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Received: 25 February 2018    Revised: 22 October 2018    Accepted: 23 October 2018

DOI: 10.1111/1755-5922.12475

ORIGINAL RESEARCH ARTICLE

The incidence of atrial fibrillation with trastuzumab treatment:

A systematic review and meta‐analysis

Ming Yuan1 | Gary Tse2,3 | Zhiwei Zhang1 | Xu Han4 | William K. K. Wu5 | 

Guangping Li1 | Yunlong Xia4 | Tong Liu1

1
Tianjin Key Laboratory of Ionic‐Molecular
Function of Cardiovascular Disease, Summary
Department of Cardiology, Tianjin Institute Aim: Cases of cardiotoxicity related to trastuzumab have been reported. This sys-
of Cardiology, Second Hospital of Tianjin
Medical University, Tianjin, China tematic review and meta‐analysis evaluated the risk of atrial fibrillation (AF) in pa-
2
Department of Medicine and tients of breast cancer treated with trastuzumab.
Therapeutics, Chinese University of Hong
Methods: PubMed and EMBASE were searched until September 2017 for articles
Kong, Hong Kong, SAR, China
3 that investigated AF incidence in patients receiving trastuzumab for breast cancer.
Li Ka Shing Institute of Health Sciences,
Chinese University of Hong Kong, Hong Results: A total of 15 studies involving 8124 patients treated with trastuzumab were
Kong, SAR, China
included. Of the total cohort, 37 patients suffered from AF, giving rise to an incidence
4
Department of Cardiology, First Affiliated
Hospital of Dalian Medical University, of 1.22% (95% confidence interval [CI]: 0.56%‐2.68%). No significant difference in
Dalian, China the incidence of AF was found between ado‐trastuzumab emtansine (0.95%, 95% CI:
5
Department of Anaesthesia and Intensive 0.36%‐2.52%) and trastuzumab groups (1.32%, 95% CI: 0.52%‐3.34%), trastuzumab
Care, Faculty of Medicine, The Chinese
University of Hong Kong, Hong Kong, China combined with other antineoplastic agents (2.09%, 95% CI: 1.16%‐3.73%) and trastu-
zumab alone (0.36%, 95% CI: 0.04%‐3.08%), prior exposure to anthracyclines (1.72%,
Correspondence
Tong Liu, Tianjin Key Laboratory of Ionic‐ 95% CI: 0.75%‐3.88%) and no prior exposure (1.03%, 95% CI: 0.30%‐3.51%), and ra-
Molecular Function of Cardiovascular diotherapy (1.26%, 95% CI: 0.68%‐2.33%) vs. no radiotherapy (1.21%, 95% CI:
Disease, Department of Cardiology, Tianjin
Institute of Cardiology, Second Hospital of 0.35%‐4.14%).
Tianjin Medical University, Hexi District, Conclusions: Atrial fibrillation incidence in breast cancer patients receiving trastu-
Tianjin, China.
Email: liutongdoc@126.com zumab was around 1.2%. It was not influenced by the formulation of trastuzumab,
Yunlong Xia, Department of Cardiology, the additional use of neoplastic agents, anthracycline exposure status, or concurrent
First Affiliated Hospital of Dalian Medical
University, Zhongshan District, Dalian, radiotherapy.
Liaoning Province, China.
Email: yunlong_xia@126.com KEYWORDS
atrial fibrillation, breast cancer, cardiotoxicity, drug safety, trastuzumab
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 81570298,
30900618 and 81270245; Croucher
Foundation of Hong Kong

1 |  I NTRO D U C TI O N
Human epidermal growth factor receptor 2 (HER2) is a member of
the family of transmembrane receptor tyrosine kinases and is over-
expressed in 20%‐25% of women with breast cancer. Trastuzumab 1
®
(Herceptin ) is a humanized monoclonal antibody against HER2.
a
M.Y. and G.T. contributed equally to this study.
Previous studies have reported that trastuzumab significantly in-
creased overall survival (OS) and disease‐free survival in HER2‐
positive woman with early and locally advanced breast cancer.2,3
Moreover, it was shown to improve the risk of congestive heart failure
and slowed the decline of left ventricular ejection fraction (LVEF).4
2 However, data from clinical trials suggest that those receiving
trastuzumab treatment could be at higher risk of developing atrial
fibrillation (AF), which is the most common cardiac arrhythmia

Cardiovascular Therapeutics. 2018;36:e12475. wileyonlinelibrary.com/journal/cdr © 2018 John Wiley & Sons Ltd  |  1 of 7
https://doi.org/10.1111/1755-5922.12475
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2 of 7       YUAN et al.

observed in clinical practice. AF is a major risk factor for thrombo-
embolism and ischemic stroke, significantly increasing morbidity and
5
mortality. However, given the low number of AF cases reported in
clinical trials, the risk attributable to trastuzumab use is less certain.
Therefore, the aims of this systematic review and meta‐analysis are
to determine the incidence of AF in clinical trials of assessing tras-
tuzumab use and determine the various risk factors for AF develop-
ment in patients receiving this drug.
2 |  M E TH O DS
This meta‐analysis of observational studies in accordance with
the Strengthening the Reporting of Observational Studies in
Epidemiology statement.
2.1 | Search strategy and inclusion criteria
We systematically performed a literature search of the following da-
tabase (PubMed and EMBASE) in September 2017, with combination
of the terms: “trastuzumab,” “Herceptin,” “T‐mab,” and “atrial fibrilla-
tion.” Reviewers also manually searched the existing reviews on tras-
tuzumab effectiveness and checked the citations of all publications
identified by the above search. If multiple articles were derived from
the same cohort and involved the same population, we included only
the most completed data for our primary analysis.
The inclusion criteria were (a) publications in English language;
(b) human studies; (c) randomized clinical trials, phase II/III studies,
prospective/retrospective cohort studies; (d) patients receiving tras-
tuzumab alone or in combination with other anti‐neoplastic agents;
and (e) report on the number of AF in each individual studies. The
exclusion criteria were (a) case reports or animal studies, (b) studies
not investigated trastuzumab, and (c) cardiac side effects were not
reported for the trastuzumab group.
methodological quality were used by the Newcastle‐Ottawa Scale
(NOS) items,6 which with total score of nine stars, to evaluate the qual-
ity of observational studies. We defined the observational studies
with NOS score ≥7 stars as high quality and NOS score <7 stars as low
quality.
2.4 | Statistical analysis
All data analysis was performed using R software (i386, version 3.3.2).
The endpoint assessed was the incidence of AF. Crude study‐specific
AF rates were calculated by dividing the number of incident AF cases
by the total number of patients which had received trastuzumab. AF
rates were then pooled using the “metaprop” command in R, which
computes the pooled estimates after the logit transformation to sta-
bilize the variance. Statistical heterogeneity of studies was evaluated
by Cochran’s Q and the I2 statistic. An I2 value >50% was defined as
significant heterogeneity. If there have significant heterogeneity, the
random‐effects model was used. Publication bias was assessing by
constructing a funnel plot followed by analyzing using the Egger test.
P value >0.1 illustrated that there is no publication bias. Subgroup
analyses were based on the type of trastuzumab (T or T‐DM1) used,
trastuzumab alone or combined with other antineoplastic drugs; prior
exposure to anthracyclines or radiotherapy, were performed.
3 | R E S U LT S
A flow diagram of the data search and study selection is sum-
marized in Figure 1. A total of 152 records were in the PubMed

2.2 | Study selection
Two independent reviewers (M.Y. and G.T.) screened the titles and
abstracts of the studies for eligibility. Potential studies were re-
trieved using the relevant inclusion criteria mentioned in the pre-
ceding. Articles identified after title and abstract screening were
obtained in full text. Any cases of disagreements or uncertainty be-
tween the two reviewers were resolved through discussion or con-
sultation with a third reviewer (T.L.).

2.3 | Data extraction and quality assessment

The same two reviewers independently extracted data from in-
cluded studies. The following data were extracted from the eligible
manuscripts: first author of the study, year of publication, study de-
sign, disease, treatments, participant age and sex, follow‐up duration,
dose of trastuzumab treatment, weeks with one cycle, the number of
sample size, and the number of AF in T recipients. And assessed their F I G U R E 1   Flow diagram of the study selection process

YUAN et al.
F I G U R E 2   Forest plot demonstrating the incidence AF in the patients with trastuzumab treatment. AF, atrial fibrillation
and EMBASE. After excluding seven duplicates, 123 were fur-
ther excluded after screened the articles’ titles and abstracts,
because they are review articles, case reports, or irrelevant to
this meta‐analysis. The 22 remaining studies were then obtained
in full, and seven of them were excluded because they were not
7 8
published in English (n = 1) ; case reports (n = 1) ; investigated
trastuzumab combined with pertuzumab (n = 2)9,10 ; duplicate
population with another study (n = 1)11; contained incomplete in-
formation (n = 1)12; and mainly reported the therapeutic effects
13
of trastuzumab (n = 1). Therefore, 15 studies were included in
this meta‐analysis with the characteristics of the included studies
14-18
shown in Table 1. Five were phase II, single‐arm trials; three
21
were phase III trials; five22-26 were prospective cohort studies;
27,28
and two were retrospective cohort studies. All of these stud-
ies conducted on breast cancer. The dose of trastuzumab ranged
from 2 to 8 mg/kg, with 1‐3 weeks between trastuzumab cycles.
The characteristics of the included patient populations are pre-
sented in Table 2. The cohort included 8124 patients receiving
trastuzumab treatment. Of these, 37 reported AF, giving rise to an
incidence of 1.22% (95% confidence interval [CI]: 0.56%‐2.68%).
Heterogeneity among studies was significant (I2 = 79%, P < 0.01;
Figure 2). A funnel plot of standard error against the logarithm of
the transformed proportion is shown in Figure 3, with Egger test
F I G U R E 3   Funnel plot of this systematic review and meta‐
analysis
17555922, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12475 by Nat Prov Indonesia, Wiley Online Library on [09/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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      3 of 7
suggesting no publication bias (P = 0.13). Although the Egger test
did not show publication bias, we could not exclude the presence
of confounding variables.
The results from subgroup analyses are shown in Table 1. Three16-
18
studies reported the incidence of AF using ado‐trastuzumab
Emtansine (T‐DM1), which is an antibody‐drug conjugate combin-
ing trastuzumab, with the maytansinoid DM1, a potent microtu-
bule‐disrupting agent. The incidence of AF was 0.95% (95% CI:
0.36%‐2.52%) in patients with breast cancer with T‐DM1, and no
significant heterogeneity was found (I2 = 0%, P = 0.78). Pooling
data from twelve14,15,19-28 studies that reported outcomes of trastu-
19-
zumab use alone demonstrated the incidence of AF of 1.32% (95%
CI: 0.52%‐3.34%), but significant heterogeneity among studies re-
mained (I2 = 83%, P < 0.01).
Four19,20,23,28 studies and 1114-18,21,22,24-27 studies reported the
incidence of AF in patients with trastuzumab use alone or in combi-
nation with other antineoplastic drugs. AF incidence was 0.36% (95%
CI: 0.04%‐3.08%; Heterogeneity: I2 = 90%, P < 0.01) in the trastu-
zumab alone regimen and 2.09% (95% CI: 1.16%‐3.73%; I2 = 41%,
P = 0.077) in combinational trastuzumab regimen.
Seven14-18,25,26 studies reported the AF incidence with prior ex-
posure to anthracyclines, and eight19-24,28 studies reported the AF
incidence in patients without exposure to anthracyclines previously.
The pooled estimates showed that incidence of AF was 1.72% (95%
CI: 0.75%‐3.88%) in patients with previous anthracyclines exposure
and 1.03% (95% CI: 0.30%‐3.51%) in patients without previous an-
thracyclines exposure. There was significant heterogeneity among
studies (I2 = 52%, P = 0.05; I2 = 83%, P < 0.01, respectively).
Finally, six14-16,18,24,25 studies reported the adverse events of AF
with exposure to radiotherapy (RT). Pooling data from these studies
showed that the incidence of AF was 1.26% (95% CI: 0.68%‐2.33%).
No significant heterogeneity was reported (I2 = 0%, P = 0.99).
Pooling data from nine17,19-23,26-28 studies that reported outcomes of
RT nonexposure demonstrated incidence of AF was 1.21% (95% CI:
0.35%‐4.14%). There was significant heterogeneity among studies
(I2 = 88%, P < 0.01).
 17555922, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12475 by Nat Prov Indonesia, Wiley Online Library on [09/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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4 of 7       YUAN et al.

TA B L E 1   Characteristics of the studies included in the meta‐analysis

AF in T
First author and recipi‐ Median
year Study design Malignancy Treatments Sample size ents follow‐up (mo) Quality score

Goncalves Prospective BC C + M, TTP, TTP‐BCNU, T 11 1 NA 4, 1, 1

200522 cohort study
Kelly 200614 Phase II BC AC + P/T + T + RT 52 1 NA 3, 1, 2
15
Dang 2008 Phase II BC AC + P + T + RT 70 1 28 4, 1, 3
Horiguchi Phase III BC T 3181 1 NA 4, 1, 1
201119
Militello 201127 Retrospective BC An/Ta/P + T 22 1 33 4, 1, 3
cohort study
Chen 201223 Prospective BC T 233 5 NA 4, 1, 2
cohort study
Cadoo 201328 Retrospective BC T 39 1 72 4, 1, 3
cohort study
Krop 201316 Phase II BC AC/ 148 1 12 3, 1, 3
single‐arm FEC + T‐DM1 + RT + T/D
Suter 201317 Phase II BC AC/FEC + T‐DM1 + T 148 1 NA 3, 1, 3
single‐arm
Jacob 201424 Prospective BC Ad/E + C + F + P/D + T + RT 308 4 50 4, 1, 3
cohort study
Meattini 201425 Prospective BC AC + FEC + D + T + RT 95 1 52 4, 1, 3
cohort study
Wang 201426 Prospective BC AC/TCb/TC + T 239 13 50 4, 1, 3
cohort study
Krop 201518 Phase II BC AC/ 148 2 25 3, 1, 3
single‐arm FEC + T‐DM1 + T + D + RT
Pivot 201520 Phase III BC T 3380 3 55 4, 1, 3
Woodward Phase III BC Pe + T + D/P/Na‐P 50 1 NA 4, 1, 2
201621

AC: doxorubicin plus cyclophosphamide; Ad: adriamycin; AF: atrial fibrillation; An: antracyclines; BC: breast cancer; D: docetaxel; FEC: 5‐fluorouracil
plus epirubicin plus cyclophosphamide; LVEF: left ventricular ejection fraction; M: melphalan; mo: months; NA: not applicable; Na‐P: nab‐paclitaxel; P:
paclitaxel; Pe: pertuzumab; RT: radiation therapy; T: trastuzumab; Ta: taxane; TC: docetaxel/cyclophosphamide; TCb: docetaxel/carboplatin; T‐DM1:
trastuzumabemtansine; TTP: thiotepa.

4 |  D I S CU S S I O N channel dysfunction and remodeling, leading to conduction and/or

The main findings of this systematic review and meta‐analysis are
that (a) the incidence of AF in breast cancer patients receiving tras-
tuzumab therapy is just above 1% and (b) this incidence was not sig-
nificantly different due to the type of trastuzumab (whether linked
to DM1) and regimen (alone or combination with other anti‐neoplas-
tic agents or radiotherapy, or anthracyclines).
Atrial fibrillation is a known comorbidity that occurs with increas-
ing frequency in cancer patients, especially in patients who undergo-
ing surgery or chemotherapy. This represents an important aspect of
cancer management, given the significantly increased risk of throm-
boembolism. 29 Both cancer progression and cancer therapy can in-
29-31
crease the risk of AF. AF is a poor prognostic factor during cancer
therapy and leads to worsened outcomes.32 The pathophysiological
mechanism of cancer therapy‐provoked AF is complicated, includ-
ing myocardial damage due to inflammation and increased oxidative
stress.33-35 Higher levels of reactive oxygen species can cause ion
repolarization abnormalities that predispose to arrhythmogenesis.36
Trastuzumab is a monoclonal antibody used as a targeted therapy
for HER2‐positive breast cancer. It is generally effective in slowing
cancer progression, and its use has been associated with lower rates
of adverse events. Previous studies have also evaluated the relation-
ship between trastuzumab use and adverse cardiovascular events.
For example, Wang et al26 found that patients with early discontin-
uation of trastuzumab were more likely to suffer from heart failure,
cardiomyopathy, AF, and other cardiovascular events than women
who completed trastuzumab. The incidence of AF in those with early
discontinuation of T was 5.4% vs <3.2% (P = 0.006). Furthermore,
Chen et al23 demonstrated that early termination of trastuzumab
was significantly associated with AF (8.2% vs 2.1%, P = 0.02). It is
possible that high prevalence of AF among older patients, these pa-
tients may be more symptomatic after developing AF compared with
younger patients, and thus more likely to discontinue trastuzumab.
However, its cardiac toxicity profile cannot be ignored. Thus, safety
 17555922, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12475 by Nat Prov Indonesia, Wiley Online Library on [09/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
YUAN et al. |
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TA B L E 2   Patients’ characteristics of included studies

First author and Gender, Female Interval between T Basal LVEF

year Age (yr) % Dose of T (mg/kg) cycles (wk) %

Goncalves 200522 NA 100 4 (initial); 1 NA

2 (thereafter)
Kelly 48 (24‐69) 100 4,8 (initial) 1,3 NA
200614 2,6 (thereafter)
Dang 49 (27‐72) 100 4 (initial); 1 68 (55‐81)
200815 2 (thereafter)
Horiguchi 201119 58.1 ± 9.3 100 4 (initial); 1 NA
2 (thereafter)
Militello 69 (65‐76) 100 NA NA 65 (59‐74)
201127
Chen 71.5 100 NA NA NA
201223
Cadoo 65 (60‐82) 100 NA NA NA
201328
Krop NA 100 3.6 3 NA
201316
Suter NA 100 3.6 3 NA
201317
Jacob 52 (25‐83) 100 8 (initial); 3 NA
201424 6 (thereafter)
Meattini 55 (29‐76) 100 8 (initial); 3 NA
201425 6 (thereafter)
Wang 71.6 100 NA NA NA
201426
Krop NA 100 3.6 3 NA
201518
Pivot NA 100 8 (initial); 3 NA
201520 6 (thereafter)
Woodward 201621 53 98 600 mg/5 mL 3 NA

NA, not applicable.

studies in chick embryos reported that high dose of trastuzumab at trastuzumab‐induced cardiotoxicity may be related to higher levels
15 mg/egg resulted in AF development.37 Moreover, trastuzumab of oxidative stress and cellular apoptosis.38
significantly disrupted the expression of myocardial genes essential Trastuzumab emtansine (T‐DM1) is an antibody‐drug conjugate
for DNA repair and mitochondrial function in mouse models. Thus, comprising trastuzumab stably linked to the microtubule inhibitor

TA B L E 3   Subgroup analysis of the incident rate of AF in T recipents

Meta‐analysis Heterogeneity

Incidence of
Subgroup Number of studies AF, % 95% CI, % I2 P‐value

The type of T T 12 1.32 0.52‐3.34 83 <0.01

T‐DM1 3 0.95 0.36‐2.52 0 0.78
Use of T alone or combined with Alone 4 0.36 0.04‐3.08 90 <0.01
other drugs Combined 11 2.09 1.16‐3.73 41 0.077
Prior exposure or not to Yes 7 1.72 0.75‐3.88 52 0.05
anthracyclines No 8 1.03 0.30‐3.51 83 <0.01
Exposure or not to RT Yes 6 1.26 0.68‐2.33 0 0.99
No 9 1.21 0.35‐4.14 88 ＜0.01

RT, radiation therapy; T, trastuzumab; T‐DM1, trastuzumabemtansine.


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6 of 7       YUAN et al.
DM1.39 T‐DM1 delivers DM1 directly to HER2 overexpressing tumor
40
cells, depressing microtubule function, and inducing cell death.
Like trastuzumab, T‐DM1 inhibits HER2 the signaling pathway, pre-
vents HER2 shedding, and leads to antibody dependent cellular cy-
totoxicity.41 Given the efficacy and good safety profile of T‐DM1,
there is increasing interest in using T‐DM1 as a first‐line agent.
Further studies are needed to confirm whether this is better than
trastuzumab alone. Our findings suggest that AF incidence in T‐DM1
was comparable to that of using trastuzumab alone.
Concurrent chemotherapy is a valuable method for adjuvant treat-
ment of breast cancer. However, this is accompanied by significant
cardiotoxicity, mostly when patients previously exposure to anthra-
cyclines.42,43 For example, 3.9% developed severe symptomatic heart
failure and up to 34% showed echocardiographic evidence of cardiac
dysfunction when they were pretreated with anthracyclines. In our
analysis, AF incidence in the prior exposure group was not significantly
different from the incidence in patients without prior anthracycline use.
In early breast cancer, even after mastectomy, an appreciable risk
of local recurrence of the tumor is still present, for which adjuvant
radiotherapy has been shown to improve the OS.44,45 However, there
have been suggestions that the combination of anticancer therapies
can magnify cardiac toxicity, particularly after radiotherapy com-
bined with chemotherapy.46 Preclinical studies concerned that the
potential radio‐sensitizing properties of trastuzumab both in vivo
and in vitro.47 Our analysis also demonstrated that patients who con-
currently received trastuzumab and radiotherapy had similar inci-
dence of AF than those receiving trastuzumab without radiotherapy.
4.1 | Study limitations
Several potential limitations of this meta‐analysis should be noted.
First, significant heterogeneity was found. Most of the included stud-
ies were phase II single‐arm trials and cohort studies, and no control
group was established. Second, AF was evaluated at baseline, at the
end of anthracyclines treatment, after cycles of trastuzumab, as well
as before and after the start of a new treatment. However, it was not
possible to exclude the toxic effects of other antineoplastic drugs.
Third, the misclassification bias may occur because AF screening was
not sufficiently intensive to detect paroxysmal AF. Forth, the level of
baseline LVEF may one of the important factors associated with AF
development but this parameter was only reported in two studies.
Further studies are needed to determine possible confounding from
heart failure, which is a known risk factor for AF. Finally, this analysis
was not sufficiently strong to provide the basis for any treatment
recommendations or changes in practice. These need to be formally
assessed in larger prospective real‐world studies and clinical trials.
5 |  CO N C LU S I O N S
This meta‐analysis summarized and presented that the AF incidence in
breast cancer patients using trastuzumab was more than 1%. Further
studies and longer follow‐up are warranted to confirm these results.
17555922, 2018, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12475 by Nat Prov Indonesia, Wiley Online Library on [09/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
AC K N OW L E D G M E N T S
This work was supported by grants (81570298, 30900618,
81270245 to T.L.) from the National Natural Science Foundation of
China. GT is supported by the Croucher Foundation of Hong Kong.
C O N FL I C T O F I N T E R E S T
The authors declare no conflict of interest.
ORCID
Tong Liu  http://orcid.org/0000-0003-0482-0738
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How to cite this article: Yuan M, Tse G, Zhang Z, et al. The
incidence of atrial fibrillation with trastuzumab treatment: A
systematic review and meta‐analysis. Cardiovasc Ther.
2018;36:e12475. https://doi.org/10.1111/1755-5922.12475