European Journal of Heart Failure (2015) 17, 81–89

doi:10.1002/ejhf.196

Protective effects of spironolactone against

anthracycline-induced cardiomyopathy
Mahmut Akpek1*, Ibrahim Ozdogru1, Omer Sahin1, Mevlude Inanc2, Ali Dogan1,
Cevat Yazici3, Veli Berk2, Halit Karaca2, Nihat Kalay1, Abdurrahman Oguzhan1, and
Ali Ergin1
1 Erciyes
University, Department of Cardiology, Kayseri, Turkey; 2 Erciyes University, Department of Medical Oncology, Kayseri, Turkey; and 3 Erciyes University, Department of
Biochemistry, Kayseri, Turkey

Received 13 May 2014; revised 30 September 2014; accepted 10 October 2014 ; online publish-ahead-of-print 20 November 2014

Aims The protective effect of beta-blockers, ACE inhibitors, and ARBs on anthracycline cardiotoxicity has
already been demonstrated, but the effect of aldosterone antagonism, which inhibits the last step of the
renin–angiotensin–aldosterone system (RAAS), was questioned. This study sought to investigate whether
spironolactone protects the heart against anthracycline-induced cardiotoxicity.
.....................................................................................................................................................................
Methods Eighty-three female patients who were diagnosed with breast cancer were included in the study. The study population
and results was randomized into spironolactone and control groups. A dose of 25 mg/day spironolactone was administered to
the patients in the spironolactone group. There were 43 patients (mean age 50 ± 11 years) in the spironolactone
group and 40 patients (mean age 51 ± 10 years) in the control group. LVEF decreased from 67.0 ± 6.1 to 65.7 ± 7.4
(P = 0.094) in the spironolactone group, and from 67.7 ± 6.3 to 53.6 ± 6.8 in the control group (P < 0.001). When
the general linear model was applied, the interaction of LVEF decrease between groups was significantly lower in
the spironolactone group than in the control group (P < 0.001). The diastolic functional grade of subjects in the
spironolactone group was protected (P = 0.096), whereas it deteriorated in the control group (P < 0.001).
.....................................................................................................................................................................
Conclusion We showed that spironolactone administration used simultaneously with anthracycline group chemotherapeu-
tics protects both myocardial systolic and diastolic functions. Spironolactone can be used to protect against
anthracycline-induced cardiotoxicity.
.....................................................................................................................................................................
Trial NCT02053974.
registration:
..........................................................................................................
Keywords Spironolactone • Anthracycline • Cardiomyopathy

is cumulative, dose dependent, and irreversible. Improvements in

Introduction
...........................

protective mechanisms against the cardiotoxicity of anthracycline

Anthracyclines are the cornerstone in the treatment of numer-
ous haematological and solid cancers.1,2 After the introduction of
anthracycline group chemotherapeutics in the treatment of can-
cers, great advances have been achieved, and the survival rate
has increased from 30% to 70%.3,4 The most common side effect
of anthracycline is cardiotoxicity, and this may limit its use and
increases the rate of mortality and morbidity.5 – 7 Cardiotoxicity
are important to prevent the discontinuance of these chemother-
apeutics.
Spironolactone is an aldosterone antagonist which blocks the
last step of the renin–angiotensin–aldosterone system (RAAS).
The RAAS is one of the most effective systems in remod-
elling of the myocardium in post-myocardial damage.8 Accord-
ing to previous studies, in patients with severe heart failure and

*Corresponding author. Erciyes University School of Medicine, Department of Cardiology, 38039 Kayseri, Turkey. Tel: +90 533 3774712, Fax: +90 352 4375273, Email:
mahmutakpek@yahoo.com

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
82 M. Akpek et al.

myocardial infarction, the administration of aldosterone antagonists or not the patient was going through the menopause. Adriamycin and

.............................................................................................................................................
in addition to standard therapy has positive effects, particularly on epirubicin were administered to the patients as anthracycline group
cardiac fibrosis and remodelling, and substantially reduces the risk chemotherapeutics. The patients were monitored for electrolyte
of both morbidity and death.9,10 In the present study, we tested the imbalance at certain periods (once every 2–3 weeks). Three weeks
after the end of chemotherapy regimens, spironolactone and the
hypothesis that RAAS blockade with spironolactone may reduce
placebo were stopped. The whole study population underwent a
the cardiotoxicity of anthracycline group chemotherapeutics.
physical examination. Complete blood cell count, serum electrolyte
levels, and liver and kidney function tests were re-evaluated. The
spironolactone treatment period was for 24.0 ± 2.9 weeks in the
Methods spironolactone group and the placebo treatment period was for
24.3 ± 2.9 weeks on average (P = 0.642).
Study population
A total of 90 consecutive breast cancer patients were prospectively
enrolled in the present study between September 2011 and October Transthoracic echocardiography
2012. The study protocol was approved by the Ethics Committee of
Erciyes University. Patients who were diagnosed with breast cancer and Transthoracic echocardiography (TTE) was performed for each patient
underwent an anthracycline chemotherapy protocol were assessed. 1 week before the start of chemotherapy. The baseline echocardio-
Three patients refused to participate in the study. Two patients were graphic measurements were recorded. Three weeks after the end of
unable to participate due to transport problems. Two patients were the chemotherapy regimens, each patient was re-evaluated with TTE
excluded from the study due to absenting themselves from the controls for any changes. The control TTE was performed before the radio-
without any justification, and due to the inability to communicate with therapy and trastuzumab adjuvant therapy for HER2-positive patients.
them via the telephone numbers they had given. Nineteen (48%) patients in the placebo group and 21 (49%) patients in
The exclusion criteria of the study were as follows: prior breast the spironolactone group underwent the left-sided radiotherapy pro-
cancer and/or prior anthracycline exposure history; LVEF <50%; use of tocol (P = 0.903).
ACE inhibitors, ARBs, or beta-blockers; creatinine >2 mg/dL; presence Two-dimensional echocardiography was performed by using a com-
of chronic kidney failure; potassium >5.3 mg/dL; presence of adrenal mercially available machine (Vivid 7® GE Medical System, Horten,
gland diseases; presence of severe liver failure; and co-morbidities such Norway) with a 2.5 MHz transducer for TTE during at least three
as coronary heart disease, hypertension, AF, and valvular heart disease. consecutive cardiac cycles. All patients were studied in the left lat-
In addition, male patients were excluded for the homogenization of eral recumbent position after a 10 min resting period. The Simpson’s
the study. Finally, 83 patients were included in the study and informed method in the two-dimensional echocardiographic apical four-chamber
consent was obtained from all patients. view was used to assess LVEF as recommended by the guidelines.11
From the parasternal long axis, via M-mode, LV end-diastolic diameter
(LVEDD), LV end-systolic diameter (LVESD), interventricular septum
thicknesses, and posterior wall thicknesses were recorded.
Study protocol In the apical four-chamber view, with pulse wave (PW) Doppler,
This is a prospective, randomized, placebo-controlled, and mitral peak early filling (E wave) velocity, mitral late diastolic filling (A
double-blind study. The study flow diagram is shown in Figure 1. wave) velocity, transmitral E/A ratio, and mitral deceleration time (Dt)
The study population was randomized into two groups. A dose of 25 were calculated. The PW tissue Doppler measurements were made
mg/day spironolactone (ALDACTONE® 25 mg) was given to the first from the apical images, and lateral wall velocities (including s, e’, and a)
group and a placebo was given to the other group. The fixed dose of were measured.
spironolactone of 25 mg/day was administered to the spironolactone
group during the study. Spironolactone and placebo were adminis-
tered 1 week before the start of chemotherapy. At the end of week
1, patients were monitored with the intent of detecting electrolyte Laboratory analysis
imbalance. The chemotherapy regimens of the patients were recorded. In all patients, antecubital venous blood samples for laboratory anal-
The choice of the protocol was left to the medical oncologist’s discre- ysis were drawn upon admission for TTE examination 1 week before
tion. The oncologists chose the chemotherapy protocols according to chemotherapy. The patients were monitored for electrolyte imbalance
individual characteristics of the patients including, age, tumour stage at certain periods (once every 2–3 weeks). Three weeks after the
and grade, histopathological properties of the tumour, and whether chemotherapy regimens, blood samples were drawn again from the

43 patients 43 patients
Spironolactone group Spironolactone group
Randomization

CT stopped
CT started

Drugs were started Drugs were started

Patients were monitored for
TTE One week Three weeks TTE
90 patients 83 patients before
electrolyte imbalance every
later
Blood samples were 2-3 weeks Blood samples were

drawn drawn

7 patients were 40 patients 40 patients

excluded Control group Control group

Figure 1 Study flow. CT, chemotherapy; TTE, transthoracic echocardiography.

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
Effects of spironolactone on anthracycline cardiomyopathy 83

antecubital vein. Blood samples were kept at –80∘ C until the measure- To this end, we evaluated the variables in the repeated measures with

........................................................................................................................................................................
ments for oxidative biomarkers. Complete blood count, NT-proBNP, a timing factor. A P-value <0.05 was considered as significant, and the
creatine kinase (CK), creatine kinase-MB (CK-MB), and troponin-I confidence interval (CI) was 95%. The SPSS statistical package for
were measured within 5 min of sampling in a blinded fashion. Complete Windows version 15.0 (SPSS Inc., Chicago, IL, USA) was used for the
blood count parameters were measured by Sysmex K-1000 autoanal- statistical analysis.
yser within 5 min of sampling in Erciyes University central laboratories.
Highly sensitive troponin-I was measured with ADVIA Centaur Tro-
ponin I-Ultra assay (Siemens Healthcare Diagnostics Inc.). The analytic Study approval
sensitivity of the assay is 0.006 pg/mL (6 × 10−6 ng/mL). Serum con- Medical ethical committee approval was obtained on 2 August 2011.
centration of CK and CK-MB was determined using the Abbott Archi- The study was retrospectively registered on 2 January 2014 on the
tect c16000 immunoassay system (Abbott Park, IL, USA). NT-proBNP clinicaltrials.gov website after completion of the trial. Clinicaltrials.gov
serum levels were measured using an IMMULITE® 2000 immunoassay ID: NCT02053974.
system (Diagnostic Products Corporation, Los Angeles, CA, USA).
Determination of the total antioxidative capacity (TAC) was per-
formed by using a photometric test system [ImAnOx® (TAC) Kit (KC
5200), Immundiagnostik AG, Bensheim, Germany]. Briefly, this deter- Results
mination is performed by the reaction of antioxidants in the sample The baseline characteristics are shown in Table 1. There were 43
with a defined amount of exogenously provided hydrogen peroxide patients (mean age 50 ± 11 years) in the spironolactone group and
(H2 O2 ). The antioxidants in the sample eliminate a certain amount
40 patients (mean age 51 ± 10 years) in the control group. The
of the provided H2 O2 . The residual H2 O2 is determined photometri-
baseline characteristics were similar between groups. Also, there
cally by an enzymatic reaction which involves the conversion of TMB
(3,3’, 5,5’-tetramethyllbenzidine) to a coloured product. Samples were was no difference between the groups in terms of chemother-
measured at 450 nm.12 apy protocols and of doses of total anthracycline administered.
Total oxidative capacity (TOC) was determined by measuring Haematological parameters of the study population are shown in
total lipid peroxides in plasma with a photometric enzyme-linked Table 2.
immunosorbent assay [PerOx® (TOC) kit (KC 5100), Immundiagnos- In respect of cardiac biomarkers, CK-MB levels did not change
tik AG]. The kit’s principle is the determination of the peroxides which during the treatment period (15.8 ± 5.3 vs. 17.3 ± 6.0 U/L,
is performed by the reaction of a peroxidase with peroxides in the sam- P = 0.229) in the spironolactone group, while they significantly
ple followed by the conversion of TMB to a coloured product. After increased (15.4 ± 6.8 vs. 21.7 ± 9.5 U/L, P = 0.001) in the control
addition of a stop solution, the samples are measured at 450 nm in a group (Table 3; Figure 2). Troponin-I levels were also significantly
microtitre plate reader.13 The quantification is performed by the deliv-
increased in both groups during the treatment period. The increase
ered calibrator. The percentage ratio of total oxidative capacity to total
was significantly higher in the control group than in the spirono-
antioxidative capacity level was accepted as the oxidative stress index
(OSI). lactone group (P = 0.006). Serum NT-proBNP levels increased
from 71 (48–125) pg/mL to 85 (51–100) pg/mL (P = 0.549) in the
spironolactone group. In the control group, serum NT-proBNP
levels increased from 70 (56–72) pg/mL to 100 (89–138) pg/mL
Statistical analysis (P = 0.089). In both groups, the increases did not reach signifi-
A sample size analysis was performed. According to the liter- cance; however, the increase of NT-proBNP in the spironolactone
ature and our previous studies, the reduction in LVEF due to group was lower than in the control group. With respect to
anthracycline-induced cardiotoxicity is ∼13 ± 7% (SD) if no prevention pre-/post-treatment oxidative markers, while TAC decreased sig-
is used. We estimated that we could protect ∼10% of the LVEF
nificantly in the control group (from 295.0 ± 47.5 to 250.4 ± 19.7
with the administration of spironolactone. According to sample size
μmol/L, P < 0.001), it also decreased in the spironolactone group
analyses, this study must recruit at least 20 individuals for each group
to have 90% power with 5% type 1 error level to detect a minimum (from 286.1 ± 44.7 to 275.4 ± 37.6 μmol/L, P = 0.083), but did not
clinically significant difference of 10% in LVEF between groups after reach significance. The change in TAC levels between groups dur-
the treatment period. Thus, we performed a power analysis according ing the treatment period was significantly different in the general
to changes in LVEF between groups in repeated measures and found linear model (P = 0.001). While TOC increased in both groups,
a power of >0.978 for the present study. Continuous variables were the increase in the control group was higher than in the spirono-
tested for normal distribution by the Kolmogorov–Smirnov test. lactone group, but neither of them reached significance. The OSI
The variables are expressed as means ± SDs or median (interquartile did not change significantly (1.61 ± 0.80 vs. 1.79 ± 0.79, P = 0.282)
range). Numerical variables were compared using the Student’s t-test in the spironolactone group after anthracycline treatment, while
or Mann–Whitney U statistical test, as appropriate. Categorical it increased significantly in the control group (1.60 ± 0.90 vs.
variables are presented as percentages, and compared with the 𝜒 2
2.37 ± 1.45, P = 0.004). The interaction of change in OSI between
test. Two-tailed paired sample t-test was used for comparisons of
groups did not reach significance in the general linear model
parameters before and after treatments in all subjects, and ordinal
variables were compared with Wilcoxon signed rank test. The Spear- (P = 0.055).
man correlation coefficient was examined to evaluate the degree of The pre- and post-treatment echocardiography values of the
association between the anthracycline dosage taken and the LVEF. study population are given in Table 4. The LVEF decreased from
The general linear model was used to investigate the significance of 67.0 ± 6.1 to 65.7 ± 7.4 (P = 0.094) in the spironolactone group
changes of numerical values with treatment period between groups. and from 67.7 ± 6.3 to 53.6 ± 6.8 (P < 0.001) in the control group

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
84 M. Akpek et al.

Table 1 Baseline characteristics of the study population

Spironolactone group (n = 43) Control group (n = 40) P-value

...........................................................................................................................................
Age (years) 50.0 ± 10.8 50.6 ± 10.1 0.784
Height (cm) 157 ± 6 156 ± 7 0.326
Weight (kg) 72.4 ± 10.7 74.2 ± 10.5 0.453
Body surface area (m2 ) 1.72 ± 0.12 1.72 ± 0.14 0.995
Stage of tumour 0.100
1 (%) 1 (2%) 4 (10%)
2 (%) 17 (40%) 9 (23%)
3 (%) 23 (54%) 21 (53%)
4 (%) 2 (5%) 6 (15%)
Chemotherapy protocol 0.367
FEC 100 (%) 9 (21%) 4 (10%)
AC + P (%) 14 (33%) 15 (38%)
CEF 75 (%) 19 (44%) 17 (43%)
TAC (%) 1 (2%) 2 (5%)
AT (%) 0 (0%) 2 (5%)
Surgery
Modified radical mastectomy (%) 27 (63%) 19 (48%) 0.197
Breast-conserving surgery (%) 15 (35%) 19 (48%)
Surgery prior to chemotherapy (%) 42 (98%) 38 (95%) 0.514
Total adriamycin dose (mg) 430.2 ± 52.2 394.2 ± 71.9 0.123
Total epirubicin dose (mg) 688.9 ± 136.0 726.6 ± 120.5 0.316
Spironolactone or placebo treatment period (weeks) 24.0 ± 2.9 24.3 ± 2.9 0.642

Values are mean ± SD or n (%).

AC, adriamycin, cyclophosphamide; AT, adriamycin, docetaxel; CEF, 5-flourouracil, epirubicin, and cyclophosphamide; FEC, 5-flourouracil, epirubicin, and cyclophosphamide;
P, paclitaxel; TAC, docetaxel, adriamycin, cyclophosphamide.

(Figure 3). The decrease in LVEF in the control group was signifi- Discussion
.............................................................................

cantly higher than that in the spironolactone group (P < 0.001). In

addition, there was a significant positive correlation in the placebo In the present study, we showed that anthracyclines have adverse
group between total dose of anthracycline and LVEF deterioration effects on the myocardium. Anthracyclines cause deterioration of
that is supported by the literature (r = 0.655, P = 0.001 for epiru- both systolic and diastolic functions. In addition, anthracyclines
bicin and r = 0.717, P = 0.001 for adriamycin) (Figure 4). have a pro-oxidant effect. There are three major findings of the
Mitral E velocity decreased significantly in both groups after present study. First, spironolactone protects LV systolic functions
treatment. The mitral E/A ratio decreased significantly in the against the adverse effects of anthracycline group chemothera-
control group (1.29 ± 0.32 vs. 0.97 ± 0.33, P < 0.001), and also peutics. Not only LVEF but also LV systolic and diastolic diame-
decreased in the spironolactone group but did not reach signifi- ters were protected by spironolactone. Secondly, spironolactone
cance. The interaction between groups for decrease in the mitral showed an antioxidant effect against anthracycline-induced oxida-
E/A ratio during the treatment period was not different between tive stress. Thirdly, spironolactone protects the diastolic functional
groups (P = 0.060). The lateral e’ velocity in tissue Doppler imaging grade against anthracyclines.
was significantly decreased in both the spironolactone (11.2 ± 2.1 The RAAS is the most effective system in the remodelling of
vs. 10.0 ± 2.7 m/s, P = 0.007) and control groups (11.0 ± 2.4 vs. the myocardium.8 The RAAS facilitates cardiac oxidative damage
7.7 ± 2.4 m/s, P < 0.001). The decrease in lateral e’ velocity was and it has been proved in various studies that the remodelling
significantly higher in the control group than in the spironolactone process after this damage may be reduced via blockade of this
group (P < 0.001). The E/e’ ratio was preserved in the spirono- system.8 In the RALES study, one of the most important studies
lactone group (8.3 ± 1.6 8.5 ± 2.6, P = 0.625), while a significant conducted on this issue, it has been shown that the administration
increase was observed in the control group (8.3 ± 2.1 vs. 9.3 ± 2.8, of 25 mg/day spironolactone in addition to routine treatment has
P = 0.022). When we classified the diastolic functional grade of the positive effects particularly on cardiac fibrosis and remodelling.9
study population according to the American Society of Echocar- In the EPHESUS study, on the other hand, it was demonstrated
diography diastolic function guidelines, no meaningful change was that administering an aldosterone antagonist on the third to fourth
observed in the spironolactone group (P = 0.096). However, a sig- days after acute myocardial infarction to patients with low EF
nificant deterioration was seen in the control group (P < 0.001) (<40%) had positive effects on the EF and primary endpoints.10
(Figure 5). In another study, conducted by Hiyashi et al., spironolactone was

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
Effects of spironolactone on anthracycline cardiomyopathy 85

Table 2 Haematological parameters of the study population

Spironolactone group (n = 43) Control group (n = 40)

...................................... ..............................
Before After P-value Before After P-value P-value*
...........................................................................................................................................
White blood cells (103 /𝜇L) 7.7 ± 2.0 5.6 ± 1.8 <0.001 8.1 ± 2.7 5.1 ± 1.5 <0.001 0.126
Haemoglobin (g/dl) 12.6 ± 1.5 12.2 ± 1.0 0.128 13.1 ± 1.7 12.4 ± 1.0 0.012 0.319
Platelets (103 /𝜇L) 351 ± 116 273 ± 86 <0.001 369 ± 122 284 ± 77 <0.001 0.818
BUN (mg/dL) 12 (10–15) 11 (10–13) 0.822 12 (9–15) 13 (9–15) 0.546 0.875
Creatinine (mg/dL) 0.78 ± 0.21 0.71 ± 0.18 0.079 0.76 ± 0.2 0.71 ± 0.17 0.198 0.702
Uric acid (mg/dL) 4.5 ± 0.9 4.9 ± 1.8 0.184 4.6 ± 1.1 4.7 ± 1.2 0.508 0.404
Sodium (mmol/L) 142 ± 3 139 ± 3 <0.001 141 ± 3 139 ± 3 0.010 0.056
Potassium (mmol/L) 4.4 ± 0.3 4.5 ± 0.5 0.084 4.4 ± 0.3 4.4 ± 0.5 0.714 0.337
Total bilirubin (mg/dL) 0.5 (0.4–0.7) 0.5 (0.4–0.5) 0.274 0.5 (0.4–0.6) 0.5 (0.4–0.5) 0.503 0.893
Direct bilirubin (mg/dL) 0.1 (0.1–0.2) 0.2 (0.1–0.2) 0.597 0.1 (0.1–0.2) 0.2 (0.1–0.2) 0.129 0.512
AST (U/L) 22 (17–26) 22 (18–30) 0.941 21 (17–24) 23 (18–30) 0.571 0.690
ALT (U/L) 20 (15–38) 25 (17–30) 0.457 23 (15–29) 20 (16–33) 0.978 0.653
CA 15-3 (U/mL) 20 (15–33) 25 (16–34) 0.336 25 (13–38) 26 (14–38) 0.430 0.636
CEA (ng/mL) 0.9 (0.5–1.8) 1.4 (0.7–1.9) 0.973 1.2 (0.4–1.8) 0.6 (0.5–1.9) 0.939 0.937

Values are the mean ± SD or median (interquartile range).

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CA, cancer antigen; CEA, carcinoembryonic antigen.
* P-value for interaction between groups in the general linear model.

Table 3 Cardiac and oxidative biomarkers

Spironolactone group (n = 43) Control group (n = 40)

.......................................... ..........................................
Before After P-value Before After P-value P-value*
...........................................................................................................................................
Creatine kinase (U/L) 74 (55–77) 69 (53–98) 0.877 70 (55–98) 87 (70–102) 0.132 0.546
Creatine kinase-MB (U/L) 15.8 ± 5.3 17.3 ± 6.0 0.229 15.4 ± 6.8 21.7 ± 9.5 0.001 0.018
Troponin-I (ng/mL) 0.010 (0.001–0.020) 0.015 (0.004–0.032) 0.002 0.010 (0.001–0.021) 0.026 (0.010–0.053) <0.001 0.006
NT-proBNP (pg/mL) 71 (48–125) 85 (51–100) 0.549 70 (56–72) 100 (89–138) 0.089 0.130
TAC (μmol/L) 286.1 ± 44.7 275.4 ± 37.6 0.083 295.0 ± 47.5 250.4 ± 19.7 <0.001 0.001
TOC (μmol/L) 449.7 ± 222.5 487.0 ± 211.0 0.449 465.0 ± 256.4 594.8 ± 372.1 0.057 0.259
OSI 1.61 ± 0.80 1.79 ± 0.79 0.282 1.60 ± 0.90 2.37 ± 1.45 0.004 0.055

Values are the mean ± SD or median (interquartile range).

OSI, oxidative stress index; TAC, total antioxidant capacity; TOC, total oxidant capacity.
* P-value for interaction between groups in the general linear model.

administered to patients with acute myocardial infarction on the studies show us that the adverse changes in the myocardial tissue
...............................................

first day of admission, and LVEF significantly increased in the group are affected by the aldosterone system. It has been reported in
which received spironolactone in comparison with the control other studies that oxidative stress occurring in the heart tissue
group (P = 0.012). Researchers successfully showed the antifibrotic causes up-regulation of the mineralocorticoid receptors, and aldos-
effects of the 25 mg/day spironolactone dose, which was applied terone causes oxidative stress-mediated myocardial damage and
in addition to the standard treatment, and the effects thereof on apoptosis.17,18 Therefore, the clinical benefits to be attained via
remodelling as well.14 Wei et al. showed that spironolactone pre- aldosterone antagonism are (i) it has beneficial effects on remod-
vents apoptosis in the cell, independent of its antihypertensive elling after myocardial damage due to an antifibrotic effect; (ii) it
efficacy, and significantly decreases lipid peroxidation by way of lowers oxidative stress known as an antioxidant effect; and (iii) it
exhibiting an antioxidant effect in patients with hypertension.15 prevents apoptosis. We suggest that aldosterone suppression with
In another study, Michea et al. investigated the preventive effects spironolactone was responsible for such beneficial effects. In our
of spironolactone against oxidative stress in the heart of uraemic study, we found that spironolactone, when given simultaneously
rats. Uraemic rats exhibited a significant increase in superoxide with anthracycline, limited the increase of troponin-I, CK-MB, and
production and reduced expression of NADP oxidase subunits in NT-proBNP levels in the spironolactone group and protected the
the left ventricle. These authors successfully showed the benefi- myocardium against proapoptotic and pro-oxidative anthracycline
cial effects of spironolactone in cardiac oxidative stress.16 These damage.

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
86 M. Akpek et al.

Figure 2 Serum levels of creatine kinase (A), creatine kinase-MB (B), troponin-I (C), and NT-proBNP (D) between the spironolactone and
control groups. Values are the means. *P-value for interaction between groups in the general linear model.

Anthracyclines are seen as the cornerstone in the treatment In recent years, two important studies were performed in our
........................................................

of numerous haematological and solid cancers. The most signifi- clinic. We enrolled 50 patients with various solid or haematolog-
cant indicator of this is that they have been the unvarying agent ical malignancies, who had been given anthracyclines, and these
in various combinations for >50 years. It is known that the most were randomized into two different groups, receiving carvedilol or
critical side effect of these important chemotherapeutics is car- placebo. At the end of the 6-month period, an important protec-
diotoxicity, and this may limit their use.5,6 Anthracyclines increase tion was achieved in the systolic functions of the carvedilol group
morbidity and mortality risk during the treatment period.7 Anthra- with the administration of 12.5 mg carvedilol orally per day.24 In our
cyclines manifest their effects by directly affecting DNA and oxida- second study, 45 patients with breast cancer who were adminis-
tive DNA damage.19,20 The development of protective mechanisms tered anthracycline were randomized into two groups. A 5 mg/day
against cardiotoxicity is very important to prevent the discontin- dose of nebivolol was administered to the nebivolol group. We con-
uance, because anthracyclines provide great advances in the sur- cluded that both systolic and diastolic functions were protected
vival of patients with malignancies. Unfortunately, the only clinically in the nebivolol group.25 In recent years, studies have focused
accepted method to minimize the cardiotoxicity is dose modifica- on RAAS blockers for this purpose. In a rat study conducted by
tion and discontinuation of the anthracyclines. Several protective Ibrahim et al.,26 the authors demonstrated that telmisartan and cap-
mechanisms have been demonstrated against cardiotoxicity. The topril showed biochemical cardioprotective efficacy against anthra-
use of agents such as digitoxin, ouabain, strophanthin dexrazoxane, cycline cardiotoxicity. Oxidative stress indicators were further
and alpha-tocopherol has been examined in several experimen- examined in the same study. In addition, a histopathological exam-
tal studies.21 – 23 However, significant improvement has not been ination of the myocardium of rats was performed. Accordingly,
demonstrated yet. telmisartan and captopril were shown to lower cardiac fibrosis

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
Effects of spironolactone on anthracycline cardiomyopathy 87

Table 4 Echocardiographic properties of the study population

Spironolactone group (n = 43) Control group (n = 40)

..................................... .............................
Before After P-value Before After P-value P-value*
...........................................................................................................................................
LVEF (%) 67.0 ± 6.1 65.7 ± 7.4 0.094 67.7 ± 6.3 53.6 ± 6.8 <0.001 <0.001
LVESD (cm) 2.9 ± 0.3 3.1 ± 0.3 0.007 2.9 ± 0.4 3.6 ± 0.5 <0.001 <0.001
LVEDD (cm) 4.6 ± 0.4 4.9 ± 0.4 0.001 4.6 ± 0.5 5.2 ± 0.4 <0.001 0.002
Mitral E (m/s) 91 ± 16 80 ± 17 <0.001 88 ± 17 67 ± 15 <0.001 0.008
Mitral A (m/s) 74 ± 21 71 ± 17 0.274 72 ± 17 71 ± 16 0.791 0.515
Mitral E/A 1.31 ± 0.37 1.19 ± 0.39 0.079 1.29 ± 0.32 0.97 ± 0.33 <0.001 0.060
Mitral Dt (ms) 189 ± 27 190 ± 30 0.906 187 ± 31 198 ± 32 0.050 0.136
Lateral e’ (m/s) 11.2 ± 2.1 10.0 ± 2.7 0.007 11.0 ± 2.4 7.7 ± 2.4 <0.001 <0.001
E/e’ 8.3 ± 1.6 8.5 ± 2.6 0.625 8.3 ± 2.1 9.3 ± 2.8 0.022 0.179
Systolic blood pressure (mmHg) 113 ± 14 113 ± 13 0.982 111 ± 15 112 ± 15 0.630 0.715
Diastolic blood pressure (mmHg) 75 ± 8 76 ± 7 0.497 75 ± 8 75 ± 8 0.809 0.514
Weight (kg) 72.4 ± 10.7 71.1 ± 10.6 <0.001 74.2 ± 10.5 73.2 ± 10.6 <0.001 0.418
Heart rate (b.p.m.) 75 ± 10 76 ± 13 0.560 75 ± 11 77 ± 10 0.401 0.849

Values are mean ± SD.

Dt, deceleration time; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter.
* P-value for interaction between groups in the general linear model.

Figure 3 Individual systolic function data at baseline and after chemotherapy in the control and spironolactone groups.

meaningfully when compared with the control group. It was con- and renal functions did not change during the treatment period
.........................................................

cluded that both telmisartan and captopril showed similar protec- in either group. Thus, spironolactone is also a reliable treatment
tive efficacy against anthracycline-related cardiotoxicity. In another strategy in the protection against anthracycline-related myocardial
rat study, Iqbal et al.27 demonstrated that telmisartan is an effec- damage.
tive agent against anthracycline-related cardiotoxicity. After the The average cumulative doses of anthracyclines were not
protective effect of beta-blockers, ACE inhibitors, and ARBs on exceeded in this study. Based primarily on clinical events reported,
anthracycline cardiotoxicity was demonstrated, the effect of aldos- the incidence of apparent cardiotoxicity is ∼27% at cumulative con-
terone antagonism, which inhibits the last step of the RAAS, was ventional adriamycin doses up to 550 mg/m2 and epirubicin doses
questioned. Therefore, we planned the present study to exam- up to 900 mg/m2 .28,29 When we added the effects of radiation and
ine the effects of spironolactone on anthracycline cardiotoxicity. trastuzumab, if applied, the risk of adverse events is even higher.
We showed that spironolactone has antioxidant effects and ben- In the present study, there were no clinically apparent adverse
eficial efficacy on cardiac remodelling after the administration of cardiovascular events. We found a significant decrease in LVEF in
anthracycline group chemotherapeutics. The blood values of tro- the control group whereas it did not change in the spironolactone
ponin and NT-proBNP remained consistent at normal limits, but group. Therefore, subclinical cardiotoxicity occurred. We suggest
the increase in the control group was more than in the spirono- that limiting the adverse effects of anthracyclines, although subclin-
lactone group. We suggest that subclinical myocardial damage was ical, is important to reduce the mortality rates due to anthracy-
more frequently seen in the control group than in the spironolac- clines as well as to make it possible to use anthracyclines again if
tone group. Therefore, spironolactone protects the myocardium required and other additional therapies such as radiotherapy and
against anthracycline-related myocardial damage. Serum potassium trastuzumab.

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
88 M. Akpek et al.

Figure 4 Correlation between the change in EF (ΔEF) and total epirubicin dose (A) and adriamycin dose (B) in the control group.

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