Search Results and Selection
Our first comprehensive search resulted in a total of 541 entries. After the removal of duplicates using Rayyan Software, 474 articles were available (17). After the assessment by title and abstract, 30 articles were selected to full text analysis. After full text analysis, one was excluded because not all the participants were exposed to ANT, one was excluded because the aim was to assess at the time at which prophylactic therapy introduction was more effective, one was not obtainable and three were excluded since they were not in English. There is a total of 24 articles integrating this review.
A total of 3159 participants were included in the studies and 2974 were women (94%). The mean age of participants ranges from 36 to 61 years. The most frequent type of cancer studied was breast, followed by lymphoma (Hodgkin and Non-Hodgkin) and lung. Of the 24 studies, 16 studies included only patients with breast cancer (8, 18–32). Only two studies did not include patients with breast cancer (33, 34). In 17 studies the chemotherapy regime used was ANT without TZB (ANT only) (8, 9, 18, 24–30, 33–39). In 2 studies the chemotherapy regime used was ANT and TZB (ANT + TZB) (31, 32). In 3 studies the chemotherapy regime used was ANT and some patients also received TZB (ANT ± TZB) (19–21). In 2 studies the chemotherapy regime used was TZB and some patients received ANT (TZB ± ANT) (22, 23).
The therapy administered was ACEi in 5 studies (19, 22, 23, 33, 39), ARA in 4 studies (20, 32, 34, 35), BB in 11 studies (18, 20, 22, 23, 25–27, 31, 33, 36, 37), Spironolactone in 1 study (30) and Dexrazoxane in 3 studies (8, 28, 29). Salidroside, Prenylamine, N-Acetylcysteine and rosuvastatin were only administered in one trial each (9, 21, 24, 38). All studies compared the intervention group to control groups. 3 trials compared simultaneously BB and ACEi (22, 23, 33). One study compared BB and ARA (20).
All studies resorted to echocardiography to evaluate cardiac function, except for one study that used only Cardiac Magnetic Resonance Imaging (MRI) and Multiple-Gated Acquisition (MUGA) (22). Ten studies also assessed cardiac damage through the measurement of inflammatory markers, cardiac enzymes and natriuretic peptides (9, 19, 20, 24, 26, 27, 30, 34, 35, 38).
The range of follow-up between studies was from 1 week to 10 years, although in most studies it was located between 3 months to a year. In two studies the follow-up was not disclosed in time, ending after an ANT cumulative dose of 400 mg/m2 was reached according to the institutions’ protocols (24, 35). This information in summarized in Table 1.
Table 1
Characterization of Studies
Chemotherapy
|
Drug Class
|
Drug intervention
|
Authors
|
Year
|
Population
|
Females (%)
|
Age (Mean ± SD)
|
Types of Cancer
|
Assessment of Cardiac Function
|
Length of follow up
|
ANT Only
|
ACEi
|
Enalapril
|
Janbabai et al. (39)
|
2017
|
69
|
93
|
Enalapril: 47,76 ± 11,81
Control: 47,06 ± 12,39
|
Breast, Hodgkin Lymphoma, Wilms' Tumor, Lung, Bone sarcoma
|
Echocardiography and Tissue Doppler Imaging
|
6 months
|
ARA
|
Valsartan
|
Nakamae et al. (34)
|
2005
|
55
|
38
|
55 ± 10
|
Non-Hodgkin Lymphoma
|
Echocardiography, Electrocardiography, BNP, ANP
|
7 days
|
Telmisartan
|
Cadeddu et al. (35)
|
2010
|
49
|
76
|
Telmisartan: 52,9 ± 9
Control: 53 ± 10
|
Endometrium, Salivary Glands, Non-Hodgkin Lymphoma, Breast, Ovary, Lung
|
Echocardiography and Tissue Doppler Imaging, Assessment of inflammatory and stress oxidative markers
|
Until ANT cumulative dosage of 400 was reached
|
BB
|
Carvedilol
|
Kalay et al. (36)
|
2006
|
50
|
86
|
Carvedilol: 46,8 ± 14
Control: 49 ± 9,8
|
Breast, Lymphoma, Other
|
Echocardiography and Tissue Doppler Imaging
|
6 months
|
Elitok et al. (18)
|
2014
|
80
|
100
|
Carvedilol: 54,3 ± 9,3
Control: 52,9 ± 11,2
|
Breast
|
Echocardiography, Strain imaging
|
6 months
|
Beheshti et al. (25)
|
2016
|
70
|
100
|
Carvedilol: 42 (29–54)
Control: 39,9 (29–54)
|
Breast
|
Echocardiography, Strain imaging
|
3 months
|
Abuosa et al. (37)
|
2018
|
154
|
73
|
Carvedilol (6,25mg): 46,1 ± 13,0
Carvedilol (12,5mg): 41,3 ± 18,2
Carvedilol (25mg): 42,0 ± 15,0
Control: 40,4 ± 14,0
|
Breast, Non-Hodgkin Lymphoma, Others
|
Echocardiography and Tissue Doppler Imaging
|
6 months
|
Avila et al. (26)
|
2018
|
192
|
100
|
Carvedilol: 50,80 ± 10,10
Control: 52,90 ± 9,05
|
Breast
|
Echocardiography and Tissue Doppler Imaging, BNP, Tn I
|
6 months
|
Nebivolol
|
Kaya et al. (27)
|
2013
|
45
|
100
|
Nebivolol: 51,4 ± 9,4
Control: 50,5 ± 11,1
|
Breast
|
Echocardiography and Tissue Doppler Imaging, NT-pro-BNP
|
6 months
|
Chemotherapy
|
Drug Class
|
Drug intervention
|
Authors
|
Year
|
Population
|
% of Females
|
Age (Mean ± SD) •
|
Types of Cancer
|
Assessment of Cardiac Function
|
Length of follow up
|
ANT Only
|
Mineralocorticoid Receptor Antagonist
|
Spironolactone
|
Akpek et al. (30)
|
2014
|
83
|
100
|
Spironolactone: 50 ± 10,8
Control: 50,6 ± 10,1
|
Breast
|
Echocardiography and Tissue Doppler Imaging, CK-MB, NT-pro-BNP, Tn I, Total Antioxidative Capacity, Total Oxidative Capacity
|
6 months
|
ANT Only
|
Anti-Oxidative Effect
|
Dexrazoxane
|
Venturini et al. (29)
|
1996
|
162
|
100
|
Dexrazoxane: 57 (range: 32–73)
Control: 57 (range: 34–74)
|
Breast
|
Multiple-Gated Acquisition, Electrocardiography
|
3 years
|
Swain et al. (8)
|
1997
|
534
|
100
|
Dexrazoxane (Group A): 58 (range: 26–84)
Dexrazoxane (Group B): 56 (range: 35–76)
Control (Group A): 56 (range: 25–82)
Control (Group B): 59,5 (range: 23–79)
|
Breast
|
Multiple-Gated Acquisition
|
4 years
|
Marty et al. (28)
|
2005
|
164
|
100
|
Dexrazoxane: 50 (range 31–76)
Control: 52 (range 30–71)
|
Breast
|
Echocardiography, Multiple-Gated Acquisition
|
3 years
|
Prenylamine
|
Milei et al. (38)
|
1987
|
26
|
65
|
61,5
|
Miscellaneous
|
Echocardiography, Electrocardiography
|
6 months
|
Salidroside
|
Zhang et al. (24)
|
2012
|
60
|
100
|
Salidroside: 51 ± 7
Control: 52 ± 6
|
Miscellaneous
|
Echocardiography, Electrocardiography
|
Until ANT cumulative dosage of 400 mg/m2 was reached
|
NAC
|
Jo et al. (9)
|
2013
|
103
|
88
|
NAC: 51,5 ± 9,8
Control: 48,3 ± 8,4
|
Breast, Lymphoma
Intervention group:
|
Echocardiography, CK-MB, TnI
|
6 months
|
Combination
|
BB + ACEi
|
Georgakopoulos et al. (33)
|
2019
|
125
|
48%
|
Enalapril: 47.4 ± 16.2
Metoprolol: 51.0 ± 18.0
Control: 49.1 ± 19.4
|
Hodgkin and Non-Hodgkin Lymphoma
|
Echocardiography, Electrocardiography, Chest X-Ray,
|
10 years
|
ANT + TZB
|
BB
|
Carvedilol
|
Farahani et al. (31)
|
2018
|
71
|
100%
|
Carvedilol: 57,3 ± 7,3
Control: 57,4 ± 8,8
|
Breast
|
Echocardiography, Strain imaging
|
3 months
|
ARA
|
Candersartan
|
Boekhout et al. (32)
|
2016
|
206
|
100
|
Candesartan: 50 (25–69)
Control: 50 (30–67)
|
Breast
|
Echocardiography, Multiple-Gated Acquisition
|
1,5 years
|
Chemotherapy
|
Drug Class
|
Drug intervention
|
Authors
|
Year
|
Population
|
% of Females
|
Age (Mean ± SD) •
|
Type of Cancer
|
Assessment of Cardiac Function
|
Length of follow up
|
ANT ± TZB
|
ACEi
|
Ramipril
|
Słowik et al. (19)
|
2020
|
96
|
100
|
Ramipril: 45 (38–54)
Control: 45 (42–53)
|
Breast
|
Echocardiography, NT-pro-BNP, TnI
|
12 months
|
Combination
|
BB + ARA
|
Gulati et al. (20)
|
2016
|
120
|
100%
|
Candesartan + Metoprolol: 50 ± 8,9
Candesartan: 51,7 ± 10,7
Metoprolol: 50,5 ± 9,1
Control: 50,8 ± 9,2
|
Breast
|
Echocardiography, Strain imaging, Cardiac MRI, BNP, TnI
|
61 weeks
|
Anti-Oxidative Effect
|
Rosuvastatin
|
Nabati et al. (21)
|
2018
|
83
|
100%
|
Rosuvastatin: 47,74 ± 9,7
Control: 50,74 ± 12,4
|
Breast
|
Echocardiography and Tissue Doppler Imaging
|
6 months
|
TZB ± ANT
|
Combination
|
BB + ACEi
|
Pituskin et al. (22)
|
2017
|
94
|
100%
|
Bisoprolol: 53 ± 10
Perindopril: 50 ± 8
Control: 51 ± 7
|
Breast
|
Cardiac MRI, Multiple-Gated Acquisition
|
12 months
|
Guglin et al. (23)
|
2019
|
468
|
100%
|
Carvedilol: 51,58 ± 10,93
Lisinopril: 50,58 ± 10,91
Control: 51,11 ± 10,71
|
Breast
|
Echocardiography, Multiple-Gated Acquisition; BNP
|
12 months
|
ACEi- aldosterone conversion enzyme inhibitor; ANP- atrial natriuretic peptide; ANT- anthracyclines; ARA- aldosterone receptor antagonist; BB- beta adrenergic receptor blocker; CK-MB: creatinine kinase MB enzyme; MRI: Magnetic Resonance Imaging; NAC- n-acetylcysteine; SD- standard deviation; TZB – trastuzumab; • - when mean ± SD were not available, range of ages was used, if possible. |
Quality Assessment and Risk of Bias
Only two articles achieved maximal performance in the quality assessment (22, 37). Given that some parameters were not available for analysis and taking into account only the information exposed, other 5 also achieved maximal performance (20, 24, 27, 30, 34). The complete bias analysis is available in Supplementary Files 2.1 and 2.2.
Considering all the groups included (ANT only, ANT + TZB and ANT ± TZB), BB did not show any combined effect on LVEF (p = 0,17). The subgroup analysis for ANT + TZB group (p = 0,39) and for ANT ± TZB group (p = 1,00) also failed to show any effect. However, the ANT only group (p = 0,04) showed a significant increase in LVEF the in BB group − 0,86 (95%CI: [0,03;1,70]). However, high heterogeneity was attained in this group (I2 = 78%). This information is depicted on Supplementary File 3.
Given the high heterogeneity on ANT only subgroup, an exploratory analysis was made considering each individual BB which allowed for a lower heterogeneity (I2 = 28%). In this analysis, the overall effect for carvedilol was lost (p = 0,25), but the effects of nebivolol appear significant (p < 0.0001). This is based on the results by Kaya et al. with a mean difference of 6,30 (95%CI: [3,32;9,28])(27). This information is depicted on Supplementary File 4.
The results by Georgakopoulos et al. were not included due to its distinctive follow up length and Kalay et al. did not display the information needed for the analysis (33, 36).
The results by Pituskin et al. and Guglin et al. were not able for comparison due to their different representations of LVEF (as continuous outcome and as a dichotomous event rate) (22, 23).
Considering the articles not included in the meta-analysis, Kalay et al. found a decrease in LVEF in the control group at the end of follow-up (36). The three authors who compared a BB to an ACEi, found conflicting results. Georgakopoulos et al. and Guglin et al. did not found any effect on LVEF (23, 33). On the other hand, Pituskin et al. that found LVEF reduction to be attenuated on bisoprolol group compared to perindopril and control groups. Their results also show bisoprolol to have a protective effect compared to perindopril which showed no protective effect (22).
In the work by Farahani et al., all patients underwent ANT and TZB and found that GLS was higher in carvedilol group when compared to control after chemotherapy. In the control group, there was a fall of 0,82 ± 8% in GLS, whereas in carvedilol group an improvement of 0,32 ± 8% was found (31). These results contrast with the findings from Gulati et al. in which a GLS did not change on the entire studyin patients treated only with ANT. Even though Gulati et al. present with a higher population, the GLS comparison made by the authors does not reflect a true comparison between BB and a control group. This is due to the design of the study in which patients on metoprolol where compared to patients that where on candesartan or placebo (20). A meta-analysis for the effects on GLS was not possible due to different chemotherapeutic schemes.
Meta-analysis was performed to assess the possible effect on E/A ratio including six studies (18, 27, 31, 36, 37). The results obtained showed a combined effect of 0,12 (95% CI:[0,05;0,19]), with a significant effect (p < 0.0004) and a low heterogeneity (I2 = 11%). These results are depicted on Supplementary File 5.
There was scope for a meta-analysis on E/e’ ratio since it was measured by 5 articles (20, 27, 31, 33, 37). One article was not included on the analysis due to its distinctive follow up length (33). The results show a combined effect of 0,37 (95%CI :[0.2; 0.54]) increase with a significant effect (p < 0,0001), with low heterogeneity (I2 = 0%). These results are depicted on Supplementary File 6.
LA diameter was studied in two articles (18, 26). The results of our meta-analysis did not show any difference with BB (p = 0,33) for a combined effect of 0,46 reduction (95%CI:[-1,39; 0,47]) and a low heterogeneity (I2 = 0%). These results are depicted in Supplementary File 7.
Four studies measured BNP/ NT-pro-BNP levels (20, 23, 26, 27). Kaya et al. found the NT-pro-BNP levels to increase in the control group during chemotherapy and this raise to be significantly higher than in the nebivolol group (27). These results are conflicting to those of Gulati et al. which found BNP levels to increase in metoprolol group (20). The other two studies did not found any differences in BNP levels (23, 26).
Two studies measured TnI (20, 26). Gulati et al. did not find any differences in TnI (20). Contrasting with the findings of Avila et al. that found TnI to increase in all participants, with a significantly higher increase in control group when compared to carvedilol (26).
There was no opportunity for a meta-analysis, since the studies had different chemotherapy schemes or measurement units
The results of BB on LVEF, GLS, diastolic function and cardiac biomarkers are summarized in Table 2.
Table 2
Summary of results from BB studies
Chemotherapy Scheme
|
Authors
|
Comparison
|
LVEF
|
GLS
|
E/A Ratio
|
LA diameter
|
E/e'
|
BNP / NT-pro-BNP
|
Troponin I
|
ANT only
|
Georgakopoulos et al.
|
Control vs Intervention
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
No difference
|
No difference
|
Metoprolol at the end of follow-up
|
No difference
|
No difference
|
No difference
|
Kalay et al.
|
Control vs Carvedilol
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
Lower
|
Lower
|
Carvedilol at the end of follow-up
|
No difference
|
No difference
|
Elitok et al.
|
Control vs Carvedilol
|
No difference
|
N/A
|
No difference
|
No difference
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
N/A
|
N/A
|
N/A
|
Carvedilol at the end of follow-up
|
N/A
|
N/A
|
N/A
|
Beheshti et al
|
Control vs Carvedilol
|
No difference
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
Carvedilol at the end of follow-up
|
No difference
|
Abuosa et al.
|
Control vs Carvedilol
|
No difference
|
N/A
|
No difference
|
N/A
|
No difference
|
N/A
|
N/A
|
Control at the end of follow-up
|
Lower
|
No difference
|
No difference
|
Carvedilol at the end of follow-up
|
No difference
|
No difference
|
Higher in 12,5 mg group
|
Avila et al.
|
Control vs Carvedilol
|
No difference
|
N/A
|
N/A
|
No difference
|
N/A
|
|
Higher
|
Control at the end of follow-up
|
No difference
|
No difference
|
No difference
|
Higher
|
Carvedilol at the end of follow-up
|
No difference
|
No difference
|
No difference
|
Higher
|
Kaya et al.
|
Control vs Intervention
|
Lower
|
N/A
|
N/A
|
N/A
|
No difference
|
Higher
|
N/A
|
Control at the end of follow-up
|
Lower
|
N/A
|
No difference
|
Higher
|
Nebivolol at the end of follow-up
|
No difference
|
No difference
|
No difference
|
No difference
|
Chemotherapy Scheme
|
Authors
|
Comparison
|
LVEF
|
GLS
|
E/A Ratio
|
LA diameter
|
E/e'
|
BNP / NT-pro-BNP
|
Troponin I
|
ANT + TZB
|
Farahani et al.
|
Control vs Carvedilol
|
No difference
|
Lower
|
Lower
|
N/A
|
No difference
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
Lower
|
Lower
|
No difference
|
Carvedilol at the end of follow-up
|
No difference
|
No difference
|
No difference
|
No difference
|
ANT ± TZB
|
Gulati et al.
|
Control vs Candesartan + Metoprolol
|
No difference
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Metoprolol vs. Non-Metoprolol
|
No difference
|
No difference
|
Higher
|
Higher
|
No difference
|
TZB ± ANT
|
Pituskin et al.
|
Control vs. Bisoprolol
|
Lower
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Perindopril vs. Bisoprolol
|
Lower
|
Control at the end of follow-up
|
Lower
|
Bisoprolol at the end of follow-up
|
No difference
|
Guglin et al.
|
Control vs. Carvedilol
|
No difference§
|
N/A
|
N/A
|
N/A
|
N/A
|
No difference
|
N/A
|
Control vs. Lisinopril
|
No difference§
|
No difference
|
Carvedilol vs. Lisinopril
|
No difference§
|
No difference
|
N/A: Item not studied or information not available. § differences measured through incidence rates |
Angiotensin Conversion Enzyme Inhibitors
All five studies with ACEi assessed LVEF (19, 22, 23, 33, 39). Słowik et al. did not found any differences in LVEF during the treatment (19). Janbabai et al. found a significant decrease in LVEF in control group during follow-up and also found this decline to differ significantly from enalapril group (39). Three studies compared a BB and an ACEi and found conflicting results (22, 23, 33). Georgakopopulos et al. and Guglin et al. did not find any differences in LVEF. On the other hand, Pituskin et al. that found LVEF to decrease both in perindopril and control groups when compared to bisoprolol group. These results by Pituskin et al. elicit an absent protective effect of ACEi in cardiotoxicity(22).
There was no opportunity for a meta-analysis, since the studies had different chemotherapy schemes or had different representations of LVEF (as continuous outcome and as a dichotomous event rate).
Two studies analyzed E/A ratio. Georgakopoulos et al. did not find any differences between groups (33). Janbabai et al. found it to decrease in control, however, despite of that, the groups were considered similar at the end of follow-up (39). Regarding to the E/e’ ratio, only Janbabai et al. found statistically significant differences. They found it to increase in the control group and found this rise to be statistically significant when compared to enalapril. They also assessed LA diameter and found it to increase in control group and this rise to be significant when compared to enalapril group (39). There was no opportunity for a meta-analysis, since the studies had too discrepant follow-up lengths
Two articles measured BNP/NT-pro-BNP levels (19, 23). Słowik et al. found the control group to have a higher incidence of increased values. However, the groups were similar at the end of follow-up. They also did not find any differences in TnI levels (19).
Guglin et al. did not find any differences in BNP levels (23). There was no opportunity for a meta-analysis, since the studies had different chemotherapy schemes.
The results for ACEi on LVEF, diastolic function and cardiac biomarkers are summarized in Table 3.
Table 3
Summary of results from ACEi studies
Chemotherapy Scheme
|
Authors
|
Comparison
|
LVEF
|
E/A Ratio
|
LA diameter
|
E/e'
|
BNP / NT-pro-BNP
|
Troponin I
|
ANT only
|
Janbabai et al.
|
Control vs Enalapril
|
Lower
|
No difference
|
Higher
|
Higher
|
N/A
|
N/A
|
Control at the end of follow-up
|
Lower
|
Lower
|
Higher
|
Higher
|
Enalapril at the end of follow-up
|
No difference
|
No difference
|
No difference
|
No difference
|
Georgakopoulos et al.
|
Control vs Enalapril
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
No difference
|
No difference
|
Enalapril at the end of follow-up
|
No difference
|
No difference
|
No difference
|
ANT ± TZB
|
Słowik et al.
|
Control vs Enalapril
|
No difference
|
N/A
|
N/A
|
N/A
|
No difference
|
No difference
|
Control at the end of follow-up
|
No difference
|
Higher§
|
No difference
|
Ramipril at the end of follow-up
|
No difference
|
No difference
|
No difference
|
TZB ± ANT
|
Pituskin et al.
|
Control vs. Perindopril
|
No difference
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Perindopril vs. Bisoprolol
|
Lower
|
Control at the end of follow-up
|
Lower
|
Perindopril at the end of follow-up
|
Lower
|
Guglin et al.
|
Control vs. Lisinopril
|
No difference§
|
N/A
|
N/A
|
N/A
|
No difference§
|
N/A
|
Carvedilol vs. Lisinopril
|
No difference§
|
No difference§
|
N/A: Item not studied or information not available. § differences measured through incidence rates. Outcomes that were not measured in any study were omitted |
Angiotensin II Receptor Antagonists
Considering the 4 studies that included ARA, only one found that an ARA, namely candesartan, to be protective of LVEF (20, 32, 34, 35). Two articles analyzed the E/A ratio, and only Cadeddu et al. found it to decrease in control group and to remain identical in the intervention group at the end of chemotherapy (34, 35). However, no comparison was made between control and intervention group (35). Only Gulati et al. measured E/e’ and GLS and did not found any differences (20).
Three studies measured BNP (20, 32, 34). Only Gulati et al. found it to be increased in control group at the end of follow-up (20). Two articles measured TnI and did not find any significant differences between the groups (20, 32).
There was no opportunity for a meta-analysis, since the studies had different chemotherapy schemes or too discrepant follow-up lengths. These results are summarized in Table 4.
Table 4
Summary of results from ARA studies
Chemotherapy Scheme
|
Authors
|
Comparisons
|
LVEF
|
GLS
|
E/A Ratio
|
E/e'
|
BNP
|
Troponin I
|
ANT only
|
Nakamae et al
|
Control vs Valsartan
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
N/A
|
Higher
|
Valsartan at the end of follow-up
|
N/A
|
No difference
|
No difference
|
Cadeddu et al.
|
Control vs Telmisartan
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
Lower
|
Intervention at the end of follow-up
|
No difference
|
No difference
|
ANT ± TZB
|
Gulati et al.
|
Control vs Candesartan + Metoprolol
|
No difference
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Candesartan vs Non-Candersartan
|
No difference
|
No difference
|
No difference
|
No difference
|
No difference
|
ANT + TZB
|
Boekhout et al.
|
Control vs Candesartan
|
No difference
|
N/A
|
N/A
|
N/A
|
No difference
|
No difference
|
Control at the end of follow-up
|
No difference
|
No difference
|
No difference
|
Candesartan at the end of follow-up
|
No difference
|
No difference
|
No difference
|
N/A: Item not studied or information not available. Outcomes that were not measured in any study were omitted |
Aldosterone Receptor Antagonists
Akpek et al. studied spironolactone and found LVEF to decrease in control group and this decline to be significant when compared to intervention group. It also found E/A ratio to decrease in control group during follow-up. It did not find any differences in NT-pro-BNP, however, it found TnI increase in both groups, but with a higher increase in the control group (30). These results are summarized in Table 5.
Table 5
Summary of results from Spironolactone and Anti-oxidative Therapies
Authors
|
Comparison
|
LVEF
|
GLS
|
E/A Ratio
|
LA diameter
|
E/e'
|
BNP / NT-pro-BNP
|
Troponin I
|
Akpek et al.
|
Control vs Spironolactone
|
Lower
|
N/A
|
No difference
|
N/A
|
No difference
|
No difference
|
Higher
|
Control at the end of follow-up
|
Lower
|
Lower
|
Higher
|
No difference
|
Higher
|
Spironolactone at the end of follow-up
|
No difference
|
No difference
|
No difference
|
No difference
|
Higher
|
Marty et al.
|
Control vs Dexrazoxane
|
Higher incidence of cardiac events
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Swain et al.
|
Control vs Dexrazoxane
|
Higher incidence of cardiac events
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Venturini et al.
|
Control vs Dexrazoxane
|
Higher incidence of cardiac events
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Nabati et al.
|
Control vs. Rosuvastatin
|
Lower
|
No difference
|
N/A
|
Higher
|
Higher
|
N/A
|
N/A
|
Control at the end of follow-up
|
Lower
|
Lower
|
Higher
|
Higher
|
Rosuvastatin at the end of follow-up
|
No difference
|
Lower
|
Lower
|
No difference
|
Milei et al.
|
Control vs Prenylamine
|
N/A
|
N/A
|
N/A
|
No difference
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
Prenylamine at the end of follow-up
|
No difference
|
Zhang et al.
|
Control vs Salidroside
|
No difference
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Control at the end of follow-up
|
No difference
|
Salidroside at the end of follow-up
|
No difference
|
Jo et al.
|
Control vs NAC
|
No difference
|
N/A
|
No difference
|
N/A
|
No difference
|
N/A
|
No difference
|
Control at the end of follow-up
|
Lower
|
No difference
|
No difference
|
No difference
|
NAC at the end of follow-up
|
Lower
|
No difference
|
No difference
|
No difference
|
N/A: Item not studied or information not available. |
Antioxidative Therapies
Dexrazoxane
Three articles analyzed the effect of dexrazoxane in LVEF (8, 28, 29). They defined cardiac events based on LVEF reduction and compared their incidence between the groups. The criteria for cardiac event for each article are displayed in the Supplementary File 3. We performed a meta-analysis that found a combined risk ratio of 0,28 (95%CI:[0,16; 0,47]) with statistical significance (p < 0,00001) and a low heterogeneity (I2 = 9%). These results are depicted in Supplementary File 8 and summarized on Table 5
One article studied the effect of rosuvastatin and found LVEF to decrease in control group and this decline to be significant when compared to intervention group. Despite finding lower absolute GLS values both in the control and rosuvastatin group at the end of the study, it did not find them to be different.
They also analyzed LA diameter and E/e’ ratio. LA diameter was reduced in intervention group and increased in control during chemotherapy and were different at the end of follow-up. Similarly, E/e’ ratio increased in control group and that increase was significantly different form rosuvastatin group (21). These results are summarized in Table 5.
Salidroside was administered in one study, however it did not find any significant changes in LVEF (24). These results are summarized in Table 5.
NAC was administered in one trial. A significant decrease in LVEF was found both in control and intervention during chemotherapy. Yet a difference between groups was not find. No differences were found in E/A ratio or TnI(9). These results are summarized in Table 5
Prenylamine was administered in one trial. Only LA diameter was assessed, and no differences were found between groups (38). These results are summarized in Table 5