patients’ compliance and might drive the
­oncologist to discontinue the best anticancer therapy
[2, 7].
Ivabradine is a heart rate-lowering medication that in-
hibits the If channel in the sinoatrial node without effects
on inotropy, systemic blood pressure, and vascular resis-
tance [8, 9]. In patients with heart failure and reduced left
ventricular ejection fraction (LVEF), ivabradine im-
proves functional class and LVEF, reduces hospitaliza-
tion for heart failure, and cardiovascular death [10]. Sig-
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316 Chemotherapy 2018;63:315–320 Sarocchi et al.

DOI: 10.1159/000495576
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 Table 1. Echocardiographic parameters during the study

Echocardiography Baseline visit Follow-up visit p

mean SD mean SD

LV EDD, mm 50.2 5.4 50.5 4.1 0.64

LV ESD, mm 35.4 5.2 32.2 4.8 <0.001
LV EF, % 45.1 6.4 53.2 3.9 <0.001
WMSI 1.22 0.21 1.12 0.14 <0.001
Left atrial diameter, mm 37.5 7.8 38.0 7.0 0.39
PASP estimated, mm Hg 31.4 7.8 32.4 10.4 0.61
Mitral regurgitation Patients % Patients % p
Mild 21 70 20 67 0.04
Moderate 6 20 5 17
Severe 1 3 0 0

LV mass calculated by the Deauville formula. EDD, end-diastolic diameter; EF, ejection fraction; ESD, end-
systolic diameter; PASP, pulmonary artery systolic pressure; WMSI, wall motion score index.

nificant hypotension, fatigue, and severe bradycardia are Results

uncommon, due to its peculiar mechanism of action [11].
For all these reasons, ivabradine could be well tolerated in
cancer-treated patients.
The aim of our study was to confirm the efficacy and
handling of ivabradine treatment in cancer patients with
CTrLVD.
Patients and Methods
A retrospective observational analysis of patients with CTrLVD
treated with ivabradine was performed at the Cardio-Oncology
Outpatient Clinic of the San Martino Policlinic Hospital in Genoa
from 2014 to 2017.
We included patients with a CTrLVD defined as (1) a reduction
of LVEF below 50% if previously normal (≥55%), or (2) >10 per-
centage point loss if previously subnormal, in the absence of any
other explanation. Since anticancer treatments may be withheld,
stopped, or changed when a cardiovascular complication occurs,
we considered a “change of treatment” any unscheduled delay or
variation lasting for more than two cycles of the cancer therapy.
Continuous variables are presented as mean and standard de-
viation, unless otherwise specified. Hypothesis testing was per-
formed using Student’s t test for paired data (continuous variables)
and the Wilcoxon signed-rank test (ordinal variables), and a two-
tailed p < 0.05 was considered significant. The duration of the ob-
servation period was normalized by log-transformation. Correla-
tions between LVEF change and other continuous variables were
assessed by Pearson’s correlation test, while Kendall’s test was used
for New York Heart Association (NYHA) class. Associations in-
volving LVEF change were also examined in a univariate and mul-
tivariate linear regression model with heart rate change and the
observation period as covariates.
Of 37 CTrLVD patients treated with ivabradine, 7
were excluded because they did not have clinical and
echocardiographic evaluations after ivabradine introduc-
tion owing to missing follow-up visits (n = 3), noncardiac
death (n = 3), or early ivabradine discontinuation (n = 1)
decided by the general practitioner without providing
any reason.
The study cohort included 30 patients (23 females, 7
males) with a median age of 54 years (interquartile range:
44–66). Eleven patients were smokers, while patients with
hypertension, type 2 diabetes, and dyslipidemia were 9, 2,
and 14, respectively. Six patients had stable ischemic or
nonischemic cardiac disease before CTrLVD. Breast can-
cer and hematological diseases accounted for 40 and 57%
of the diagnoses of malignancy, respectively. CTrLVD
was attributed to anthracyclines (n = 6), trastuzumab
(n = 11), or allogeneic stem cell transplant (n = 10) in
most cases. The mean duration of follow-up was 6.5
months (median 5.6, interquartile range: 4.2–7.2).
The main clinical and echocardiographic results are
represented in Figure 1 and Table 1. NYHA class amelio-
rated in 11 patients, while 1 patient referred functional
class worsening, but further testing revealed an opportu-
nistic pneumonia. Eight patients reported resolution or
improvement of fatigue. Mean LVEF increased from
45.1% (SD = 6.4) to 53.2% (SD = 3.9; p < 0.001). The ex-
tent of LVEF improvement was slightly correlated to a
longer observation period (r2 = 0.18; p = 0.02). Neverthe-
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Ivabradine in Cardiotoxicity Chemotherapy 2018;63:315–320 317

DOI: 10.1159/000495576
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 Table 2. Ivabradine and other cardiovascular drugs in the study

25
Cardiovascular treatment Baseline Follow-up p
visit visit
20
r2 = 0.22
patients % patients %
15
Ivabradine
LVEF change, %

2.5 mg/b.i.d. 18 60 13 43 0.06

10 5 mg/b.i.d. 12 40 15 50
7.5 mg/b.i.d. 0 0 2 7
5 BB
<25% target dose 4 13 3 10 0.78
25 to <50% target dose 6 20 6 20
0
≥50% target dose* 2 7 3 10
ACEi or ARB 13 43 14 47 1.00
−5 Loop diuretics 9 30 13 43 0.07
−60 −40 −20 0 20 MRA 4 13 9 30 0.03
HR change, bpm
ACEi, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker; BB, β-blockers; MRA, mineral-
corticoid receptor blocker.
Fig. 2. Heart rate (HR) and left ventricular ejection fraction (LVEF)
*  Target dose: bisoprolol 10 mg o.d.; carvedilol 25 mg b.i.d.;
changes from baseline after ivabradine. Univariate model (r2 =
nebivolol 10 mg o.d.; metoprolol succinate 200 mg o.d. (as defined
0.22, β = –0.47, p < 0.01). In a multivariate model including the
in the 2016 guidelines for the diagnosis and treatment of acute and
log-transformed observation period (OP), the HR relation to
chronic heart failure by the European Society of Cardiology).
LVEF remained significant (HR: β = –0.45, p < 0.01; OP: β = 0.40,
p = 0.01; r2 = 0.38, p < 0.01).

less, LVEF improvement was significant in the subgroup
of 15 patients observed in an early time window before
the median value of the study follow-up (from 47.0%
SD = 2.9–53.6 SD = 3.2, p < 0.001). No relation between
NYHA class changes and the observation period was
found (tau = 0.04, p = 0.78).
Of note, a significant correlation (r2 = 0.22; p < 0.01)
between heart rate reduction and LVEF improvement
was found. The strength of the association with heart rate
did not change when the observation period was added in
a multivariate model (Fig. 2).
Ivabradine was chosen because blood pressure val-
ues, fatigue, dizziness, and drug intolerance cautioned
against the introduction or the increase of BB and an
ACEi/ARB. Hypotension (77%) and fatigue (70%) were
the most common causes limiting the treatment with
these drugs.
Concomitant cardiovascular medications are shown
in Table 2. BB and ACEi/ARB doses did not change in
most patients and were slightly increased in few patients.
The dose of loop diuretic and mineralocorticoid receptor
antagonist was increased in 7 patients, but NYHA class
did not ameliorate in 6 of them. NYHA class and LVEF
improvements were significant (p < 0.05 and p < 0.001,
respectively) in patients who did not require diuretic,
ACEi/ARB, and BB dose increase.
In 8 patients, the oncologist changed the anticancer
treatments to prevent a more severe scenario of cardiac
impairment. They had a lower LVEF and a more severe
NYHA class, but the improvement was not greater in
these patients when compared to those who continued
treatment. Serum troponin I was minimally altered in 12
patients (TnI+) in at least one determination during an-
ticancer treatment, without clinical or electrocardio-
graphic signs of myocardial ischemia. LVEF improve-
ment was similar in TnI+ and TnI– patients. Likewise, the
LVEF increase was consistent across cancer treatment
groups. Notably, all anthracycline treated patients ame-
liorated, 4 out of them showing more than 10 percentage
point gain of LVEF.
Anemia did not have a significant effect in the study.
The hemoglobin value did not change significantly dur-
ing follow-up, and only 5 patients had a hemoglobin val-
ue below 10.0 g/dL, but still >9.0 g/dL.
Ivabradine was well tolerated in all patients. No seri-
ous symptomatic bradycardia was reported. Two patients
reported mild phosphine-type visual disturbances soon
after drug initiation, which are a well-known, usually re-
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318 Chemotherapy 2018;63:315–320 Sarocchi et al.

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versible side effect. Accordingly, a brief, temporary sus-
pension of ivabradine was enough to resolve the symp-
toms completely.
Discussion
Our study documents that the addition of ivabradine
to the best medical therapy improves LVEF and symp-
toms in patients with CTrLVD. The LVEF improvement
did not come at the expense of worsening symptoms, as
may happen when BB or ACEi/ARB are uptitrated but,
on the contrary, joined a remarkable improvement of fa-
tigue, palpitations, and effort tolerance. This point is of
paramount importance for cancer patients. In fact, the
above-quoted symptoms not only impair the quality of
life but also limit the compliance to cancer therapies,
worsening the clinical outcome.
Ivabradine was additional, not alternative, to standard
treatment. Following the introduction of ivabradine,
there were minor therapy adjustments, including the in-
troduction of ACEi/ARB in 1 patient and a small uptitra-
tion of BB in few patients. This more effective use of ACEi
and BB that was eased by better clinical conditions – pos-
sibly achieved by the addition of ivabradine – can in turn
have contributed to improve symptoms and LVEF. Con-
versely, the addition of loop diuretic and/or mineralocor-
ticoid receptor antagonist appears not to be associated
with a better outcome.
Notably, the significant correlation that was found be-
tween heart rate reduction and LVEF improvements sup-
ports the pivotal role of heart rate in the pathophysiology
of LVD and heart failure and provides an explanation of
the mechanism through which ivabradine exerts its ben-
eficial effects in CTrLVD.
We should not forget that an association between
heart rate and cancer mortality had already been docu-
mented [12]. Moreover, a recent prospective study
showed that heart rate is associated with mortality in
patients with different types of cancer, irrespective of
other comorbidities, particularly infections and ane-
mia [13]. Heart rate therefore has been seen as a poten-
tial modifiable risk factor [14] that, based on these
findings, can be treated pharmacologically. Unlike BB,
ivabradine reduces the heart rate without causing
­hypotension and improves diastolic function, which
seems to precede CTrLVD [15]. Moreover, anticancer
treatments cause substantial endothelial dysfunction
[16, 17] that may be reduced through heart rate reduc-
tion with ivabradine [18].
Ivabradine in Cardiotoxicity
To the best of our knowledge, no previous clinical
study investigated the role of ivabradine in the treatment
of CTrLVD. De Gregorio et al. [19] reported a case of se-
vere cardiotoxicity responsive to a lisinopril-ivabradine-
multivitamin treatment, while Colak et al. [20] showed
that ivabradine pretreatment mitigates doxorubicin-in-
duced hemodynamic and biomarker alteration in rats.
Noteworthy, patients with anthracycline cardiotoxic-
ity – widely considered not reversible – showed a relevant
LVEF improvement in our study. This result may depend
on how quickly we initiated the cardiovascular treatment
[3]. In our cardio-oncology outpatient clinic, we evaluate
asymptomatic patients at risk of cardiotoxicity to identify
CTrLVD as soon as possible and to start treatment with-
out delay [21]. The small number of withdrawal of anti-
cancer treatment indicates that such practice is clinically
effective. This course of action is consistent with the mod-
ern concept of “actionable cardiotoxicity” that suggests
not to deprive patients of highly effective anticancer drugs
because of cardiotoxicity but to adopt all the diagnostic
and therapeutic tools, such as ivabradine, to mitigate the
toxicity [7].
This is a retrospective study with major limitations.
Ivabradine in the cardio-oncologic setting was pre-
scribed only in selected patients. As a result, our study
has a small sample size and lacks a control group, which
could not be matched by the propensity score. In addi-
tion, patients were collected during a long-time span,
and the different periods of observation may have influ-
enced the study findings. LVEF improved more in pa-
tients with a longer observation period, while changes in
the NYHA class were not affected by the length of ob-
servation time.
Prospective investigations are needed to overcome
these limitations and to support our results that confirm
the efficacy and safety in cancer patients with CTrLVD
previously seen in a large heart failure trial [10].
Conclusions
This is the first structured study that looked at the use
of ivabradine in cardio-oncology. Data derived by our ob-
servations support the claim that ivabradine might im-
prove LVEF, NYHA class, and symptoms in patients with
CTrLVD. When frailty limits other cardiovascular thera-
pies in cancer patients, ivabradine might allow a prompt
treatment of cardiotoxicity to avoid irreversible cardiac
damage and to preserve anticancer treatment opportuni-
ties.
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Chemotherapy 2018;63:315–320 319
DOI: 10.1159/000495576
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 Statement of Ethics
The study was approved by the local institutional review board.
All procedures in the study were in accordance with national stan-
dards and the Helsinki declaration.
Disclosure Statement
Dr. Paolo Spallarossa received speaker honoraria from Servier.
The other authors have no conflicts of interest to disclose.
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