Literature retrieval results
According to the retrieval strategy, a total of 11,272 articles were retrieved, including 328 from PubMed, 324 from the Cochrane Library, 300 from Embase, 7855 from Web of Science, 1396 from CNKI, and 1019 from Wanfang, VIP obtained 50 articles: 2465 articles in Chinese and 8807 articles in English. Preliminary retrieval results: After 7008 review articles and 1143 articles that could not be accessed were screened out, the remaining articles were imported into the ENDNOTE literature management tool, and 1199 duplicate articles were automatically identified and removed. For the remaining 1,922 studies, the titles and abstracts were preliminarily screened, and 1,726 studies with obvious similarity and irrelevant abstract data were excluded. For the remaining 196 papers, the full-text was downloaded and read carefully according to the inclusion and exclusion standards for secondary screening, resulting in 146 studies being eliminated. For the remaining 50 articles, after strict quality evaluation, we ruled out low-quality studies and checked references from 13 studies, resulting in 37 studies derived from references, including 32 studies in Chinese and 5 studies in English. The document selection flow chart is shown in Figure 1.
Basic characteristics of the included studies
A total of 37 studies published between 2000 and 2022 were included, including 11 published before 2014 and 26 published after 2014. The total sample size was 5706, including 1 patient who was lost to follow-up, so the actual sample size was 5705. Of the 5705 patients, the youngest was 22 years, and the oldest was 77 years, with a median number of patients included was 70 (range 20-436). Since the 12 studies had divided the patients into multiple study groups based on different factors (drug, dose, duration, etc.), we ultimately reviewed 46 treatment groups. Of the 46 treatment groups, 13 were treated with an anthracycline alone, the most commonly used anthracycline being doxorubicin, and 33 were treated with combination chemotherapy, such as CAF, TA or TE, the most common being CAF. Eleven of the 46 studies assessed agents protecting against chemotherapy-associated arrhythmias, for which only control data (placebo rather than a cardioprotective agent) were used. Anthracycline was administered at doses of 75-800 mg/m2. 22 treatment groups received intravenous infusion, 2 treatment groups received oral administration, and the remaining 21 treatment groups did not have specific reports of administration route. The basic characteristics of the included studies are shown in Table 1.
Table 1
The basic characteristics of the included studies
|
Study
|
Year
|
Language
|
Total Patients
|
No. Event
|
Changes in ECG
|
Subtype of Events
|
Treatmen-t plan
|
Treatment cycle
|
Dosage(mg/m2)
|
Administratio-n mode
|
MINO-RS
score
|
He F
|
2017
|
Chinese
|
213
|
72
|
T wave change(40)ST-T segment change(11)
|
Conduction block(5)Sinus tachycardia(13)Sinus bradycardia(6)Sinus arrhythmia(6)Ventricular premature beat(1)
|
ADR
|
1-6cycle
|
/
|
/
|
12
|
Zhang KK
|
2014
|
Chinese
|
78
|
45
|
ST segment change(15)
QT interval change(4)
|
Atrial premature beat(8)
Ventricular premature beat(6)
Sinus arrhythmia(12)
|
TA
|
4cycle
|
200
|
/
|
14
|
Yi SY
|
2008
|
Chinese
|
30
|
9
|
ST-T segment change(4)QRS low voltage(1)
|
Sinus tachycardia(2)Premature beat(2)
|
PA
|
4cycle
|
200
|
iv
|
13
|
Zhang MM
|
2018
|
Chinese
|
291
|
133
|
ST segment change(48)
|
Atrial premature contraction(41)Ventricular premature contraction(42)
|
AC/EC
|
6-8cycle
|
240-320
|
/
|
15
|
Pan Y
|
2008
|
Chinese
|
59
|
21
|
ST-T segment change(5)QRS low voltage(2)
|
Ventricular premature contraction(1)Third degree atrioventricular block(1)Sinus tachycardia(2)
|
EPI
|
6M-5Y
|
32-478.6
|
iv drop
|
12
|
Zhang SJ
|
2011
|
Chinese
|
50
|
12
|
ST-T segment change(3)Low voltage(1)
|
Sinus tachycardia
(3)Ventricular premature beat(4)Atrial premature beat(1)
|
FAC
|
6cycle
|
300
|
/
|
12
|
Feng LF
|
2014
|
Chinese
|
40
|
17
|
ST-T segment change(10)
|
Atrial premature contraction(2)Ventricular premature contraction(1)Atrioventricular block(1)Sinus bradycardia/Sinus tachycardia(3)
|
TAC
|
6cycle
|
300
|
/
|
17
|
Wang F
|
2016
|
Chinese
|
20
|
7
|
ST segment depression(1)T wave change(2)
|
Premature beat(2)Sinus tachycardia
(1)First degree atrioventricular block(1)
|
TE
|
6cycle
|
450
|
p.o.
|
17
|
Ma L
|
2000
|
Chinese
|
83
|
26
|
Low voltage(6)ST-T segment change(5)
|
Sinus tachycardia(9)Atrial premature beat(2)Ventricular premature beat(3)RBBB(1)
|
ADR
|
3-10cycle
|
120-400
|
iv
|
12
|
Ding SQ
|
2014
|
Chinese
|
26
|
16
|
ST-T segment change(8)P wave change(3)
|
Sinus bradycardia/Sinus tachycardia(4)Premature beat(1)
|
AC/EC
|
4cycle
|
450-550
|
/
|
12
|
Ding SQ
|
2014
|
Chinese
|
26
|
12
|
ST-T segment change(8)P wave change(1)
|
Sinus bradycardia/Sinus tachycardia(4)Premature beat(1)
|
AC/EC
|
6cycle
|
450-550
|
|
12
|
He C
|
2012
|
Chinese
|
207
|
123
|
ST-T segment change(22)T wave change(17)QRS low voltage(26)QT interval change(32)
|
Premature beat(16)
|
FAC/FEC/AC
|
6cycle
|
/
|
/
|
18
|
Meng KX
|
2015
|
Chinese
|
35
|
25
|
ST-T segment change(8)QT interval change(2)
|
Sinus tachycardia(2)﹐Sinus bradycardia(1)Atrial premature contraction(10)﹐Ventricular premature contraction(2)
|
EC-T
|
4cycle
|
360
|
iv drop
|
18
|
Qi CC
|
2017
|
Chinese
|
123
|
73
|
ST-T segment change(30)T wave change(13)P wave change(14)Electric axis deflection(8)
|
Sinus tachycardia(7)Conduction block(11)
|
AC-T/CAF-T
|
6cycle
|
300
|
iv drop
|
14
|
Wang ZH
|
2017
|
Chinese
|
78
|
19
|
ST-T segment change(9)
|
Atrioventricular block(3)Sinus bradycardia(2)
Ventricular premature contraction(1)
Atrial premature contraction(4)
|
AC-T
|
8cycle
|
400
|
/
|
18
|
Xiong P
|
2006
|
Chinese
|
43
|
24
|
QT-QTc change(12)QRS low voltage(4)
ST-T segment change(1)
|
Sinus tachycardia(2)Atrial premature beat(2)Ventricular premature beat(3)
|
CAF
|
10cycle
|
500
|
iv drop
|
14
|
Xu GQ
|
2017
|
Chinese
|
42
|
17
|
ST-T segment change(3)
QT interval change(2)
|
Atrial/Ventricular premature beat(9)
Atrial fibrillation(7)
Sinus tachycardia(12)
|
TEC
|
6cycle
|
420
|
p.o.
|
17
|
Lv Y
|
2021
|
Chinese
|
191
|
62
|
/
|
/
|
AC/AC-T
|
1cycle
|
/
|
/
|
14
|
Lv Y
|
2021
|
Chinese
|
191
|
76
|
ST-T segment change(35)
|
Sinus bradycardia/Sinus tachycardia(28)Atrial premature beat/Ventricular premature beat(7)Sinus arrhythmia(6)
|
ADR
|
4cycle
|
/
|
/
|
14
|
Feng YY
|
2014
|
Chinese
|
232
|
47
|
ST-T segment change(15)QRS low voltage(2)
|
Sinus arrhythmia(17)Sinus tachycardia(12)Sinus bradycardia(5)Atrial premature beat(5)Ventricular premature beat(4)First degree atrioventricular block(2)Atrial fibrillation(1)Supraventricular tachycardia(1)
|
ADR
|
4-8cycle
|
240-800
|
iv drop
|
13
|
Yang ZJ
|
2010
|
Chinese
|
272
|
88
|
ST-T segment change(18)QRS Low voltage(2)
|
First degree atrioventricular block(2)Sinus tachycardia(22)Sinus bradycardia(20)Ventricular premature beat(15)Atrial fibrillation(9)
|
CAF
|
6cycle
|
/
|
/
|
12
|
Yang M
|
2018
|
Chinese
|
266
|
104
|
Short PR interval(3)ST-T segment change(17)T wave change(52)
|
Sinus tachycardia(27)Sinus bradycardia(9)Atrial premature contraction(8)Ventricular premature contraction(13)Atrioventricular block(1)Bundle branch block(6)
|
FAC/FEC/TAC/AC/EC
|
4cycle
|
/
|
/
|
14
|
Cheng Y
|
2017
|
Chinese
|
253
|
92
|
QTc change(31)T wave change(25)ST segment change(16)Abnormal Q wave(2)
|
Atrioventricular block(2)RBBB(1)Borderline premature beat(1)Sinus tachycardia(10)Sinus bradycardia(9)Atrial premature contraction(7)Ventricular premature contraction(5)
|
AC/AC-T/TA/CAF
|
/
|
276
|
/
|
12
|
Yang XL
|
2008
|
Chinese
|
436
|
155
|
ST-T segment change(58)QT interval change(24)QRS low voltage(16)
|
Sinus tachycardia(18)Atrial premature beat(22)Ventricular premature beat(15)Atrioventricular block(2)
|
CAF
|
6cycle
|
480-540
|
/
|
19
|
Ren JL
|
2020
|
Chinese
|
50
|
22
|
ST-T segment change(10)
|
Atrial/Ventricular premature contraction(6)Sinus bradycardia/Sinus tachycardia(3)Atrioventricular block(3)
|
ADR
|
4cycle
|
/
|
/
|
18
|
Wu YT
|
2020
|
Chinese
|
276
|
110
|
T wave change(57)ST segment change(38)
|
Sinus arrhythmia(27)Supraventricular tachycardia/Sinus tachycardia(10)
|
ADR
|
/
|
/
|
/
|
13
|
Zhao L
|
2019
|
Chinese
|
58
|
21
|
ST-T segment change(8)
|
Ventricular premature contraction(1)Atrial premature contraction(4)Atrioventricular block(2)Sinus tachycardia or bradycardia(6)
|
CAF
|
6cycle
|
450
|
iv drop
|
18
|
Guan WF
|
2021
|
Chinese
|
107
|
53
|
ST-T segment change(8)QRS low voltage(6)
|
Sinus tachycardia(13)Sinus bradycardia(6)Ventricular premature contraction(5)Atrial premature contraction(6)Atrioventricular block(3)Bundle branch block(4)Supraventricular tachycardia(2)
|
ADR
|
4-6cycle
|
300—400
|
/
|
13
|
Guan WF
|
2021
|
Chinese
|
123
|
40
|
ST-T segment change(7)QRS low voltage(4)
|
Sinus tachycardia(8)Sinus bradycardia(6)Ventricular premature contraction(4)Atrial premature contraction(5)Atrioventricular block(2)Bundle branch block(4)
|
ADR
|
4-6cycle
|
200—300
|
/
|
13
|
Feng BH
|
2019
|
Chinese
|
93
|
32
|
ST-T segment change(5)QRS low voltage(3)QT-QTc change(2)
|
Sinus tachycardia(7)Sinus bradycardia(4)Ventricular premature beat(1)Atrial premature beat(6)Bundle branch block(4)
|
CAF
|
6cycle
|
300
|
iv
|
15
|
Feng BH
|
2019
|
Chinese
|
92
|
49
|
ST-T segment change(8)QRS low voltage(5)QT-QTc change(4)
|
Sinus tachycardia(11)Sinus bradycardia(5)Ventricular premature beat(3)Atrial premature beat(8)Supraventricular tachycardia(1)Bundle branch block(4)
|
CAF
|
6cycle
|
450
|
iv
|
15
|
Dong XJ
|
2020
|
Chinese
|
279
|
160
|
QTc change(78)ST-T segment change(22)Chest lead low voltage(7)Reverse clock transposition(7)Clockwise transposition(3)Limb lead low voltage(3)Left ventricular high voltage(2)
|
Sinus bradycardia(18)First degree atrioventricular block(8)Ventricular premature beat(5)Sinus arrhythmia(4)Atrial premature beat(3)
|
ADR
|
4cycle
|
120-360
|
iv drop
|
14
|
Chen MC
|
2020
|
Chinese
|
40
|
21
|
/
|
Frequent ventricular premature beats(20)Paired ventricular premature beats(21)Short array ventricular tachycardia(21)
|
THP
|
4cycle
|
600
|
iv drop
|
17
|
Chen MC
|
2020
|
Chinese
|
40
|
27
|
/
|
Frequent ventricular premature beats(26)Paired ventricular premature beats(27)Short array ventricular tachycardia(26)
|
THP
|
6cycle
|
600
|
iv drop
|
17
|
Shen X
|
2011
|
Chinese
|
30
|
18
|
ST-T segment change(9)QT-QTc change(2)QRS low voltage(3)
|
Sinus tachycardia(2)Atrial premature beat(3)Ventricular premature beat(1)
|
EPB
|
/
|
/
|
/
|
16
|
Ma YF
|
2016
|
Chinese
|
40
|
10
|
R-wave low voltage(2)T wave change(7)ST segment
change(4)QT interval change(1)
|
Sinus tachycardia/Sinus bradycardia(1)RBBB(2)PAC(1)PVC(1)AVB(2)
|
TE
|
1cycle
|
75
|
iv drop
|
16
|
Ma YF
|
2016
|
Chinese
|
40
|
15
|
R-wave low voltage(6)
T wave change(11)
ST segment change(15)
QT interval change(1)
|
Sinus tachycardia/Sinus bradycardia(4)RBBB(3)PAC(3)PVC(2)AVB(2)
|
TE
|
2cycle
|
150
|
iv drop
|
16
|
Ma YF
|
2016
|
Chinese
|
40
|
21
|
R-wave low voltage(9)
T wave change(14)
ST segment change(20)
QT interval change(5)
|
Sinus tachycardia/Sinus bradycardia(7)RBBB(5)PAC(7)PVC(5)AVB(3)
|
TE
|
3cycle
|
225
|
iv drop
|
16
|
Qi YX
|
2017
|
Chinese
|
152
|
43
|
R-wave low voltage(29)T wave change(9)ST segment elevation(36)ST segment depression(19)QT interval change(23)
|
Atrioventricular block(9)RBBB(3)Sinus tachycardia(16)Sinus bradycardia(18)Premature beat(9)
|
AC-T
|
3cycle
|
225
|
/
|
14
|
Wu QD
|
2016
|
Chinese
|
70
|
35
|
QRS low voltage(4)ST-T segment change(6)
|
Sinus bradycardia(4)Sinus tachycardia(8)Atrial premature contraction(4)Ventricular premature contraction(3)Supraventricular tachycardia(1)Bundle branch block(3)Atrioventricular block(2)
|
AC/FAC
|
6cycle
|
300-400
|
iv
|
15
|
Wu QD
|
2016
|
Chinese
|
70
|
23
|
QRS low voltage(2)ST-T segment change(4)
|
Sinus bradycardia(3)Sinus tachycardia(5)Atrial premature contraction(3)Ventricular premature contraction(2)Bundle branch block(3)Atrioventricular block(1)
|
AC/FAC
|
6cycle
|
200-300
|
iv
|
15
|
Liu B
|
2018
|
English
|
409
|
101
|
ST-T segment change(45)QRS low voltage(14)
|
Sinus tachycardia(37)Sinus arrhythmia(8)Sinus bradycardia(4)Ventricular premature contraction(3)Atrial premature contraction(2)RBBB(2)Atrial flutter and borderline premature beat(1)
|
EC/CAF/EC-T/ET/TAC
|
4-6cycle
|
360-540、200-300
|
/
|
15
|
Hu G.
|
2022
|
English
|
60
|
28
|
ST-T segment change(2)QT-QTc change(3)QRS low voltage(3)
|
Atrial premature beat(6)Ventricular premature beat(4)Sinus tachycardia(4)Sinus bradycardia(4)Ventricular block(2)
|
ADR
|
6cycle
|
300
|
iv drop
|
16
|
Hu G.
|
2022
|
English
|
62
|
35
|
ST-T segment change(3)QT-QTc change(3)QRS low voltage(2)
|
Atrial premature beat(7)Ventricular premature beat(5)Supraventricular tachycardia(2)Sinus tachycardia(7)Sinus bradycardia(4)Ventricular block(2)
|
ADR
|
6cycle
|
450
|
iv drop
|
16
|
Huang ZQ
|
2004
|
English
|
250
|
107
|
Limb lead low voltage(12)T wave change(29)T wave change(12)ST segment depression(18)QT interval change(28)
|
Sinus tachycardia(8)
|
AC/EC
|
10cycle
|
70
|
iv drop
|
15
|
Ando M
|
2000
|
English
|
39
|
11
|
ST-T segment change(2)
|
Atrial arrhythmia(3)Ventricular arrhythmia(2)Atrioventricular block(4)
|
ADR
|
6-8cycle
|
300
|
iv drop
|
13
|
Results of the meta-analysis
Incidence of anthracycline-associated arrhythmias
A total of 2,257 anthracycline-associated arrhythmia events were reported in the 37 studies (n=5705), with a wide incidence range from 20% to 71%. Due to significant heterogeneity between studies (I2=84.6%, P <0.001), a random effects model was used for analysis, and Figure 2 shows a forest map of the incidences of anthracycline-induced arrhythmias in breast cancer. A pooled analysis of the 37 studies showed that the incidence of cardiotoxicity in breast cancer patients receiving anthracycline chemotherapy was approximately 0.41 (0.37, 0.44).
Subgroup analysis
Subgroup analysis was performed according to publication year, sample size, and dose and duration of administration.
To explore the source of heterogeneity, subgroup analysis was performed based on year of publication, sample size, and dose and duration of anthracycline administration. As shown in Table 2, treatment cycle may be one of the sources of heterogeneity in this study.
The results (shown by year of publication in Table 2) showed that the incidence of anthracycline-associated arrhythmias was 0.39 (0.32, 0.46) in 11 treatment groups of 11 studies published before 2014 and 0.41 (0.37, 0.46) in 35 treatment groups of 26 studies published in 2014 and after. The heterogeneity between groups was p=0.604.
For the analysis based on sample size (Table 2), we defined subgroups: sample size < 100 was considered a small sample size, sample size = 100-200 was considered a medium sample size, and sample size > 200 was considered a large sample size. Subgroup analysis showed that the incidence of anthracycline-associated arrhythmias was 0.44 (0.39, 0.49) in 27 treatment groups of 20 studies with small sample sizes. The incidence of anthracycline-associated arrhythmias was 0.37 (0.31, 0.42) in six treatment groups of five studies with moderate sample sizes. The incidence of anthracycline-associated arrhythmias was 0.39 (0.32, 0.45) in 12 treatment groups in 12 studies with large sample sizes. The intergroup heterogeneity was P=0.158.
A subgroup analysis according to dose of anthracycline was also performed (Table 2). To explore the effect of different doses of anthracyclines on the incidence of arrhythmia, We divided the study into Group A (cumulative dose < 200 mg/m2), Group B(cumulative dose 200-399 mg/m2), and Group C (cumulative dose ≥400 mg/m2) according to the cumulative dose of anthracycline. The treatment dose was clearly not reported for 12 treatment groups in 11 studies, including the studies of He, F and others, so these studies were not included in the subgroup analysis. The results of the subgroup analysis of the remaining studies showed that the number of studies in Group A was less than or equal to 3, which was too low for STATA and Metaprop to be used for the subgroup analysis (the number of study groups needs to be > 3). Therefore, subgroup analysis could not be performed. There were 16 studies in Group B and 19 in the treatment group, and the combined analysis showed that the cumulative dose of anthracycline ranged from 200 mg/m2 to 399 mg/m2. The incidence of arrhythmia was 0.41 (0.35, 0.47). There were 10 studies in Group C and 12 in the treatment group. The combined analysis results showed that the cumulative dose of anthracycline was ≥400 mg/m2. The incidence of arrhythmia was 0.46 (0.39, 0.54). The intergroup heterogeneity was p=0.304.
Subgroup analysis based on anthracycline cycle was also performed (Table 2), and studies in which patients received less than four cycles of chemotherapy were included in Group A. Studies in which patients received four cycles of chemotherapy were included in Group B. Studies in which patients received six cycles of chemotherapy were included in Group C, and studies in which patients received more than six cycles of chemotherapy were included in Group D. The study of Feng YY and 8 other studies (including 9 treatment groups) were not included in the subgroup analysis due to their unclear report of anthracycline cycle. Subgroup analysis of the remaining studies showed that group A included 3 studies and 5 treatment groups. Combined analysis showed that the incidence of arrhythmias was 0.34 (0.27, 0.41) with no more than 3 cycles of anthracycline therapy. A total of 8 studies and 8 treatment groups were included in Group B, and the combined analysis showed that the incidence of arrhythmia was 0.50 (0.41, 0.58). A total of 14 studies and 18 treatment groups were included in Group C, and the combined analysis results showed that the incidence of arrhythmia was 0.43 (0.38, 0.49). There were 6 studies and 6 treatment groups in Group D, and the combined analysis showed that the incidence of arrhythmia was 0.39 (0.31, 0.47). The intergroup heterogeneity was P=0.04 (< 0.05), so chemotherapy cycle may be one of the sources of heterogeneity in this study.
Table.2
subgroup analysis based on publication year, sample size, and dose and duration of administration
|
Datasets
|
Total
|
Event
|
Proportion (95% CI)
|
p
|
I2
|
heterogeneity between groups(P)
|
Year of publication
|
Before 2014
|
11
|
1499
|
594
|
0.39(0.32,0.46)
|
<0.001
|
84.34%
|
0.604
|
After 2014
|
35
|
4206
|
1638
|
0.41(0.37,0.46)
|
<0.001
|
85.08%
|
Sample size
|
<100
|
28
|
1434
|
618
|
0.44(0.39,0.49)
|
<0.001
|
71.76%
|
0.158
|
100-200
|
6
|
884
|
322
|
0.37(0.31,0.42)
|
0.01
|
67.57%
|
>200
|
12
|
3171
|
1220
|
0.39(0.32,0.45)
|
<0.001
|
94.32%
|
Dosage
|
<200mg/m2
|
3
|
330
|
132
|
/
|
/
|
/
|
0.304
|
200-399mg/m2
|
19
|
2342
|
928
|
0.41(0.35,0.47)
|
<0.001
|
87.25%
|
≥400mg/m2
|
12
|
963
|
403
|
0.46(0.39,0.54)
|
<0.001
|
77.56%
|
Cycle
|
<4 cycle
|
5
|
463
|
151
|
0.34(0.27,0.41)
|
0.05
|
57.06%
|
0.04
|
4 cycle
|
8
|
955
|
457
|
0.50(0.41,0.58)
|
<0.001
|
82.63%
|
6 cycle
|
18
|
1801
|
750
|
0.43(0.38,0.49)
|
<0.001
|
79.14%
|
>6 cycle
|
6
|
760
|
315
|
0.39(0.31,0.47)
|
<0.001
|
74.55%
|
Subgroup analysis based on type of ECG change
Subgroup analysis based on type of ECG change, including QT-QTc interphase change, PR interphase change, P wave change, ST-T segment change, and low voltage abnormality, was also performed. (Table 3)
QT-QTc interphase change
Zhang KK et al. reported prolongation of the QT-QTc interval induced by anthracycline chemotherapy in 20 treatment groups in 16 studies. In a total of 2291 patients, 255 patients developed QT-QTc prolongation, with an incidence of 0.03-0.28. Analysis of the combined results showed that the incidence was 0.08 (0.05, 0.11) (Table 3).
PR interphase change
The study by Yang M was the only study to report a short PR interval induced by anthracycline chemotherapy, with an incidence of 0.01. A study conducted by Chen MC explored the influence of treatment cycle on the incidence of short PR interval. The incidence was 0.55 with 4 cycles of chemotherapy and increased to 0.65 with 6 cycles, showing a certain dose-related relationship.
P wave change
Two studies by Ding SQ et al. and three treatment groups reported anthracycline-related P wave changes, including 18 patients with P wave changes (14 of them with P wave broadening) in a total of 175 patients, with an incidence of 0.03-0.11. The combined analysis showed an incidence of 0.10 (0.05, 0.15) (Table 3).
ST-T period change
ST-T changes were the most common ECG changes in anthracycline-associated arrhythmias, reported in 45 treatment groups in 37 studies and in 1011 of 5514 patients, for an incidence of 0.03-0.70. The combined analysis showed that the incidence of ST-T segment change associated with anthracycline was 0.19 (0.15, 0.23).
Wang F et al. reported 7 studies and 9 treatment groups of patients with only ST segment changes. Among 1337 patients, 197 patients showed ST segment changes (including ST segment elevation in 37 patients and ST segment decline in 44 patients), with an incidence of 0.05-0.40. The combined analysis showed an incidence of 0.17 (0.09, 0.27).
Yang M et al., in 10 studies and 12 treatment groups, reported only T-segment changes in 289 of 1880 patients (including 14 patients with T-wave decrease and 12 patients with T-wave inversion), and the combined analysis showed a 0.15 (0.12, 0.19) incidence of T-wave changes associated with anthracycline chemotherapy (Table 3).
Low voltage abnormalities
Low-voltage abnormalities induced by anthracycline therapy in breast cancer was described in 18 studies, 24 treatment groups, and 161 of 2920 patients, for an incidence ranging from 0.01 to 0.23, and the pooled analysis showed an incidence of 0.05 (0.03, 0.08).
Among the studies, the study by Yi SY et al., 11 studies and 15 treatment groups reported anthracycline-associated QRS low voltage, and 82 of 1714 patients developed QRS low voltage, for an incidence of 0.01-0.13. The combined analysis showed an incidence of 0.04 (0.03, 0.06). The incidence of low R-wave voltage was reported in two studies and four treatment groups, for a combined incidence of 0.16 (0.09, 0.24). Other low voltage abnormalities were limb lead low voltage (0.03, 23/884) and chest lead low voltage (0.03, 7/279) (Table 3).
Subgroup analysis based on arrhythmia.
Finally, subgroup analysis based on arrhythmia subtype, including conduction block, heart rate changes, premature beats, and other arrhythmias, was performed. (Table 3)
Conduction block
Anthracycline-induced block was reported in 29 treatment groups in 26 studies and 127 of 3859 patients, for an incidence ranging from 0.01 to 0.20, and the pooled analysis showed an incidence of 0.04 (0.02, 0.05).
Yang M et al. reported the incidence of bundle branch block in 9 studies and 14 treatment groups, and 47 of 1798 patients developed bundle branch block, for an incidence ranging from 0.01 to 0.11. The combined analysis showed that the incidence was 0.03 (0.02, 0.04). Among the studies, 5 studies including HeF and 7 treatment groups reported the incidence of complete right bundle branch block in detail: 19 of 977 patients developed complete right bundle branch block. The combined analysis showed that the incidence was 0.03 (0.01, 0.05). In addition, He F reported two cases of incomplete right bundle branch block and one case of left anterior bundle branch block in a study of 213 people.
Pan Y et al. reported the incidence of anthracycline-related atrioventricular block in 17 studies and 21 treatment groups. A total of 57 patients developed atrioventricular block in 2724 patients, including 13 cases of first-degree atrioventricular block, 2 cases of second-degree atrioventricular block, and 1 case of third-degree atrioventricular block. The incidence of atrioventricular block ranged from 0.01 to 0.10, and the incidence in the pooled analysis was 0.02 (0.01, 0.03). In addition, a study with a sample size of 101 conducted by Hu and G showed 4 cases of ventricular block (Table 3).
Heart rate change
Changes in heart rate associated with anthracycline use were reported in 42 treatment groups in 34 studies and in 576 of 4977 patients, for an incidence ranging from 0.01 to 0.54. The incidence in the pooled analysis was 0.12 (0.10, 0.15).
Yi SY et al. reported the occurrence of anthracycline-related tachycardia in 25 studies and 30 treatment groups. A total of 285 cases of tachycardia occurred in 4003 patients, for an incidence of 0.03-0.29. The combined analysis showed that the incidence was 0.07 (0.06, 0.09).
Meng KX et al. reported anthracycline-related bradycardia in 14 studies and 18 treatment groups, and 130 of 2866 patients developed bradycardia, for an incidence of 0.01-0.13. The combined analysis showed an incidence of 0.05 (0.03, 0.06).
Three studies by Feng YY et al. and four treatment groups reported anthracycline-related supraventricular tachycardia, and 6 of 493 patients developed supraventricular tachycardia, for an incidence of 0.01-0.03. The combined analysis showed an incidence of 0.01 (0.00, 0.02).
In addition, Wu QD et al. reported one case of ventricular tachycardia induced by anthracycline chemotherapy, and Chen MC et al. reported 47 cases of shortwave ventricular tachycardia induced by anthracycline chemotherapy (Table 3).
Premature beat
Premature beat induced by anthracycline therapy in breast cancer was described in 31 studies in 38 treatment groups, with 399 cases occurring in 4716 patients, for an incidence ranging from 0.01 to 0.34. The incidence in the pooled analysis was 0.09 (0.07, 0.11).
The study of Zhang KK et al., 21 studies and 27 treatment groups reported anthracycline-related atrial premature beats, and 179 of 3487 patients had atrial premature beats, for an incidence of 0.01-0.29. The combined analysis showed an incidence of 0.05 (0.04, 0.07).
He, F et al. reported anthracycline-related premature ventricular contractions in 23 studies and 29 treatment groups, and 163 of 3972 patients developed premature ventricular contractions, for an incidence ranging from 0.01 to 0.15. The combined analysis showed an incidence of 0.04 (0.02, 0.05).
In addition, Cheng Y and Liu BL reported one case of premature beat, while Chen MC et al. reported 26 cases of frequent premature ventricular beat and 27 cases of paired premature ventricular beat in their study (n=80). (Table 3)
Other ECG changes
Xu GQ et al. reported 17 cases of atrial fibrillation induced by anthracyclines in 3 studies (n=546), and the combined results showed that the incidence was 0.04 (0.00, 0.12) (Table 3). A study by Liu BL (n=409) reported a case of anthracycline-associated atrial flutter. A study by Dong XJ (n=279) reported 3 patients with clockwise and 7 patients with counterclockwise flutter, a study by Qi CC (n=123) reported 8 patients with electroaxial flutter, and a study by Dong XJ (n=279) reported 2 patients with left ventricular hypervoltage.
Table.3
Subgroup analysis based on type of ECG change and arrhythmia
|
Datasets
|
Total
|
Event
|
Proportion (95%CI)
|
p
|
I2
|
ECG changes
|
QT-QTc interval
|
QT-QTc interval change
|
20
|
2291
|
255
|
0.08 (0.05,0.11)
|
<0.001
|
85.40%
|
P wave
|
P wave change
|
3
|
175
|
18
|
0.10(0.05,0.15)
|
0.53
|
0.00%
|
ST-T segment
|
ST-T segment change
|
45
|
5144
|
1011
|
0.19(0.15,0.23)
|
<0.001
|
92.77%
|
ST segment change
|
9
|
1337
|
197
|
0.17(0.09,0.27)
|
<0.001
|
94.36%
|
T segment change
|
12
|
1880
|
289
|
0.15(0.12,0.19)
|
<0.001
|
76.20%
|
Low voltage
|
Low voltage
|
24
|
2920
|
161
|
0.05(0.03,0.08)
|
<0.001
|
79.36%
|
QRS low voltage
|
15
|
1714
|
82
|
0.04(0.03,0.06)
|
<0.001
|
60.26%
|
R-wave low voltage
|
4
|
272
|
89
|
0.16(0.09,0.24)
|
0.06
|
58.73%
|
Arrhythmia
|
Conduction block
|
Conduction block
|
29
|
3859
|
127
|
0.04(0.02,0.05)
|
<0.001
|
76.47%
|
Branch bundle block
|
14
|
1798
|
47
|
0.03(0.02,0.04)
|
<0.001
|
59.20%
|
RBBB
|
7
|
977
|
19
|
0.03(0.01,0.05)
|
<0.001
|
73.18%
|
Atrioventricular block
|
21
|
2724
|
57
|
0.02(0.01,0.03)
|
<0.001
|
61.47%
|
Heart rate
|
Heart rate change
|
42
|
4977
|
576
|
0.12(0.10,0.15)
|
<0.001
|
82.95%
|
Tachycardia
|
30
|
4003
|
285
|
0.07(0.06,0.09)
|
<0.001
|
57.41%
|
Bradycardia
|
18
|
2866
|
130
|
0.05(0.03,0.06)
|
<0.001
|
66.21%
|
Supraventricular tachycardia
|
4
|
493
|
6
|
0.01(0.00,0.02)
|
0.31
|
16.23%
|
Premature beat
|
Premature beat
|
38
|
4716
|
399
|
0.09(0.07,0.11)
|
<0.001
|
86.63%
|
Atrial premature beat
|
27
|
3487
|
179
|
0.05(0.04,0.07)
|
<0.001
|
80.20%
|
Ventricular premature beat
|
29
|
3972
|
163
|
0.04(0.02,0.05)
|
<0.001
|
74.41%
|
atrial fibrillation
|
atrial fibrillation
|
3
|
546
|
17
|
0.04(0.00,0.12)
|
<0.001
|
89.67%
|
Publication bias
Funnel plots and Begg's and Egger's tests were used to evaluate publication bias. The funnel plot is shown in Figure 3. The included study scatter points were basically symmetrically distributed along the midline. The funnel plot was complete and symmetrical, suggesting that there was no publication bias. Publication bias is defined as P<0.05 in Begg's and Egger's tests. The results of Begg's test (P =0.103) and Egger's test (P =0.083) are shown in Fig. 4 and Fig. 5, , and there was no evidence of publication bias in this assessment of the incidence of anthracycline-related cardiotoxicity. Since there was no obvious publication bias in the included literature in this study, it was not necessary to evaluate the impact of publication bias on the results by sequentially removing each study and reanalyzing the data.