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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 · were the main causes limiting the treatment with ACEi/ARB
Cancer · Adverse drug reaction · Hypotension 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-
Abstract cer therapy, no difference in LVEF changes across the
Background: Patients developing cancer treatment-relat- groups was found. NYHA class ameliorated in 11 patients,
ed left ventricular dysfunction (CTrLVD) require a prompt while fatigue improved in 8 patients. No serious cardiovas-
therapy. Hypotension, dizziness, and fatigue often limit the cular side effects were reported. Conclusions: The ability to
use of angiotensin-converting enzyme inhibitors (ACEi), an- improve symptoms and LVEF in unfit cancer patients makes
giotensin receptor blockers (ARB), and β-blockers (BB) in ivabradine a reasonable pharmacological tool for treating
cancer patients who may already be afflicted by these CTrLVD. © 2019 S. Karger AG, Basel
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 Introduction
of ivabradine to treat CTrLVD. Methods: A retrospective
analysis in a cohort of 30 patients with CTrLVD (LVEF <50%) Left-ventricular dysfunction (LVD) related to can-
receiving ivabradine on top of the maximal tolerated dose cer treatment (CTrLVD) is a threatening cardiovascu-
of ACEi/ARB and BB was performed. We evaluated cardio- lar complication of many chemotherapeutic agents
vascular treatment, oncologic treatment, LVEF, functional and molecular-targeted therapies [1, 2] that should be
class (New York Heart Association [NYHA]), and fatigue dur- treated as soon as possible [3]. Patients who develop
ing the study period. Results: Ivabradine was initially start- this complication are likely to benefit from angioten-
ed at the dose of 2.5 mg/b.i.d. in most patients and then 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 influence patients’ compliance and might drive the
to a similar extent as in the general population [1]. ­oncologist to discontinue the best anticancer therapy
There are, however, conflicting reports in this regard [2, 7].
[4], as well as concerns about the side effects of these Ivabradine is a heart rate-lowering medication that in-
drugs in patients undergoing active cancer treatments hibits the If channel in the sinoatrial node without effects
[5, 6]. Cancer and cancer treatment may induce varia- on inotropy, systemic blood pressure, and vascular resis-
tions in volume load, heart rate, and blood pressure. tance [8, 9]. In patients with heart failure and reduced left
Accordingly, it is not surprising that the use of vasoac- ventricular ejection fraction (LVEF), ivabradine im-
tive medications in oncologic patients may exacerbate proves functional class and LVEF, reduces hospitaliza-
dizziness, hypotension, and fatigue, which are likely to 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 Of 37 CTrLVD patients treated with ivabradine, 7
cancer-treated patients. were excluded because they did not have clinical and
The aim of our study was to confirm the efficacy and echocardiographic evaluations after ivabradine introduc-
handling of ivabradine treatment in cancer patients with tion owing to missing follow-up visits (n = 3), noncardiac
CTrLVD. death (n = 3), or early ivabradine discontinuation (n = 1)
decided by the general practitioner without providing
any reason.
Patients and Methods The study cohort included 30 patients (23 females, 7
males) with a median age of 54 years (interquartile range:
A retrospective observational analysis of patients with CTrLVD
44–66). Eleven patients were smokers, while patients with
treated with ivabradine was performed at the Cardio-Oncology
Outpatient Clinic of the San Martino Policlinic Hospital in Genoa hypertension, type 2 diabetes, and dyslipidemia were 9, 2,
from 2014 to 2017. and 14, respectively. Six patients had stable ischemic or
We included patients with a CTrLVD defined as (1) a reduction nonischemic cardiac disease before CTrLVD. Breast can-
of LVEF below 50% if previously normal (≥55%), or (2) >10 per- cer and hematological diseases accounted for 40 and 57%
centage point loss if previously subnormal, in the absence of any
of the diagnoses of malignancy, respectively. CTrLVD
other explanation. Since anticancer treatments may be withheld,
stopped, or changed when a cardiovascular complication occurs, was attributed to anthracyclines (n = 6), trastuzumab
we considered a “change of treatment” any unscheduled delay or (n = 11), or allogeneic stem cell transplant (n = 10) in
variation lasting for more than two cycles of the cancer therapy. most cases. The mean duration of follow-up was 6.5
Continuous variables are presented as mean and standard de- months (median 5.6, interquartile range: 4.2–7.2).
viation, unless otherwise specified. Hypothesis testing was per-
The main clinical and echocardiographic results are
formed using Student’s t test for paired data (continuous variables)
and the Wilcoxon signed-rank test (ordinal variables), and a two- represented in Figure 1 and Table 1. NYHA class amelio-
tailed p < 0.05 was considered significant. The duration of the ob- rated in 11 patients, while 1 patient referred functional
servation period was normalized by log-transformation. Correla- class worsening, but further testing revealed an opportu-
tions between LVEF change and other continuous variables were nistic pneumonia. Eight patients reported resolution or
assessed by Pearson’s correlation test, while Kendall’s test was used
improvement of fatigue. Mean LVEF increased from
for New York Heart Association (NYHA) class. Associations in-
volving LVEF change were also examined in a univariate and mul- 45.1% (SD = 6.4) to 53.2% (SD = 3.9; p < 0.001). The ex-
tivariate linear regression model with heart rate change and the tent of LVEF improvement was slightly correlated to a
observation period as covariates. longer observation period (r2 = 0.18; p = 0.02). Neverthe-
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Ivabradine in Cardiotoxicity Chemotherapy 2018;63:315–320 317


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


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


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Statement of Ethics Funding Sources

The study was approved by the local institutional review board. This study received no external funding.
All procedures in the study were in accordance with national stan-
dards and the Helsinki declaration.
Author Contributions

Disclosure Statement Study design: M.S., E.A., G.G., C. Brunelli, P.S. Manuscript ed-
iting: M.S., G.G., P.S. Data collection and analysis: M.S., R.M., C.
Dr. Paolo Spallarossa received speaker honoraria from Servier. Bighin, F.G., V.S., M.B., P.S. Manuscript revision and approval: all
The other authors have no conflicts of interest to disclose. authors.

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