Received: 7 November 2017 Revised: 3 June 2018 Accepted: 4 June 2018

DOI: 10.1002/pbc.27308

Pediatric
RESEARCH ARTICLE Blood &
The American Society of
Cancer Pediatric Hematology/Oncology

Role of ACE inhibitors in anthracycline-induced cardiotoxicity:

A randomized, double-blind, placebo-controlled trial

Vineeta Gupta1 Sunil Kumar Singh1 Vikas Agrawal2 Tej Bali Singh3

1 Department of Pediatrics, Institute of Medical

Sciences, Banaras Hindu University, Varanasi, Abstract

India Background: Several measures including drugs have been tried to reduce anthracycline cardiotox-
2 Department of Cardiology, Institute of Medical
icity. The lack of randomized trials prompted this study to assess the role of an angiotensin con-
Sciences, Banaras Hindu University, Varanasi, verting enzyme (ACE) inhibitor (enalapril) in anthracycline-induced cardiotoxicity in children with
India
hematological malignancies.
3 Division of Biostatistics, Department of Com-

munity Medicine, Institute of Medical Sciences,
Banaras Hindu University, Varanasi, India
Correspondence
Vineeta Gupta, Professor, Division of
Hematology Oncology, Department of
Pediatrics, Institute of Medical Sciences, Banaras
Hindu University, Varanasi 221005, India.
Email: vineetaguptabhu@gmail.com
The abstract of this paper was presented as
an oral presentation at the 49th Congress of
International Society of Pediatric Oncology,
Washington, DC, USA, October 12–15, 2017
Methods: A randomized, double-blind, placebo-controlled trial was conducted on 84 patients with
leukemia (41) and lymphoma (43) who received anthracyclines (doxorubicin and/or daunorubicin)
at cumulative dose ≥200 mg/m2 . The patients were randomized to receive either enalapril [group
A (n = 44)] or placebo [group B (n = 40)] for 6 months. Left ventricular ejection fraction (LVEF) and
cardiac biomarkers (cardiac troponin I [cTnI], probrain natriuretic peptide [proBNP], and creatine
kinase MB [CK-MB]) were assessed at baseline and 6 months. The primary outcome was a mea-
sured decrease in LVEF (≥20%). Secondary outcome measures were changes in cardiac biomark-
ers and the development of heart failure or arrhythmias.
Results: LVEF decreased in both groups at 6 months, more so in group B (62.25 ± 5.49 vs
56.15 ± 4.79, P < 0.001). A ≥20% decrease was seen in 3 patients in group B but none in group
A (P = 0.21). Cardiac biomarkers increased more in group B at 6 months, and the increase was
significant for proBNP (49.60 ± 35.97 vs 98.60 ± 54.24, P < 0.001) and cTnI (0.01 ± 0.00 vs
0.011 ± 0.003, P = 0.035) but not significant for CK-MB (1.08 ± 0.18 vs 1.21 ± 0.44, P = 0.079). In
group A, 9.1% of the patients showed an increase in proBNP level ≥100 compared with 37.5% in
group B (P < 0.001). No patient developed heart failure or arrhythmia.

Conclusion: Enalapril has a role in reducing cardiac toxicity after anthracycline administration.

KEYWORDS
angiotensin converting enzyme inhibitor, anthracyclines, cardiotoxicity, late effects

1 INTRODUCTION Anthracyclines are a key component of many cytotoxic regimens

Over the past several decades, there has been a significant improve-
ment in the survival rate of children with cancer due to the introduction
of new therapeutic strategies. Five-year survival for childhood malig-
nancies is almost 80% now, resulting in a large number of childhood
cancer survivors. Unfortunately, improved survival is associated with
numerous adverse effects of treatment that may not manifest clini-
cally for several years.1,2 One of the serious late effects of treatment
is cardiotoxicity.3 Treatment-related cardiac dysfunction is mainly
attributed to the use of anthracyclines and mediastinal irradiation.
Abbreviations: ACE, angiotensin converting enzyme; CK-MB, creatine kinase MB; cTnI,
cardiac troponin I; LVEF, left ventricular ejection fraction; proBNP, probrain natriuretic
peptide; SD, standard deviation
and are incorporated in more than 50% of the pediatric treatment
protocols. Despite their success as antineoplastic agents, their use is
limited by cardiotoxicity.4 The cardiotoxic effects of anthracyclines
are variable and may range from asymptomatic electrocardiographic
abnormalities to long-term cardiomyopathy. Early identification of car-
diotoxicity and the measures to reduce it have been an area of research
in recent years. There are few studies that have shown a beneficial
effect of the angiotensin converting enzyme (ACE) inhibitor enalapril
in anthracycline-induced cardiotoxicity,5,6 but these were not random-
ized controlled trials carried out exclusively in pediatric patients.
The aim of the present study was to evaluate the role of enalapril
(an ACE inhibitor) in anthracycline cardiotoxicity, as measured by eval-
uation of left ventricular ejection fraction (LVEF) by 2-dimensional
echocardiography and levels of cardio-specific biomarkers [cardiac

Pediatr Blood Cancer. 2018;e27308. wileyonlinelibrary.com/journal/pbc 

c 2018 Wiley Periodicals, Inc. 1 of 6
https://doi.org/10.1002/pbc.27308
2 of 6
troponin I (cTnI), probrain natriuretic peptide (proBNP), and creatine
kinase MB (CK-MB)] at baseline and after 6 months of treatment with
anthracyclines. Our hypothesis was that the use of enalapril may have
a cardioprotective role in patients exposed to anthracyclines during
chemotherapy.
2 PATIENTS AND METHODS
The study was conducted in the Division of Hematology Oncol-
ogy, Department of Pediatrics, in collaboration with Department
of Cardiology and Biostatistics of the Institute of Medical Sci-
ences, Banaras Hindu University in Varanasi, India. This was a ran-
domized, double-blind, placebo-controlled trial (Trial registration no.
CTRI/2015/09/006174). The study was conducted from August 1,
2014, to September 30, 2016, over a period of 26 months. All chil-
dren receiving anthracyclines as part of their chemotherapy proto-
col were considered as a target population for the study. Children
whose projected cumulative anthracycline dose was ≥200 mg/m2
comprised the study population. The inclusion criteria were age 2–
16 years at the time of diagnosis, confirmed diagnosis of acute
lymphoblastic leukemia/lymphoma (Hodgkin and non-Hodgkin lym-
phoma), estimated cumulative anthracycline dose ≥200 mg/m2 , reg-
ular follow-up and willingness to participate in the study by giv-
ing “informed consent.” The exclusion criteria were relapsed disease,
previously treated (defaulter/irregular treatment), resting ejection
fraction < 50% or fractional shortening < 25%, preexisting cardiac
disease (valvular disease, cardiomyopathy), significant renal disease
(serum creatinine > 3 times normal and/or estimated glomerular fil-
tration rate < 30 mL/min/m2 , or significant hepatic disease (> 3 times
alanine aminotransferase/aspartate aminotransferate). The socioeco-
nomic status of patients was classified via the Kuppuswamy scale.7 The
nutritional status of patients and controls was evaluated according to
the Centers for Disease Control growth charts (2000). Patients were
treated with standard doses of chemotherapy as per the unit protocol.
The study was approved by the Institute Ethics Committee. Informed
written consent was obtained from parents/guardians.
2.1 Sample size
In a previous study on Indian pediatric patients receiving
anthracycline-based chemotherapy, 13 of 32 patients developed
cardiotoxicity, yielding an incidence of 40%.8 The incidence of
cardiotoxicity in this study was higher than the 7% cardiotoxicity
previously reported in another study,9 which may have been because
of a small sample size in the former. Because there were no studies
on Indian pediatric oncology patients, we based our hypothesis on
the Indian study. We hypothesized that with the use of the intended
drug in the intervention arm, the incidence of cardiotoxicity would
be reduced by 50%. With 𝛼 error of 10%, power of study 85% and
level of confidence 90%, the sample size was calculated to be 40
in each arm. To account for a dropout rate of 10%, the sample size
was kept at 45 in each arm. Patients fulfilling the inclusion criteria
were randomized into experimental/intervention and control groups
through computer-generated randomization tables.
GUPTA ET AL .
2.2 Intervention
Patients in the intervention arm were given enalapril (tab Envas; man-
ufactured by Cadila Pharmaceuticals Limited, Ahmedabad, Gujarat,
India) in a dosage of 0.1 mg/kg/day once a day from the first day
of chemotherapy for a period of 6 months. Patients in the control
group were given placebo. Both placebo and drug were dispensed in
sealed opaque envelopes. The placebo was prepared in the Depart-
ment of Pharmaceutics, Indian Institute of Technology, Banaras Hindu
University. Patients, as well as the treating doctor, were unaware of
the type of intervention. The patients were closely monitored for side
effects.
2.3 Evaluation
Two-dimensional echocardiography and estimation of cardiac
biomarkers (cTnI, proBNP, and CK-MB) were performed before start-
ing chemotherapy in all patients of both the intervention and control
arms (baseline evaluation). These investigations were repeated after
6 months in both groups (end of study). Cardiac biomarkers were
assessed by an Alere Triage Cardio3 Panel, which is a fluorescence
immunoassay. This assay was used with a point-of-care Triage Meter-
Pro instrument for quantitative measurements of cTnI, proBNP,
and CK-MB. Two-dimensional echocardiography was performed
by a single operator on an ACOSON CV70 cardiovascular system
(SIEMENS). The following values were considered as normal and
abnormal:
Cardiac biomarker Normal range Abnormal Unit
CK-MB 0.0–4.3 > 4.3 ng/mL
cTnI 0.0–0.02 > 0.02 ng/mL
proBNP 0.0–100 > 100 pg/mL
2.4 Outcome measures
The primary outcome measure was decrease in the incidence or
proportion of cardiotoxicity, where cardiotoxicity was defined as a
decrease in LVEF of ≥20% from baseline to 6 months. Although mea-
surement of LVEF is a relatively insensitive marker for the detection
of cardiotoxicity at an early stage, it has been the most commonly
accepted parameter of cardiac function.10 Adult guidelines have taken
an absolute decline of > 10% in LVEF for defining cardiotoxicity. How-
ever, no such guidelines could be found for pediatric patients. A relative
decrease of ≥20% from baseline was taken as significant in our study,
assuming that this will indicate significant myocardial damage and may
have clinical implications. Secondary outcome measures were levels of
cardiac biomarkers (cTnI, proBNP, and CK-MB) at 6 months and the
development of heart failure or arrhythmias during this period.
2.5 Statistical analysis
The data were analyzed using the statistical program SPSS version 16.0
(SPSS Inc., Chicago, IL, USA). The data are presented as the mean ±
standard deviation (SD) for continuous variables and as frequency with
their respective percentages for categorical variables. For categorical
variables, 𝜒 2 and Fisher exact tests were used. For comparing means of
GUPTA ET AL . 3 of 6

FIGURE 1 Flow diagram showing the randomization of patients

two groups, Student t test was used. A P value of < 0.05 was considered TA B L E 1 Demographic profile of the study population
statistically significant. Group A (enalapril) Group B (placebo)
No. of patients No. of patients
Parameters n = 44 (%) n = 40 (%) P value
Age (years), 8.85 ± 3.15 8.77 ± 2.86 0.90
3 RESULTS mean ± SD
Sex
Of the 98 patients enrolled in the study, 92 met the eligibility crite-
Male 31 (70%) 30 (75%) 0.64
ria. Eight patients were then excluded due to various reasons (irregular
Female 13 (30%) 10 (25%)
follow-up and subsequent withdrawal of consent). The remaining 84
Type of malignancy
patients were randomized into two groups. Forty-four patients were
randomized to group A (intervention group) and 40 patients to group B Acute leukemia 22 (50%) 19 (48%) 0.82

(placebo group). The flow of patient selection is presented in Figure 1. Lymphoma 22 (50%) 21 (52%)

Table 1 shows the demographic characteristics of the study pop- Cumulative 272.73 ± 78.62 263.64 ± 80.90 0.79
anthracycline
ulation. The mean ages of the patients were 8.85 ± 3.15 and dose (mg/m2 )
8.77 ± 2.86 years in the two groups. The majority of the patients
BMI (kg/m2 ), 12.38 ± 4.13 13.28 ± 2.86 0.25
were males. There were almost equal numbers of acute lymphoblas- mean ± SD
tic leukemia (high risk) and Hodgkin lymphoma cases. Patients in both Socio economic
the groups were comparable with respect to age, sex, socioeconomic status

status, body mass index (BMI), and type of malignancy. The cumulative Upper 05 (11%) 03 (8%) 0.81
doses of anthracyclines in groups A and B were 272.73 ± 78.62 and Middle 10 (23%) 09 (22%)
263.64 ± 80.90 mg/m2 (P = 0.79), respectively. Lower 29 (66%) 28 (70%)
Table 2 shows the number of patients with the percentage of
decrease in LVEF, using a cutoff of ≥20% in the two groups. None of
the patients in group A had a decrease in LVEF of ≥20%. In group pared between the two groups at 6 months (Table 3). The values were
B, 3 patients showed a ≥20% decrease in LVEF function, whereas 37 comparable at baseline but there was significant difference in LVEF
patients had a < 20% decrease in LVEF. The difference between the two at 6 months between groups A and B (62.25 ± 5.49 vs 56.15 ± 4.79,
groups was not statistically significant (P = 0.21). LVEF was also com- P < 0.001).
4 of 6 GUPTA ET AL .

TA B L E 2 Percentage decrease in LVEF in both groups
Percentage Group A (enalapril) No. Group B (placebo) No.
decrease of patients n = 44 (%) of patients n = 40 (%)
<20 44 (100%) 37 (92%)
≥20 0 3 (8%)
Total 44 (100%) 40 (100%)
P = 0.21
Table 3 shows the mean levels of cardiac biomarkers between
groups A and B at baseline and 6 months. There was a significant
increase in the mean level of cTnI in group B at 6 months. The lev-
els were 0.010 ± 0.00 and 0.011 ± 0.003 in groups A (intervention
group) and B (placebo group), respectively, at 6 months (P = 0.035).
Similarly, there was a significant increase in proBNP levels in group B
compared with group A at 6 months (49.60 ± 35.97 vs 98.60 ± 54.24).
The difference was highly significant (P < 0.001). However, there was
no difference in the mean levels of CK-MB between the two groups
(P = 0.079). The distribution of patients in the two groups taking a
cutoff for proBNP level as ≥100 pg/mL was also compared. Only 4
(9.1%) patients in group A had proBNP levels ≥100 pg/mL as compared
with 15 (37.5%) patients in group B. The difference was statistically
significant (P < 0.001).
4 DISCUSSION
Anthracyclines have been in use for almost five decades, but the mech-
anism of chemotherapeutic activity and cardiotoxicity is not very clear.
Free radical generation inducing lipid peroxidation and membrane
damage are some of the possible mechanisms of toxicity. The heart is
especially susceptible to this damage due to the high affinity of anthra-
cyclines for cardiolipin.11 Cardiotoxicity may be acute, early onset,
or late onset depending on the time of onset. Acute toxicity is seen
as a transient decrease in left ventricular contractility immediately
after anthracycline administration. Early-onset cardiotoxicity develops
within the first year after treatment, whereas late-onset cardiotoxicity
develops after one year of therapy and follows a chronic, progressive
course.
Cardiac biomarkers such as N-terminal proBNP, cTnI and cardiac
troponin T and CK-MB have been used to assess cardiotoxicity.12,13
Among these, proBNP has shown promise as an early marker of
late toxicity,14,15 and it also correlates with left ventricular systolic
and diastolic function.16 Toxicity is dose- and time dependent,
with more toxicity observed in patients receiving higher doses of
anthracyclines.17–19 Several cardioprotective strategies, such as lim-
iting the cumulative dose of anthracyclines; prolonging the dura-
tion of infusion without reducing the dose; the use of anthracycline
analogs and drugs including N-acetylcysteine, dexrazoxane, carvedilol;
and various ACE inhibitors, such as captopril and enalapril, have
been used as chemotherapy adjuvants to reduce oxidative stress
and minimize the production of free radicals in a bid to reduce
cardiotoxicity.20
In our study, we evaluated the levels of the cardiac biomarkers cTnI,
proBNP, and CK-MB along with the measurement of LVEF at base-
line before patients started chemotherapy and again after 6 months
of receiving chemotherapy with or without enalapril. Levels of all
three markers increased at 6 months in both the groups. However,
the increase was more pronounced in the placebo group compared
with the group that received enalapril with chemotherapy. This result
suggested that use of enalapril in patients receiving anthracyclines
had some protective effect on early-onset cardiotoxicity. When we
looked at the LVEF in the two groups, the values had decreased in
both, but the decrease was more pronounced in the placebo group.
When we compared our results with those from other studies, an
early study in adult patients receiving anthracyclines with or with-
out enalapril showed that there was a significant reduction in LVEF
and an increase in end-diastolic and end-systolic volumes in patients
who did not receive enalapril.5 The study concluded that early treat-
ment with enalapril seemed to prevent the development of late toxic-
ity. Another study that was very similar to ours measured cTnI CK-MB
and LVEF at 0 and 6 months in two groups of patients receiving anthra-
cyclines with or without enalapril. The authors concluded that enalapril
appeared efficacious in preserving systolic and diastolic functions.21
On the other hand, a small study conducted on childhood cancer sur-
vivors questioned whether or not use of ACE inhibitors improves
the long-term outcome of anthracycline-induced cardiomyopathy.6 In
that same study, improvements in echocardiographic parameters after
enalapril initiation did not persist after 6 years of treatment. All the
symptomatic children at the start of therapy either required a heart
transplant or experienced cardiac-related death. However, enalapril
was started very late in this study, at an average of 7 years after

TA B L E 3 Comparison of LVEF and cardiac biomarkers at 0 and at 6 months between groups

Group A (enalapril) Group B (placebo)

Variables Time period mean ± SD n = 44 mean ± SD n = 40 P value
LVEF 0 months 65.73 ± 5.41 64.85 ± 4.94 0.442
6 months 62.25 ± 5.49 56.15 ± 4.79 <0.001
cTnI 0 months 0.01 ± 0.00 0.01 ± 0.00 1.00
6 months 0.01 ± 0.00 0.011 ± 0.003 0.035
proBNP 0 months 5.00 ± 0.00 5.00 ± 0.00 –
6 months 49.60 ± 35.97 98.60 ± 54.24 <0.001
CK-MB 0 months 1.00 ± 0.00 1.00 ± 0.00 –
6 months 1.08 ± 0.18 1.21 ± 0.44 0.079
GUPTA ET AL .
doxorubicin treatment. A meta-review of 18 studies analyzing strate-
gies to reduce the risk of cardiotoxicity by employing medical inter-
ventions such as enalapril or phosphocreatine concluded that these
measures did not significantly improve EF or mortality. The studies
were conducted on an adult population.22 A similar review in childhood
cancer patients came across only two randomized clinical trials, one
of which compared enalapril with placebo in asymptomatic survivors
with cardiac dysfunction. There was some evidence that enalapril tem-
porarily improved one parameter of cardiac function, but it was unclear
whether enalapril improved the clinical outcome.23 In an update of this
study, the authors could not identify any additional studies.24 An Indian
study observed a high incidence of doxorubicin (adriamycin) toxicity in
the form of decreased LVEF or abnormality in myocardial movements
in children with solid tumors receiving a low cumulative dose of 180–
200 mg/m2 .8
A protective role of enalapril on anthracycline-induced early-onset
cardiotoxicity was found in the present study. The strengths of this
study are that it is a randomized placebo-controlled trial with an ade-
quate number of patients and good follow-up. A limitation of the study
is the relatively short follow-up of 6 months. It is not known if and how
long the protective effect of enalapril will last. It will be worthwhile to
follow-up with these children and assess their cardiac function at regu-
lar intervals. An additional study should be carried out in a larger num-
ber of children to see if the results can be duplicated. The abstract of
this paper was presented as an oral presentation at the 49th Congress
of International Society of Pediatric Oncology, Washington, DC, USA,
October 12–15, 2017.25
CONFLICT OF INTEREST
The authors have no conflict of interest.
ORCID
Vineeta Gupta http://orcid.org/0000-0002-3598-7533
REFERENCES
1. Landier W, Armenia S, Bhatia S. Late effects of childhood cancer and
its treatment. Pediatr Clin North Am. 2015;62:275–300.
2. Armstrong GT, Liu Q, Gietema JA, Cardiovascular toxicity caused by
cancer treatment: strategies for early detection. Lancet Oncol 2009;10:
391–399.
3. Altena R, Perik PJ, van Veldhuisen DJ, de vries EG, Gietema JA. Car-
diovascular toxicity caused by cancer treatment: strategies for early
detection. Lancet Oncol 2009;10:391–399.
4. Anderson B, Sawyer DB. Predicting and preventing the cardiotox-
icity of cancer therapy. Expert Rev Cardiovasc Ther. 2008;6:1023–
1033.
5. Cardinale D, Colombo A, Sandri MT, et al. Prevntion of high
dose chemotherapy induced cardiotoxicity in high risk patients
by angiotensin converting enzyme inhibition. Circulation. 2006;114:
2474–2481.
6. Lipshultz SE, Sambatakos P, Maguire M, et al. Cardiotoxicity and car-
dioprotection in childhood cancer. Acta Haematol. 2014;132:391–399.
5 of 6
7. Gadhave S, Nagarkar A. Kuppuswamy scale for measuring socio eco-
nomic status: revised monthly income figures for 2015. Indian J Pediatr.
2015;82:1175–1176.
8. Agarwala S, Kumar R, Bhatnagar R, Bajpai M, Gupta DK, Mitra DK. High
incidence of adriamycin cardiotoxicity in children even at low cumu-
lative doses: role of radionuclide cardiac angiography. J Pediatr Surg.
2000;35:1786–1789.
9. Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Sto-
vall M, et al. Cardiac outcomes in a cohort of adult survivors of child-
hood and adolescent cancer: retrospective analysis of the childhood
cancer survivor study cohort. BMJ. 2009;339:b4606.
10. Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer
treatments: epidemiology, detection and management. CA Cancer J
Clin. 2016;66:309–325.
11. Elliott P. Pathogenesis of cardiotoxicity induced by anthracyclines.
Semin Oncol. 2006;33:S2–S7.
12. Stevens PL, Lenihan DJ. Cardiotoxicity due to chemotherapy: the role
of biomarkers. Curr Cardiol Rep. 2015;17:603.
13. Christensen ES, James T, Agrawal V, Park BH. Use of biomarkers
for the assessment of chemotherapy-induced cardiac toxicity. Clin
Biochem. 2015;48:223–235.
14. Zidan A, Sherif LM, El-Sheikh A, et al. NT Pro BNP as early
marker of subclinical late cardiotoxicity after doxorubicin therapy
and mediastinal irradiation in childhood cancer survivors. Dis Markers.
2015;2015:513219.
15. Mladosievicova B, Urbanova D, Radvanska E, Slakovsky P, Simkova I.
Role of NT-proBNP in detection of myocardial damage in childhood
leukemia survivors treated with and without anthracyclines. J Exp Clin
Cancer Res. 2012;31:86.
16. Pongprot Y, Sittiwangkul R, Charoenkwan P, Silvilairat S. Use of
cardiac markers for monitoring of doxorubicin-induced cardiotoxi-
city in children with cancer. J PediatrHematol Oncol. 2012;34:589–
595.
17. Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysarrhythmias
6–19 years after anthracycline therapy: a series of 15 patients. Med
Pediatr Oncol. 1995;24:352–361.
18. Hudson MM. Anthracycline cardiotoxicity in long term survivors of
childhood cancer: the light is not at the end of tunnel. Pediatr Blood Can-
cer. 2007;48:649–650.
19. Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Car-
diotoxicity in childhood cancer survivors: strategies for prevention
and management. Future Cardiol. 2012;8. https://doi.org/10.2217/fca.
12.44.
20. Janababai G, Nabati M, Faqhihinia M, Azizi S, Borhani S, Yazdani J.
Effect of enalapril on preventing anthracycline-induced cardiomyopa-
thy. Cardiovasc Toxicol. 2017;17:130–139.
21. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Long-term enelapril therapy for
left ventricular dysfunction in doxorubicin-treated survivors of child-
hood cancer. J Clin Oncol. 2002;20:4517–4522.
22. Conway A, Mc Carthy AL, Lawrence P, Clark RA. The preven-
tion, detection and management of cancer treatment induced car-
diotoxicity: a meta review. BMC Cancer. 2015;15:366. https://doi.org/
10.1186/s. 12885-015-1407-6.
23. Sieswerda E, van Dalen EC, Postma A, Cheuk DK, Caron HN, Kre-
mer LC. Medical interventions for treating anthracycline-induced
symptomatic and asymptomatic cardiotoxicity during and after treat-
ment for childhood cancer. Cochrane Database Syst Rev. 2011;9:
CD008011.
24. Cheuk DK, Sieswerda E, van Dalen EC, Postma A, Kremer LC. Medi-
cal interventions for treating anthracycline-induced symptomatic and
6 of 6
asymptomatic cardiotoxicity during and after treatment for childhood
cancer. Cochrane Database Syst Rev. 2016;8:CD008011.
25. Gupta V, Singh SK, Agrawal V, Singh TB, Role of ACE inhibitors
in anthracycline induced cardiotoxicity: a randomized double-blind
placebo-controlled trial. Abstract presented at the 49th Congress of
International Society of Pediatric Oncology, Washington DC, USA,
October 12–15, 2017.
GUPTA ET AL .
How to cite this article: Gupta V, Kumar Singh S, Agrawal V,
Bali Singh T. Role of ACE inhibitors in anthracycline-induced
cardiotoxicity: A randomized, double-blind, placebo-controlled
trial. Pediatr Blood Cancer. 2018;e27308. https://doi.org/10.
1002/pbc.27308