REVIEW ARTICLE

A Systematic Review on Cardioprotection Strategies

to Prevent Breast Cancer Therapy Cardiotoxicity
Sidhi Laksono 1.2*, Nathania Purnomo 3, Hillary Kusharsamita 4
1
.Department of Cardiology and Vascular Medicine, Diagram Heart Hospital Siloam Cinere, Indonesia
2
.Faculty of Medicine, Universitas Muhammadiyah Prof Dr Hamka, Tangerang, Indonesia
3
.Department of Emergency Medicine, TB SImatupang Siloam Hospital, South Jakarta, Indonesia
4
.Department of Emergency Medicine, Pertamina Central Hospital, South Jakarta, Indonesia

ARTICLE INFO ABSTRACT

Received : 23 December 2022
Reviewed : 24 January 2023
Accepted : 06 April 2023
Keywords:
cardioprotection strategies,
cardiotoxicity, cancer-therapy-
related cardiac dysfunction
Background: Breast cancer is the most prevalent malignancy among women on a global scale,
affecting an average of 2.1 million individuals annually. In addition, several studies have shown
that it is often treated using chemotherapy drugs and targeted therapy, but these treatment
methods have been reported to have side effects on the cardiovascular system. This indicates
that there is a need to develop new and effective strategies to prevent the associated side
effects. Therefore, this systematic review aims to obtain cardioprotection strategies to prevent
cardiotoxicity in breast cancer patients receiving chemotherapy or targeted therapy.
Methods: Data collection was carried out using the online database PubMed with keywords
((cardioprotection) AND (breast cancer therapy) AND (cardiotoxic) OR (Cardiac dysfunction.))
From the initial search, a total of 150 studies were obtained, while articles that did not meet the
eligibility criteria were excluded. Furthermore, the articles were reviewed using full-text reading,
leading to the inclusion of nineteen in this systematic review.

*Corresponding author:
Sidhi Laksono
Faculty of Medicine, Universitas
Muhammadiyah Prof Dr Hamka,
Tangerang, Indonesia
sidhilaksono@uhamka.ac.id
Results: A total of eleven studies evaluated the effect of cardio-protective drugs on Anthracycline
(ANT), and nine assessed Trastuzumab. The results showed that eight studies used Beta-blocker
(BB) as cardio-protective strategies, while one, one, three, two, one, one, and one utilized
Angiotensin receptor blockers (ARB), ARB + Beta-blocker, ACE-inhibitor (ACE-I) + Beta-blocker,
ACE-I/ARB/BB, spironolactone, statin, and Dexrazoxane (DZR), respectively. In large reports, the
risk of CTRCD was reduced by the use of a combination of RAAS inhibitors and Beta-blockers.
Furthermore, spironolactone, statins, and DZR mitigated the decrease in LVEF compared to the
control group in small studies
Conclusions: Based on the results, chemotherapy decreased left ventricular ejection fraction
(LVEF) and induced heart failure. Furthermore, the review showed that a combination of renin-
angiotensin-aldosterone system (RAAS) inhibitors and Beta-blockers reduced CTRCD. Future
studies in larger settings were needed to investigate the efficacy of other strategies, such as
statins, Spironolactone, exercise, and DZR.

INTRODUCTION advancements in early detection and advanced cancer

Breast cancer is widely recognized as the most
prevalent malignancy affecting women globally. The
condition affects over 2.1 million women annually,
making it the leading cause of cancer-related mortalities.
According to previous studies, breast cancer has claimed
the lives of over 627,000 patients, accounting for 15%
of all female cancer-related deaths [1]. Despite significant
therapies, such as targeted therapy, the number of
long-term survivors has been reported to be on an
increasing trend. However, these treatments have also
been reported to have acute and chronic side effects.
Among these, cardiovascular complications stand out
as the most common, posing a threat to both the quality
of life and the life span of survivors [2].

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DOI: http://dx.doi.org/10.33371/ijoc.v17i4.996
CTRCD, Cardioprotection Strategies
The use of cancer therapy, including chemotherapy
and targeted therapy, has been associated with an
elevated risk of cardiotoxicity or CTRCD (Cancer-Therapy
Related Cardiac Dysfunction) [3]. Anthracycline (ANT) is
a dose-dependent and primary chemotherapeutic agent
for the treatment of breast cancer in adjuvant and
metastatic conditions. Furthermore, the administration
of ANT with a cumulative dose of 400 mg/m2 increases
the morbidity of heart failure by 5%, which escalates
to 16% at 500 mg/m2, and peaks at 48% at 700 mg/m2.
ANT is well known for its irreversible cardiotoxicity
effect, necessitating interruptions or cessation of
chemotherapy. Several studies have shown that
discontinuing its usage can lead to unfavorable cancer
prognosis outcomes [4]. Trastuzumab is a HER2-targeted
therapy in breast cancer patients with HER2-positive
tumors. The treatment has demonstrated its efficacy
in increasing survival rates by reducing the risk of
recurrence in the adjuvant setting and prolonging
survival in metastatic disease. Compared to Anthracycline,
which is associated with irreversible cardiomyocyte
necrosis, Trastuzumab is known for causing fully or partly
reversible cardiotoxicity [5]. The sequential use of ANT
and Trastuzumab has been linked to a higher risk for
CTRCD. In this context, 7.5% of patients experienced
asymptomatic reduction in left ventricle (LV) systolic
function, and 2% of sufferers developed symptomatic
heart failure [6]. A multicentre cohort study comprising
10,209 breast cancer survivors reported that the five-
year incidence of heart failure was 4.5% for patients
treated with ANT and Trastuzumab therapy, compared
to 0.8% for others treated with only ANT [7].
The occurrence of LV dysfunction, heart failure, or
cardiomyopathy can manifest during or after the
completion of cancer therapy. Cardiotoxicity is
characterized by a reduction in left ventricular ejection
fraction (LVEF) by 10% from baseline, leading to an LVEF
value falling below the normal range of < 53% [8]. This
indicates that cardioprotective management and
strategies are needed to minimize the CTRCD. Therefore,
this systematic review aims to discuss the efficacy and
recommendations of prophylactic cardio-protection.
MATERIAL AND METHODS
Search Strategy
A literature systematic search for journals online
was carried out with the keywords ((cardioprotection)
AND (breast cancer therapy) AND (cardiotoxic) OR
(Cardiac dysfunction.)). Journals containing randomized
control trials (RCT) on breast cancer patients receiving
chemotherapy and/or targeted therapy were included.
Patients also received drugs that were known to function
in the treatment of heart failure. Relevant titles and
abstracts were chosen and evaluated using the PRISMA
search strategy.
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SIDHI LAKSONO, ET AL
Eligibility criteria were used for inclusion, including
i. Randomized controlled trial (RCT) or cohort studies;
ii. Breast cancer patients ≥18 years old; iii. Breast cancer
therapy with Anthracycline and/or Trastuzumab; iv.
Intervention with any form of cardio-protection strategy
during breast cancer therapy; v. Studies needed to
report the cardiotoxicity outcomes with changes in LVEF;
vi. Timing of outcome was anytime; vii. The study was
published from 2012–2022. The exclusion criteria
included studies written in other than English and full-
text access was not available
Study Selection
A total of two independent reviewers selected the
articles, extracted data, and conducted the analysis.
Furthermore, potential titles and abstracts were assessed
further for full-text evaluation. Any disparities were
resolved by consensus between the reviewers.
Disagreements between reviewers were settled by
consensus or the decision of a third independent
reviewer when needed. In this review, any disagreement
was resolved by consensus by reaching a common
understanding through discussions. The reviewers
evaluated the titles and abstracts for all studies using
the PRISMA search strategy. References in reviewed
and excluded papers were examined to identify studies
that were not identified through the primary search
strategy. The search was limited to the English language,
and a list of potential articles for inclusion in the
systematic review was generated through the process
Data Extraction
Extracted data included details regarding the study
name or authors, year of publication, study type, the
total number of participants, type of breast cancer
chemotherapy, cardioprotection strategy, and description
of primary outcomes. Furthermore, the data extraction
process was conducted by all authors during the review.
Outcome Definition
The primary outcome was the effect of cardio-
protection therapy in preventing cardiotoxicity among
breast cancer patients undergoing chemotherapy or
targeted therapy. The cardio-protective effect was
defined by a reduction in mean LVEF by ≥10% or more
from any baseline value, in the intervention group
compared to the control group.
Quality Assessment
The quality of each study was assessed using the
Cochrane Risk of Bias tool for randomized trials (RoB 2)
and the Newcastle-Ottawa Scale (NOS) for cohort and
case-control studies. Each RCT was evaluated for random
sequence generation, allocation concealment, blinding
of outcome assessment, incomplete outcome data,
selective outcome reporting, and other potential sources
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of bias. The result of each judgment could be a “High,”
“Low,” or “Some Concerns” risk of bias. For cohort and
case-control studies, the selection, comparability, and
outcome were evaluated. Each study was then graded
as “Good,” “Fair,” or “Poor” quality. Furthermore, it
was assessed independently by two reviewers, and
disagreements were resolved by consensus through
discussions.
RESULTS
A total of 150 articles were identified through the
electronic search strategy. Figure 1 shows the resultant
PRISMA diagram (Preferred Reporting Items for
Systematic Reviews and Meta-Analysis). After the
removal of duplicate articles by screening the titles and
abstracts, a total of 120 studies were excluded because
they did not meet the inclusion criteria. For example,
the objects were mice or cell cultures, treated with
herbal therapies, the language was in Chinese, and
published before the year 2012. The full paper of the
Figure 1. PRISMA flow diagram
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SIDHI LAKSONO, ET AL
remaining 30 studies was retrieved for further evaluation.
Among these, 11 studies were excluded, because two
reported other types of cancer, one was an ongoing
trial, one was only published in Chinese, two did not
possess full text, two were study protocol, and two
were editorial comments. Therefore, a total of 19
selected publications were included in this systematic
review. Decreased heart function caused by the
administration of chemotherapy drugs or targeted
therapy to breast cancer patients could lead to heart
failure. In this review, it was found that the use of
RAAS inhibitors and beta-blocker drugs reduced the
incidence of cardiotoxicity.
Study Characteristics
The study design and population characteristics of
included studies are presented in Table 1. Mean patient
ages ranged from 40-57 years old, and some studies
included cardiac disease and the use of heart drugs.
Furthermore, all the study participants were only breast
cancer patients.
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A total of 19 eligible studies were found, consisting
of 2 cohort studies, 16 trials, and 1 retrospective case-
control. The breast cancer treatments were ANT and
Trastuzumab. Eleven reports assessed the effect of the
cardio-protective drug on ANT and nine assessed the
impact of Trastuzumab. The type of ANT used in all
the studies was Doxorubicin and Epirubicin.
LVEF with echocardiography, cardiac MRI, MUGA,
and echocardiography and MUGA were analyzed in 15
[9-13,15-22,25,26], 2 [14,23], 1 [27], and 1 [24] studies,
respectively. Cardiac biomarkers, such as NT-pro-BNP,
cardiac troponin, and cardiac troponin T were examined
in 3 [12,16,22], 3 studies [11,14,16], and 2 [18,22]
studies, respectively. A total of 3 articles described the
interruption of Trastuzumab therapy because of
cardiotoxicity and LV dysfunction [23,24,27].
The mean follow-up time for echocardiography
outcome ranged between 14 days and 3.5 years after
the beginning of chemotherapy, with most reports’
follow-up time being 6 months. A total of four studies
had follow-ups of 3 months[10,18,19,20], while 2 studies
had a time range of 3.5 years [25,26].
Based on the results, eight, one, one, three, two,
one, one, one, and one studies used Beta-blocker as
cardio-protective strategies[9-13,19-21], ARB [22], a
combination of ARB and Beta-blocker [14], a combination
of ACE-inhibitor (ACE-I) and Beta-blocker [15,23,24], a
combination of ACE-I/ARB/BB [25,26], spironolactone
[16], statin [27], Dexrazoxane [17], and exercise [18],
respectively.
Comparators were placebo or control groups with
no intervention. Among eight studies using Beta-blockers
alone, six studies used Carvedilol [9–11,19–21], with
doses ranging from 6.25 mg titrated to 25 mg twice a
day, with one study utilizing a combination of Carvedilol
10 mg and Lisinopril 10 mg [24]. Furthermore, metoprolol
was used in one study, compared with the use of
Candesartan [14]. In one article, Bisoprolol was started
24 hours before chemotherapy, with a starting dose of
1.25 mg and the combination of Lisinopril 2.5 mg, both
were titrated until they reached a target dosage of 10
mg [15]. Another report used Bisoprolol 2.5 mg and
Perindopril 2 mg, initiated 7 days before the start of
chemotherapy and was titrated as tolerated, with target
doses of 10 mg and 8 mg, respectively [23]. A total of
two studies utilized Nebivolol 5 mg as the main
treatment agent [12,13]. Dexrazoxane was administered
in one report and started 30 minutes before ANT [17].
Spironolactone 25 mg was reported in only one study
and was given 1 week before the therapy [16]. Vigorous
intensity exercise of 30 minutes that was performed
24 hours before each chemotherapy until the 4th cycle,
was used as a cardioprotective strategy in one article
[18]. Statins in moderate to high intensity (Atorvastatin
20 mg, Rosuvastatin 10 mg, Simvastatin 20 mg, and
Pravastatin 20 mg) were used in another article [27].
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Candesartan 16 mg was used in one study, started on
the first day of chemotherapy administration, and
titrated until a final dose of 32 mg [22]. A total of two
studies did not specify the drug names of RAAS inhibitors
and B-blockers [25,26].
Primary Outcomes
The outcomes assessed by this systematic review
were the change in mean LVEF by 10% or more from
the baseline value. LVEF was examined two times, by
comparison of the value before chemotherapy in the
control group and intervention group with the value
obtained after follow-up in each study. LVEF was
evaluated by echocardiography, cardiac MRI, or MUGA.
The results showed that carvedilol was not significant
in preventing the reduction of LVEF >= 10% from
baseline (p-value > 0.05 in seven studies) during ANT
or Trastuzumab therapy [9–11,19–22]. This effect was
observed in 3 months, 6 months, and 12 months from
the first day of chemotherapy. According to Farahani
et al. [19], Carvedilol 6.25 mg twice a day during
Trastuzumab therapy increased the LVEF by 0.28% from
baseline, but the p-value was not significant.
Cochera et al. [13] reported the use of Nebivolol 5
mg on 60 participants throughout the duration of the
6th cycle of Doxorubicin therapy. The results showed
that the treatment was not significant in causing changes
to LVEF. However, Kaya et al. [12] reported a significant
impact of Nebivolol 5 mg (p = 0.01) in preventing the
decrease of LVEF during Epirubicin therapy in 6 months
follow-up. The treatment was given 7 days before the
start of chemotherapy until the end of the process.
Boekhout et al. [22] studied the effect of Candesartan
16 mg in 210 patients who underwent Trastuzumab
therapy with/without ANT therapy. This study found no
difference in the reduction of LVEF between the treatment
group and the placebo group. However, the value in the
Candesartan group was found to be reduced by 3%,
compared to the reduction of 1.2% in the placebo group.
A study by Gulati et al. [14], which was a PRADA
trial, reported the use of Metoprolol and Candesartan
versus placebo in 130 patients receiving ANT with or
without Trastuzumab during 18 months of the follow-
up period. Candesartan was started on 8 mg and titrated
as tolerated until the target dose of 32 mg, as well as
Metoprolol, which was started on 50 mg and finally
reached 100 mg. In the Candesartan group, there was
a significant decrease in LVEF reduction (-0,8%, p-value
= 0.026) compared to the Metoprolol and Placebo group.
Wihandono et al. [15] evaluated the combination
of Lisinopril and Bisoprolol in 51 patients who underwent
the 6th cycle of ANT therapy. The treatment was started
24 hours before the 1st cycle of chemotherapy. Lisinopril
and Bisoprolol were started from the smallest dose,
which was 2.5 mg and 1.25 mg, respectively until it
reached the maximal dose of 10 mg. The decline of
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LVEF was significantly reduced in the combination group
compared to the placebo group (p-value 0.017). The
effect of Lisinopril was also observed in the study by
Guglin et al. [24], alongside the impact of Carvedilol
and placebo at 2 2-year follow-up. The results showed
that there was no significant difference in LVEF reduction
> 10% from baseline value in all of the groups. However,
the interruption caused by cardiotoxicity (decrease in
LVEF) was lower in patients who received Lisinopril and
Carvedilol, namely 30%, 29%, and 32% of the lisinopril,
carvedilol, and placebo groups. Pituskin et al. [23], in
the MANTICORE trial, reported the impact of a
combination of Perindopril and Bisoprolol that was
initiated within 7 days before the start of chemotherapy.
Bisoprolol and Perindopril attenuated the decline in LVEF
by -1% and -3%, respectively, with a p-value of 0.001.
In a study by Khoury et al. [25], the SAFE-HEaRt
trial, in the long-term follow-up of 3.5 years reported
improvement of LVEF (+7.2%) compared to baseline.
The study used B-blockers and/or ACE-I/ARB but did
not specify the name of the drugs. Ohtani et al. [26]
also reported that heart failure treatments (Renin-
Angiotensin Inhibitors and/or B-blockers) decreased its
reduction and enhanced the functional reversibility of
LV systolic dysfunction.
The cardio-protective effect of Spironolactone 25 mg
was reported in one study by Akpek et al. [16]. The
treatment was started one week before chemotherapy
and was followed up for six months. Furthermore,
spironolactone significantly reduced the decrease in LVEF
compared to the control group with a p-value < 0.001.
A study by Kim et al. [17] evaluated the impact of
Dexrazoxane (DZR) which was administered 30 minutes
before Doxorubicin. LVEF was higher in the DZR group,
hence, DZR reduced cardiac toxicity and delayed the
timing of cardiac toxicity (p < 0.001). Moderate to high
intensity of statin was observed in the study by Calvillo
et al. [27] with a follow-up duration of 11 months.
Statin lowered the reduction of LVEF (p 0.016) and the
risk of cardiotoxicity (OR 0.32, 95% CI 0.10–0.99, p =
0.049). Kirkham et al. [18] in a study utilizing exercise
as a cardio-protection strategy for treatment. Vigorous
exercise was started 24 hours before each chemo and
the intervention was carried out in thirty minutes. After
the 4th cycle of chemotherapy, the LVEF was evaluated
and there was no effect of exercise in attenuating the
reduction of LVEF. However, the study did not exclude
the use of cardiac medications.
DISCUSSION
This study reported the cardioprotective interventions
that had been tested by several randomized controlled
trials and cohort studies, including treatment with RAAS
inhibitors, beta-adrenoceptor blockers, statin,
Dexrazoxane, and exercise. Based on the results, the
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SIDHI LAKSONO, ET AL
cardioprotective effect of RAAS inhibitors (ACE-I, ARB)
and Beta-blockers were proven effective for the
treatment and prevention of heart failure. This indicated
that these drugs were beneficial in attenuating the
cardiotoxic impact of chemotherapy. However, the
outcomes of these medications and strategies as
cardioprotection on patients who underwent
chemotherapy varied. Included trials and studies
reported modest or no effect of the interventions on
the primary outcome of this review.
Several guidelines recommended the routine
measurement of ANT and trastuzumab-induced
cardiotoxicity through echocardiography, particularly the
LVEF [28,29]. According to previous studies, chemotherapy
reduced LVEF and induced the incidence of heart failure.
When heart failure was detected during a routine
echocardiography measurement, current oncologic
guidelines recommended suspending chemotherapy for
patients experiencing heart failure with a left ventricular
ejection fraction (LVEF) below 50%, a decline in LVEF
to less than 40%, or a substantial drop in EF (15%
absolute percentage points) to less than 50%. In such
cases, treatment with an ACE inhibitor (ACE-I) or an
angiotensin receptor blocker (ARB), along with a beta-
blocker must be initiated. Clinicians must also treat
patients with heart failure using standard care [30,31].
Apart from LVEF, other parameters that must be
carefully monitored include cardiac biomarkers. ESC and
AHA recommended NT pro-BNP as class 1A
recommendations in diagnosing patients with suspected
heart failure (HF). Changes in Troponin concentrations
could be used to predict cardiomyocyte injury. Therefore,
the measurement of cardiac biomarkers could evaluate
and predict the subsequent changes in LVEF and the
development of HF.
The end-points of this study were to evaluate the
positive effect of strategies that could prevent or reduce
the cardiotoxicity event during chemotherapy. Despite
the various results of the included studies, the reduction
of LVEF occurred only in a smaller proportion of patients
who received cardioprotective strategies. A similar
perspective was also seen in the interruptions of
chemotherapy due to heart failure occurrence. In most
studies, there was no interruption, while it occurred
at low levels in some studies in the cardioprotection
group.
This study had several limitations, including the use
of different ACE-I, ARB, Beta-blockers, statin, and other
strategies. Furthermore, there were different endpoints,
timing of intervention starting points, durations of
follow-up periods, and chemotherapy dose, making it
difficult to conclude the effects of these cardioprotective
interventions. The sample size was also very small and
could not represent the real populations. Some of the
included studies did not exclude the participants with
a history of heart disease (coronary artery disease (CAD),
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Hypertension, HF, valvular heart disease, arrhythmia),
and cardioactive medications (ACE-I, statin, CCB, ARB,
B-blockers, anti- aldosterone, and other adrenergic beta-
blockers). Further studies are advised to include larger
populations with homogeneity of pre-existing conditions
and the same timing of cardioprotective therapy
administration, as well as a longer follow-up period.
The early diagnosis of heart failure could also be
measured by the value of strain and strain rate
parameters, apart from LVEF. In previous studies, LVEF
was found to be reduced after a late period of toxic
damage to the myocardium. Therefore, another
assessment, such as GLS or other strain endpoints could
be a sensitive method to detect the early signs of
myocardial damage. Cardiac biomarker sampling must
also be monitored closely during chemotherapy cycles
as the early checkpoint of cardiotoxic effects.
CONCLUSIONS
This systematic review suggested the cardioprotective
effect of RAAS inhibitors or Beta-blockers in reducing
CTRCD (Cancer-Therapy Related Cardiac Dysfunction).
Other strategies, such as statins, Spironolactone,
exercise, or DZR must be evaluated in more studies,
as the data included in this systematic review were
limited. Studies on the accurate effect of cardioprotective
strategies must be continued to develop more targeted
approaches.
DECLARATIONS
Competing interest
The authors declare no competing interest in this study
Ethics approval and consent to participate
Not applicable
Funding
The authors declare no source of funding in this study
Acknowledgment
None
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