Table 1 Summary of included studies

Gulati 2016 [28]

Norway

candestran + metoprolol, 30

32 mg + 100 mg

Trastuzumab, taxons

1-Women aged 18–70 years

2-Eastern Cooperative Oncology Group (ECOG) performance status 0–1

3-Serum creatinine < 1.6 mg/dL or estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2

4-Systolic blood pressure ≥ 110 mmHg and < 170 mmHg

5-Left ventricular ejection fraction ≥ 50%

1-Change in LVEF by cardiac magnetic resonance imaging

"In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against an early decline in global left ventricular function."

candestran + placebo, 32

32 mg

metoprolol + placebo, 32

100 mg

placebo + placebo, 32

Gupta 2017 [29]

India

enalapril, 44

of 0.1 mg/kg/day once a day from the first day

of chemotherapy for 6 months

doxorubicin and/or daunorubicin

1- Patients aged more than 16 years at the time of diagnosis

2- Confirmed diagnosis of acute lymphoblastic leukemia/lymphoma (Hodgkin and non-Hodgkin lymphoma)

3-Estimated cumulative anthracycline dose ≥ 200 mg/m2

1-Measured decrease in LVEF (≥ 20%)

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

placebo, 40

Kalay 2006 [33]

Turkey

carvedilol, 25

12.5 mg/day

adriamycin or epirubicin

1-Patients diagnosed with malignancy

and planned ANT therapy (adriamycin or epirubicin)

2- Who have not received previous chemo or radiotherapy

3- Free of CHF and valvular disease

1-Left ventricular ejection fraction

2- Echocardiographic parameters

"Prophylactic use of carvedilol in patients receiving ANT may protect both systolic and diastolic functions of the left ventricle."

placebo, 25

NA

Cardinale 2006 [20]

USA

Enalapril, 56

an initial

dose of 2.5 mg once daily and was increased gradually through 3

steps to 20 mg once daily (5, 10, and 20 mg, respectively)

NA

1-Cancer patients undergoing HDC

2-All patients with an early TnI value of 0.07 ng/Ml

1-Left ventricular ejection fraction

2-Echocardiographic parameters

"In high-risk, HDC-treated patients, defined by an increased troponin I value, early treatment with enalapril seems to prevent the development of late cardiotoxicity."

placebo, 58

Georgakopoulos 2010 [26]

USA

metoprolol, 42

1-The diagnosis of de novo DLBCL

2- Treated with R-CHOP with or

without consolidation radiation therapy at the discretion of the attending

physician

3- And be followed at Mayo Clinic Rochester

1-LVEF

“metoprolol and enalapril do not reduce the risk of cardiotoxicity in patients treated with doxorubicin.”

enalapril, 43

NA

NA

placebo, 40

Acar 2011 [15]

USA

atorvastatin, 20

40 mg

NA

1-Mean age of 53 15 years

2- Who was undergoing ANT

chemotherapy was enrolled

1-Establishment of impairment in LV systolic

functions defined as an ejection fraction (EF) of 50%

"prophylactic use of atorvastatin could be effective in the maintenance of LVEF in patients treated with ANT."

placebo, 20

NA

NA

Salehi 2011 [41]

Iran

placebo, 22

NA

1- Patients with a diagnosis of

breast malignancies and lymphoma

2- Who was under treatment with anthracyclines

3- Those who were referred to Shahid Ghazi Clinic entered the study

1-LVEF

"Carvedilol at a daily dose of 12.5 mg has a protective effect against diastolic disorder and at a daily dose of 25 mg has a protective effect against both systolic and diastolic disorders."

carvidelol, 22

12.5 mg

NA

carvidelol, 22

25 mg

NA

Bosch 2013 [19]

Spain

Enalapril + carvedilol,45

Enalapril initial dose was 2.5 mg daiy hen increased gradulally every 3 o 6 days to 5 and 10 mg daily. Carvediolol's initial dose was 6.25 mg twice daily and gradually increased to 12.5 and 25 mg every 3 to 6 days

NA

1-Adult patients from 18 to 70 year-old

2-LVEF ≥ 50%

1-Absolute change from baseline LVEF

2-Serious adverse events

3-Death

" The combined treatment with enalapril and carvedilol may prevent LVSD in patients with malignant hemopathies treated with intensive chemotherapy. The clinical relevance of this strategy should be confirmed in larger future studies. relevance of this strategy for prevention of chemotherapy-induced cardiac damage should be confirmed in larger future studies."

control,45

NA

Kaya 2013 [34]

Turkey

nebivolol, 27

5 mg/day

adriamycin/epirubicin, cyclophosphamide,

5-Fluorouracil (5-FU) and docetaxel (DCT)-containing chemotherapy regimes

1-Female patients admitted from October 2007 to September 2008 to the medical oncology department of the Erciyes University Medical School for breast cancer

1-Left ventricular (LV) end-systolic and end-diastolic diameters

"Prophylactic use of nebivolol treatment may protect the myocardium against anthracycline-induced cardiotoxicity in breast cancer patients."

placebo, 18

Radulescu 2013 [39]

Romania

perindopril, 68

10 mg

epirubicin

patients admitted between 2007 to 2012 who had not undergone prior chemotherapies before admission

1-Left ventricular ejection fraction (EF)

"In the present echo-Doppler study we documented a preserved left ventricular systolic performance in patients with various malignancies treated with epirubicin plus perindopril. Although co-treatment with ACEI prevented the alteration of systolic performance, it failed to prevent the deterioration of the left ventricular diastolic performance impairment due to poor left ventricular compliance"

Control,68

NA

Dessì 2013 [23]

Italy

telmisartan, 25

40 mg

epirubicin

1-Patients aged 18–70

2- Blood pressure within the normal range (80/

120)

3-Echocardiographic LVEF value ≥ 55%

4-SR value in the normal range (range: 1.7–2.1 cm/sec)

5- Eastern Cooperative Oncology Group (ECOG) performance status

6-Score of 0–2 (Oken, et al. 1982)

7- Normal hepatic and renal function (bilirubin ≤ 1.5 mg/dl, creatinine ≤ 2.0 mg/dl)

8-No concomitant medications known to interfere with inflammatory and oxidative stress parameters

such as NSAIDs, aspirin, and Cox-2 inhibitors

1-LVEF

2-Echocardiographic parameters

3-Serum levels of IL-6 4- Blood levels of ROS

"The protective effect of telmisartan is long-lasting, probably by ensuring a permanent (at least up to 18-month FU) defense against chronic or late-onset types of anthracycline-induced cardiotoxicity."

placebo, 24

NA

Jhorawat 2014 [32]

India

carvedilol, 27

12.5 mg

adriamycin

1-Patients diagnosed with lymphoreticular malignancy and planned for

chemotherapy (CT) with a regimen containing ANT

(ADR) between January 2008 and February 2009

2- Not to have undergone previous CT, or radiation therapy, and have no underlying coronary artery dr or previous DCM

1-LVEF

2-Result of Doppler examination

"Prophylactic use of carvedilol in patients receiving anthracycline protected systolic functions of the left ventricle. Carvedilol can be a potential drug that can ameliorate ADR- induced CMP."

placebo, 27

NA

Elitok 2014 [24]

Turkey

carvedilol, 40

12.5 mg

NA

1-Breast cancer patients who did not previously receive chemo or radiation therapy

2- Cardioprotective drug use, such as angiotensin-converting enzyme

inhibitors, angiotensin receptor blockers, calcium channel blockers, statins, aldosterone receptor antagonists, and other beta-blockers

3- Who had no baseline cardiac dysfunction

1-LVEF

"These results indicate that carvedilol has a protective effect against the cardiotoxicity induced by ANT."

placebo, 40

NA

NA

Akpek 2014 [10]

Turkey

spironolactone, 43

25 mg

NA

1- Female patients with no prior breast

cancer and/or prior anthracycline exposure history

2- LVEF > 50%

3- No prior use of ACE inhibitors, ARBs, or beta-blockers

4- Creatinine < 2 mg/Dl

5- No presence of chronic kidney failure

6- Potassium < 5.3 mg/Dl

7- No presence of adrenal gland diseases

8- No presence of severe liver failure

9- No presence of co-morbidities such as coronary heart disease, hypertension, AF, and valvular heart disease

1-LVEF

2- Haematological parameters

"spironolactone administration used simultaneously with anthracycline group chemotherapeutics protects both myocardial systolic and diastolic functions. Spironolactone can be used to protect against anthracycline-induced cardiotoxicity. "

placebo, 40

NA

NA

Chotenimitkhun 2015 [21]

USA

statin, 14

40–80 mg daily/10–20 mg daily

b-Blockers = 7 (50%), Angiotensin-converting enzyme inhibitors = 6 (43%), Angiotensin II receptor blockers = 4 (29%), Calcium channel blockers = 4 (29%), Diuretics 7 (50%)

1- Participants who were recruited from the hematology and oncology outpatient and inpatient facilities of the Comprehensive Cancer Center at Wake Forest Health Sciences

2- And were scheduled to receive Anth-bC

1-LVEF

" These data highlight the finding that individuals receiving statin therapy for prevention of cardiovascular disease may experience less deterioration in LVEF with early receipt of Anth-bC than individuals not receiving statins. Further studies with large numbers of participants are warranted to determine if statins protect against LVEF decline in patients receiving Anth-bC."

non-statin, 37

NA

b-Blockers = 3(8%), Angiotensin-converting enzyme inhibitors = 4(11%), Angiotensin II receptor blockers = 0(0%), Calcium channel blockers = 1 (3%), Diuretics 1 (3%)

Boekhout 2016 [18]

Germany

Candesartan,106

32 mg/d

NA

1-Aged 18 years or older; early-stage HER2-positive breast cancer

2-Completion of anthracycline-based adjuvant treatment

3- Performance status 2 or lower

4- LVEF at least 50% as measured by echocardiography or multiple gate acquisition radionuclide

imaging

5- Creatinine clearance greater than 50 mL/min (by Cockcroft Gaultformula)

6- thyroid-stimulating hormone level between 0.5 and 3.9 MU/L or thyroid hormone-free thyroxine between 8 and 26 pmol/L

7- Systolic blood pressure between 100 and

180 mm Hg and diastolic blood pressure between 60 and 100

mm Hg

8- And first trastuzumab infusion received at least 3 weeks

after day 1 of the last anthracycline infusion

1-LVEF

"The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects"

PLACEBO, 104

NA

NA

Ahmad 2016

Iran

Carvedilol,30

6.25 mg

NA

1- Non menopausal women

2-No previous cardiac conditions (including ischemic heart disease, prolonged hypertension, and

clinically important congenital or acquired valvular and myocardial diseases) or diabetes, no previous chemo/radiotherapy, taking no cardiac-related drugs, and not having other cancers

1-Echocardiographic parameters (LVEF & Strain rate)

"This study shows that carvedilol can prevent doxorubicin-induced cardiotoxicity. Whether this prophylaxis should be considered as the preferred method needs further investigation."

Placebo,40

NA

NA

Janbabai 2016 [31]

Iran

enalapril,34

5 mg twice daily

NA

1-Patients aged 21–74 years with (ECOG) performance status > 2

2-Normal sinus rhythm

3- And preserved LVEF at baseline echocardiography

4-With a newly diagnosed malignancy

1-LVEF

"prophylactic use of enalapril can be beneficial in preserving both systolic and diastolic function in cancer patients treated with ANTs."

placebo,35

NA

NA

Nabati 2017 [46]

Iran

Carvedilol,46

6.7 mg /day

1-Women with newly diagnosed breast cancer treated with ANT therapy

1-LVEF

2-Echocardiographic parameters

"Prophylactic use of carvedilol may inhibit the development of anthracycline-induced cardiotoxicity, even at low doses."

Placebo,45

NA

Pituskin 2017 [38]

Canada

Placebo, 30

NA

NA

1-Patients age > 18 years

2- With newly diagnosed HER2- overexpressing EBC (stage I to IIIA)

3- Planned adjuvant treatment with trastuzumab

1-Trastuzumab-mediated left ventricular remodeling

"Perindopril and bisoprolol protected against cancer therapy-related declines in LVEF; however, they did not prevent trastuzumab-mediated left ventricular remodeling."

Perindopril, 33

8 mg/ daily

NA

Bisoprolol, 31

10 mg/daily

NA

Avila 2018 [17]

Brazil

Carvedilol,96

3.125 mg twice-a-day

NA

1-Patients with HER2-negative breast cancer tumor status

2- Therapy that included anthracycline, cyclophosphamide

1-LVEF

2-BNP

3-TnI and diastolic dysfunction

“ In this largest clinical trial of β-blockers for the prevention of cardiotoxicity under contemporary ANT dosage, we noted a 13.5 –14.5% incidence of cardiotoxicity. In this scenario, carvedilol had no impact on the incidence of early onset of LVEF reduction. However, the use of carvedilol resulted in a significant reduction in troponin levels and diastolic dysfunction.”

Placebo,96

NA

NA

Wihandono 2021 [45]

Indonesia

lisinopril and bisoprolol, 37

10 mg/day

NA

1-Patients from 18–70 years old

2- Sinus rhythm and (LVEF ≥ 50%)

3- Diagnosed with locally advanced breast cancer and submitted to receive anthracycline-based neoadjuvant chemotherapy

1-LVEF

"Combined treatment with lisinopril and bisoprolol may prevent anthracycline-induced cardiotoxicity in patients with locally advanced breast cancer treated with anthracycline-based chemotherapy"

Control,37

NA

NA

Slowik 2020 [42]

Poland

Ramipril,48

10 mg/d

NA

1-Consecutive women with stages I–III BC

2- Who underwent breast surgery and were referred for adjuvant anthracycline therapy

1-LVEF

2-Troponin I

3-NT-proBNP

4-HF or cardiac death

"In relatively young women with BC without serious comorbidities, who received anthracyclines, 1-year treatment with ramipril exerts potentially protective effects on cardiotoxicity assessed with NT -proBNP levels."

Control,48

NA

NA

Sherafati 2019

Iran

carvedilol,27

6.25 mg twice daily

NA

1- Every HER2-positive breast cancer patient

2- Who was a candidate for receiving Herceptin therapy

1-LVEF

2-Echocardiographic parameters

"In conclusion, carvedilol may have beneficial effects

in the prevention of cardiac dysfunction in patients

receiving Herceptin but a larger study with a longer

A follow-up period is recommended to determine this

hypothesis more accurately"

control, 38

NA

NA

Nabati 2019 [37]

Iran

rosuvastatin,38

20 mg

NA

1- Women were 25 to 77 years old

2-Had been newly diagnosed with breast cancer

3- Had preserved LV systolic function in which the (LVEF) 55%

4-And had normal liver, renal, and hematological functions

1-LVEF

2-GLS

3-Cardiovascular mortality

4-hospitalization

"The present study showed that the prophylactic use of rosuvastatin may

prevent the development of chemotherapy-induced cardiotoxicity"

control,39

NA

NA

Martha 2020 [44]

Indonesia

carvedilol, 40

2 × 6.25 mg daily

NA

1-Female patients with breast cancer older than 19 years old

2- Received FAC chemotherapy regimen and sinus heart rhythm

1-Left ventricular function

"Carvedilol did not prevent the decline of subclinical left ventricular function after the chemotherapy cycle. However, it may be more likely to benefit patients whose given a larger cumulative dose of anthracycline and have multiple risk factors."

placebo, 40

NA

NA

heck 2021 (from gulti 2016) [30]

Norway

Candesartan–

metoprolol,28

32 mg/100 mg daily

Trastuzumab,7

1-Patients were adult women between 18 and 70 years of age

2- With LVEF ≥ 50%

3- Normal kidney function, and no serious comorbidities

4-Who after surgery for early breast cancer was scheduled for

adjuvant anthracycline-containing therapy

1-LVEF

2-LV systolic dysfunction

"anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years but was associated with a modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease"

Candesartan–

placebo,32

32 mg daily

Trastuzumab,7

Placebo–metoprolol,30

100 mg daily

Trastuzumab,6

placebo,40

NA

Trastuzumab,7

Guglin 2019 [27]

USA

Carvedilol,156

NA

NA

1-Adult patients with normal LVEF and

without major cardiovascular comorbidities

1-Serum biomarkers

2-Troponin I

3-BNP

4-LVEF

"In patients with HER2-positive breast cancer treated with trastuzumab, both lisinopril, and carvedilol

prevented cardiotoxicity in patients receiving anthracyclines. For such patients, lisinopril or carvedilol should be considered to minimize interruptions of trastuzumab. (Lisinopril or Coreg CR in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab"

Lisinopril,158

NA

NA

Placebo,154

NA

NA

Esfandbod 2021 [35]

Iran

Carvedilol,30

12.5 mg twice a day

NA

1-Patients recently diagnosed with HER2-positive breast cancer in stages I to IIIA

2- Candidates for trastuzumab therapy

1-Ejection Fraction (EF)

2- Pulmonary Artery Pressure (PAP)

"patients with HER2-positive breast cancer treated with trastuzumab, Carvedilol showed no significant protective effect on trastuzumab-induced cardiotoxicity."

control, 30

NA

GEORGAKOPOULOS 2010 [26]

Greece

Metoprolol,42

100 mg/twice/day)

NA

1-Patients with HL and NHL

1-Incidence of HF and subclinical cardiotoxicity

2- LVEF and Echocardiographic parameters

“ Study showed that metoprolol and enalapril do not reduce the risk of cardiotoxicity in patients treated with doxorubicin”

control, 40

-

Enalapril,43

( 20 mg/ twice/day)

GEORGAKOPOULOS 2019(10 years follow up) [25]

Greece

metoprolol,27

8.8 ± 3.1 mg

NA

1-Patients > 18 yr old

2- Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 (Serum creatinine < 2.0 mg/dl

3-Normal sinus rhythm, (LVEF) > 50% Fraction shortening (FS) > 25% before CT

1- The occurrence of

doxorubicin-induced clinical or subclinical long-term cardiotoxicity

in lymphoma patients

"Clinical signs of heart failure were not seen in any patients and no statistically significant differences between baseline and 10-year findings

were seen for echocardiographic variables. No evidence of long-term cardiotoxicity was seen and neither metoprolol nor enalapril offered an additional benefit."

control, 26

enalapril,30

11 ± 0.68 mg

Davis 2019 [22]

Canada

Eplerenone,22

50 mg daily

NA

1- Stage I-III breast cancer

2-Scheduled to undergo treatment with a doxorubicin-based chemotherapy regimen

3-Able to provide informed consent

1- change in Eʹavg at 6 months

2-LEVF

'concomitant administration of eplerenone for 6 months was not associated with significant differences in systolic or diastolic function compared with placebo in patients with early or locally advanced breast cancer treated with anthracycline-based chemotherapy''

Placebo,22

NA

NA

Rizka 2021 [40]

Indonesia

ACEI,15

10–5 mg daily

NA

1-Early and locally advanced breast cancer patients

2-Who received neoadjuvant chemotherapy anthracycline-based

1- Troponin

"The treatment group that received the ACEi intervention could prevent an increase of troponin levels after chemotherapy. Overall, it can be concluded that the consumption ACEi can inhibit the rise of Troponin"

Control,15

NA

NA

Farhani 2019

Iran

Carvedilol,36

6.25 mg twice a day

NA

1- HER2/neu-positive nonmetastatic patients with breast cancer

2- Who were treated with standard anthracyclines regimens

3- Who was candidated to receive trastuzumab

1-LVEF

2- GLS

3-and the strain rate of the LV systolic function [SRS])

" Concomitant carvedilol treatment with a maximum tolerable dose in patients with nonmetastatic HER2-positive breast cancer under treatment with trastuzumab might be effective in the reduction of systolic and diastolic echocardiographic findings other than the LVEF in patients with weak markers of heart failure. "

Control,35

NA

NA