\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Cardiovascular~toxicities following the use of tyrosine kinase
inhibitors in Hepatocellular Cancer Patients: A Retrospective,
Pharmacovigilance Study}



\author[1]{Xin Lai}%
\author[1]{Qing Wan}%
\author[1]{Shou-feng Jiao}%
\author[1]{Xiao-chun Sun}%
\author[1]{Jin-fang Hu}%
\author[1]{Hong-wei Peng}%
\affil[1]{First Affiliated Hospital of Nanchang University}%


\vspace{-1em}



  
  \date{June 10, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
ABSTRACT Aims: With the extensive use of tyrosine kinases
inhibitors(TKIs) in hepatocellular cancer, cardiac adverse events(AEs)
emerged in recent years. This study explored the cardiac AEs of TKIs
through the Food and Drug Administration's Adverse Event Reporting
System (FAERS). Methods: Disproportionality analysis and Bayesian
analysis were utilized for data mining of the suspected cardiac AEs of
TKIs, based on FAERS data from January 2004 to December 2021. Results: A
total of 4708 cardiac AEs reports of sorafenib, regorafenib, lenvatinib
and cabozantinib were identifed. Among them, 17 cardiac AEs signals were
detected in regorafenib, 15 cardiac AEs signals were detected in
lenvatinib, 57 cardiac AEs signals were detected in sorafenib while 27
cardiac AEs signals were detected in cabozantinib. Hypertension accounts
for the most reported cardiac AE. Lenvatinib appears to induce cardiac
failure with the highest signals strength {[}ROR=7.7(3.46,17.17){]}.
Acute myocardial infarction were detected in lenvatinib
{[}ROR=7.91(5.64,11.09){]} and sorafenib{[}ROR=2.22(1.74, 2.84){]}.
Acute coronary syndrome were detected in lenvatinib{[}ROR=11.57(6.84,
19.58){]} and sorafenib {[}ROR=2.81(1.87,4.24){]}. Atrial fibrillation
were detected in sorafenib {[}ROR=1.82(1.55,2.14){]} and regorafenib
{[}ROR=1.36(1.03,1.81){]}. Meanwhile, aortic dissection were detected in
sorafenib {[}ROR=5.08(3.31,7.8){]} and regorafenib
{[}ROR=3.39(1.52,7.56){]}. Most patients developed hypertension and
cardiac failure within 30 days after TKIs treatment. Patients taking
lenvatinib developed acute coronary syndrome increased in the periods of
180 days(64.29\%) . Conclusion: Analysis of FAERS provides more precise
profile on the characteristics of cardiac AEs after different TKI
regimens. Distinct monitoring and appropriate management are needed in
the care of the TKIs recipients.%
\end{abstract}%



\sloppy


\textbf{1 Introduction}

Primary hepatocellular cancer was one of the major threat to human
health worldwide, in 2020, primary liver cancer has become the sixth
leading malignancy and the third cause of cancer-related deaths
worldwide{[}1{]}. Hepatocellular carcinoma (HCC), with a five-year
survival rate only 18\%, accounts for 75\%-85\% of primary liver cancer
cases{[}2{]}. Besides, incidence rate of HCC were much higher in Eastern
Asia followed by Northern Africa and South-Eastern Asia{[}3{]}. For
patients diagnosed at early- or intermediate-stage HCC, curative
treatments such as surgical procedures, which including whole or partial
hepatectomy and liver transplant, and locoregional therapies including
radiofrequency ablation, transarterial chemoembolization, and radiation
therapy could improve survival{[}4, 5{]}. However, more than half of the
patients with HCC diagnosed at advanced or incurable stage, making
systemic therapy one of few treatments available to improve
survival{[}6, 7{]}.

Great advances in understanding the mechanisms and progression of HCC
over the past decades have promoted the development of novel drugs such
as tyrosine kinases inhibitors (TKIs) to prolong the survival of
patients with advanced HCC. In 2007, FDA approved sorafenib for HCC
targeted therapy. Sorafenib was an anticancer agent with multi-targent,
it could prevent the proliferation of tumor cells and inhibit cancer
angiogenesis by suppressing the RAF/MEK/ERK pathway as well as
inhibiting vascular endothelial growth factor receptor 2/3 (VEGFR-2/3)
and platelet-derived growth factor receptors (PDGFR){[}7, 8{]}.In the
SHARP trial{[}9{]} and ORIENTAL trial{[}10{]}, the investigators
demonstrated that sorafenib could significantly increased survival of
advanced HCC patients with different territories. Thus, sorafenib became
the first line systemic therapy approved by european medicines
agency(EMA) and FDA. It almost took 10 years until lenvatinib was
approved as the second TKI for advanced HCC treatment. It acts as a
potent inhibitor of VEGFR1-3 and other receptor tyrosine kinases,
including fibroblast growth factor receptor(FGFR), KIT, and RET{[}11,
12{]}. The open-label,multicenter, non-inferiority phase III REFLECT
trial enrolled 954 aHCC patients, the result demonstrated that
lenvatinib was non-inferior compared to sorafenib. Lenvatinib group
reached a median overall survival(OS) of 13.6 months compared to 12.3
months in the sorafenib group. Furthermore, lenvatinib group exhibit
higher objective response rates(ORR) compared to sorafenib group(24.1\%
vs 9.2\%){[}13{]}.The REFLECT study established lenvatinib as first line
therapy in systematic treatment of unresectable HCC. Combination of
lenvatinib and other immunotherapies has achieved encouraging clinical
benefit. In 2017, another TKI small molecular, regorafenib was approved
for patients with advanced HCC{[}14{]} Regorafenib targets VEGFR, PDGFR,
and FGFR, RAF, RET, KIT{[}15{]}. In the phase III RESORCE study{[}16{]},
573 aHCC patients who tolerated sorafenib in 21 countries were enrolled.
Regorafenib improved overall survival with a hazard ratio of 0.63 (95\%
CI 0.50-0.79; one-sided p\textless{}0.0001) and median survival was 10.6
months for regorafenib versus 7.8 months for placebo. Hence, Regorafenib
was approved for second line treatment of HCC who have been previously
treated with sorafenib. Cabozantinib was another oral multiple tyrosine
kinase receptor inhibitor with activity against the VEGFR(VEGFR-1,
VEGFR-2, VEGFR-3), RET and KIT. It also inhibits MET and AXL, which have
previously been associated with sorafenib resistance{[}17{]}.In phase
III CELESTIAL trail{[}18{]}, 707 patients with previously treated HCC
were enrolled, and the results showed a median OS of 10.62 months in
cabozantinib group compared to 8.0 months in the placebo group. Median
progression-free survival(PFS) was 5.2 months in cabozantinib group and
1.9 months in placebo (HR for disease progression or death, 0.44; 95\%
CI, 0.36 to 0.52;~P~\textless{} 0.001), demonstrated cabozantinib as a
second-line agent in the treatment of HCC. Nowadays, most advanced HCCs
could benefit from the sound ``transformation therapy'', which indicated
that transformed inoperable advanced HCC into resectable cancer with
multimodal therapy options, targeted therapy became one of the important
strategies.

However, some serious adverse events(AEs) that may induced by TKIs were
emerged, some even fatal in cardiac system. Hypertension, QT
prolongation, arrhythmias, left ventricular systolic dysfunction, and
heart failure were the most common cardiac AEs reported{[}19-21{]}.
Safety profiles of TKIs were evaluated primarily in clinical trials,
which due to the strict study entry criteria, small sample sizes and
relatively short length of time, were scattered and insufficient to
provide a detailed overview of the risk of cardiac AEs induced by those
above four TKIs. Therefore, Pharmacovigilance study using post-marketing
safety reports can be an great supplement to the detection of cardiac
AEs of TKIs. Currently, the FDA Adverse Events Reporting System (FAERS)
was one of the largest global repository of post-marketing drug
surveillance. It contains adverse event reports, medication error
reports that were submitted to FDA.

\textbf{2 Aims}

This study aimed to comprehensively evaluate the cardiovascular safety
profile of these four TKIs in a real-world setting by analysing cardiac
AEs in the FAERS database(Figure 1).

\textbf{3 Materials and methods}

\textbf{3.1 Data source and collection}

We used data from the FAERS database published between January 2004 and
December 2021. Reports on adverse event and medication error in the
FAERS database was spontaneous reported by medical workers, consumers,
and manufacturers globally{[}22{]}. Each FAERS report contain patients
demographic information(age, gender and weight), drug
information(indication, dosage, and interval of administration), adverse
events information(occurrence time, outcome) and other
information(report year, report country and reporter occupations). In
the circumstances that there were multiple reports of the same event,
deduplicated procedure were perform in accordance with FDA
recommendation.

\textbf{3.2 Data mining}

In current study, we selected reports containing products
``lenvatinib'', ``sorafenib'', ``cabozantinib'' and ``regorafenib'' as
``primary suspect'' for further study. Arbitrary drug names may be
reported in the FAERS, therefore, the MICROMEDEX\selectlanguage{ngerman}® (Index Nominum) was
utilized as a dictionary for TKIs(Table 1). The suspected adverse
events(AEs) were coded according to the Medical Dictionary for
Regulatory Activities (MedDRA®). We grouped cardiac AEs in the MedDRA
classification (version 25.1) that are related to the same medical
condition.

\textbf{3.3 Statistical Analysis}

Mean and standard deviation for continuous variables as well as numbers
and percentages for categorical variables were used to describe the
baseline characteristics of patients with cardiac AEs after exposed to
TKIs. The reporting odds ratio (ROR), the proportional reporting ratio
(PRR), the Bayesian confidence propagation neural network (BCPNN) and
the multi-item gamma Poisson shrinker (MGPS) algorithms were used to
identify the association of drugs and AEs {[}23{]}. AEs were considered
statistically significant when at least 1 of the above 4 criteria was
met(Table 2).

\textbf{4 Results}

\textbf{4.1 Characteristics of Patients}

Overall, A total of 14464087 reports were documented in the full FAERS
database during the study period, of whom 82682{[}sorafenib,
n=31361(37.93\%); regorafenib, n=13826(16.72\%); lenvatinib,
n=8884(10.74\%); cabozantinib, n=28611(34.6\%){]} were reported as
TKIs-related AEs. Moreover, 4708 cardiac AEs reports identified TKIs as
the primary suspected drugs. Among them, 1994 reports were identified as
the suspected drug related to sorafenib; 630 reports were identified as
the suspected drug related to regorafenib. 318 reports were identified
as the suspected drug related to lenvatinib. 1766 reports were
identified as the suspected drug related to cabozantinib. According to
our results, males were more prone to be affected by cardiac AEs than
females in patients taking sorafenib, cabozantinib(69.9\% vs 26.1\%,
68.4\% vs 28.8\%, respectively), while the ratio of male to female was
similar among patients taking regorafenib or lenvatinib(56.8\% vs
40.3\%, 48.7\% vs 51.3\%, respectively). Age may be a risk factor, as
most patients who experienced cardiac AEs while taking
sorafenib(52.6\%), lenvatinib(55.7\%) or regorafenib(45.7\%) were over
65 years of age. Reports were mainly submitted by health-care
professionals. Most of the reports came from the US, Japan and France,
with the exception of those whose origin could not be identified. All
the clinical characteristics of these patients with cardiac AEs were
presented in Table 3.

\textbf{4.2 Cardiovascular Adverse Event Signal Detection Using the
FAERS Database}

Based on the criteria for the 4 algorithms (ROR,PRR,BCPNN, MGPS), there
were 17 cardiac AEs signals detected in regorafenib, 15 cardiac AEs
signals detected in lenvatinib, 57 cardiac AEs signals detected in
sorafenib and 27 cardiac AEs signals detected in cabozantinib,
respectively(Table 4, Fig 2). Among all the cardiac AEs signals,
hypertension accounts for the most reported cardiac AEs in all these
four TKIs. Furthermore, cardiac failure or cardiac failure acute signals
were detected in all these four TKIs. Lenvatinib had the highest
ROR{[}7.7(3.46,17.17){]}, while the ROR in regorafenib sorafenib and
cabozantinib was 1.42(1.05,1.92), 2.48(1.44,4.27) and 5.92(4.13,8.47),
respectively. There were cardiac AEs that show no class effect but
significantly were over-reported in specific TKI. Acute myocardial
infarction were mainly detected in lenvatinib{[}ROR=7.91(5.64,11.09){]}
and sorafenib{[}ROR=2.22(1.74, 2.84){]}. No acute myocardial infarction
signal were detected in regorafenib nor cabozantinib. Furthermore, acute
coronary syndrome were also detected in lenvatinib{[}ROR=11.57(6.84,
19.58){]} and sorafenib{[}ROR=2.81(1.87,4.24){]}. When it comes to
atrial fibrillation, signals were detected in
sorafenib{[}ROR=1.82(1.55,2.14){]} and
regorafenib{[}ROR=1.36(1.03,1.81){]} . Besides, aortic dissection were
detected in sorafenib {[}ROR=5.08(3.31,7.8){]} and regorafenib
{[}ROR=3.39(1.52,7.56){]}.

\textbf{4.3 Time to onset of TKI associatied cardiovascular adverse
event}

The times of cardiac AEs occurrence were shown in Fig 3. Over 70\%
patients developed hypertension within 30 days after the first dose of
TKIs treatment. Identical pattern were found in cardiac failure.
However, the proportion of patients who developed cardiac failure within
30 days were higher in patients administered with sorafenib (70.31\%)
and regorafenib(75\%), compared with lenvatinib (32.14\%) and
cabozantinib(46.15\%). In the case of atrial fibrillation, most patients
developed atrial fibrillation within 30 days after the first dose of
sorafenib or regorafenib. We also found that the proportion of patients
developed acute coronary syndrome increased after 180 days use of
lenvatinib compared with the first 30 days(64.29\% vs 28.57\%). The
proportion of patients developed acute myocardial infarction(AMI) within
30 days were higher in patients taking sorafenib(42.86\%) when compared
with lenvatinib(13.64\%). On the contrary, lenvatinib seemed to induce
cardiac AEs in a longer period, as the proportion of patients developed
acute myocardial infarction were higher in patients taking
lenvatinib(65.15\%) when compared with sorafenib(20\%) after 180 days
administration.

\textbf{5 Discussion}

With the extensive use of selective, mechanism-based TKIs in the
treatment of HCC, cardiac AEs following the use of TKIs has gradually
became a challenge. Some patients had to withdraw the treatment of TKIs
due to the unbearable side effects. Currently, the safety information of
TKIs were largely came from clinical trials, though it had limitations.
Drug safety information that from real-world profile had advantages in
sample size as well as follow-up time, so that attracted much attention
these years. Pharmacovigilance based on the real world data can be an
important supplement to the safety profile of TKIs. Our study mainly
focused on TKIs related cardiac AEs by analysing data from FAERS
pharmacovigilance database.

In our pharmacovigilance study, the association between hypertension and
all the four TKIs were demonstrated and was consistent with the previous
reports. In previous clinical study, all grade hypertension occurring in
42\%, 31\%, 5\% and 7\% of patients taking lenvatinib, regorafenib,
sorafenib and cabozantinib respectively{[}13, 16{]}. When it comes to
the onset time of hypertension, most of the hypertension occurred within
30 days of TKIs therapy according to our results. The occurrence of
hypertention gradually leveled off from 30 days to 180 days, which
indicated hypotensive drugs administration and carefully regular blood
pressure monitor in the first month. Most studies have unveiled the fact
that TKI-induced hypertension was associated with VEGF signaling, which
played vital role in producing nitric oxide(NO), as well as inhibiting
the production of the vasoconstrictor endothelin-1{[}24, 25{]}.
Consequently, inhibition of VEGF by TKIs resulting in disruption of NO
and endothelin-1, thus leading to the occurrence of hypertension. VEGF
signal blocking also resulted in suppression of capillary endothelial
cell survival, which could lead to apoptosis and microvascular
sparseness, and contributed to increasing of peripheral vascular
resistance. NO held the balance of redox equilibrium, as NO could
scanvenge free radicals that may injury vascular endothelium. The
reduction of NO production would lead to endothelial injury, which may
result in further reduction of microvessel density and vascular
perfusion. Though VEGF signalling block may lead to hypertention as well
as other cadiac side effects, it was well accepted that
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers
and beta blockers were all suitable anti-hypertension drugs for
TKI-induced hypertension{[}26{]}. Consequently, hypertention was well
under-control after ocurrence. Besides, as hypertension represented an
on-target effect of TKIs, some physician suggest that TKI-induced
hypertension may be a sign of drug efficacy. In the SELECT trial, which
included 392 patients, patients with treatment-induced hypertension in
the lenvatinib group benifit from both progression-free survival and
overall survival in the univariate analysis{[}27{]}. Above all,
hypertention as an ``on-target'' sign of efficacy should be monitored
carefully, especially in the first months of TKIs administration in HCC
patients. Additionally, clinicians should be aware of the risk of other
cardiovascular events caused by hypertension, especially those
life-threatening cardiac AEs.

Aortic dissection was a life-threaten condition involved the separation
of the different layers of the aortic wall due to a tear in the intimal
layer of the aorta or bleeding within the aortic wall{[}28{]}.~There
have been case reports{[}29, 30{]} as well as observational
studies{[}31{]} reported the association of sorafenib administration
and, aortic dissection. The results of the present study confirmed the
association of sorafenib and aortic dissection. Importantly, our results
also indicated that regorafenib could also induce aortic dissection with
a much higher incidence, which was not reported nor listed in FDA
instruction. It was reported that the risk factor for aortic dissection
include hypertension,~atherosclerosis, age and dyslipidemia{[}32{]}.
According to our results, one of the most common side effects followed
the use of TKIs was hypertension, which also played vital role in the
occurrence of TKI-induced aortic dissection. As reported by Dorks, M.,
et al {[}33{]}, the degree of hypertension induced by TKIs had positive
correlation with the incidence of aortic dissection.However, the
conclusion seems controversial, as there have been case reports/studies
reported patients with baseline or normal blood pressure also developed
aortic dissection after the use of TKIs{[}34, 35{]}. Thus, additional
mechanisms besides hypertension may also involved in the pathogenesis of
TKIs induced aortic dissection. Some studies suggest that inhibition of
VEGF could increase the stiffness of arteries by impairing~NO
mediated~vasodilation and vasoconstriction{[}34{]}, it is also known
that VEGF participate in endothelial-mediated regeneration and healing
after~vascular injury, in this way the inhibition of VEGF would result
in the occurrence of dissection{[}36{]}.

According to our results, sorafenib, regorafenib, lenvatinib and
cabozantinib were all associated with cardiac failure. Thus, it seems to
be a class effect that TKIs may induce cardiac failure. Moreover,
lenvatinib and cabozantinib seems to have a stronger association with
cardiac failure compared with sorafenib and regorafenib. Our analyse
found a relative higher incidence of lenvatinib compared to the
sorafenib and regorafenib. Although the real incidence rates need to be
further comfiremd by well-designed clinical trials, the current results
demonstrate a higher risk of cardiac failure in sorafenib and
regorafenib long-term usage. An hypothesis has been proposed to explain
how TKIs treatment can lead to cardiac failure{[}37{]}. Hypertension,
one of the most common cardiac AEs of TKIs, could lead to afterload
stress on the heart. Under normal physiological conditions, the heart
would adapt to the afterload stress through compensatory mechanisms
mediated by PDGFR-\selectlanguage{greek}β. \selectlanguage{english}In cardiomyocytes afterload stress models, deletion
of the PDGFR-\selectlanguage{greek}β \selectlanguage{english}gene resulted in ventricular hypertrophy, ventricular
dilation and heart failure{[}37, 38{]}. PDGFR-\selectlanguage{greek}β \selectlanguage{english}was reported to be one
of the targets of anti-angiogenic TKIs{[}39{]}. Inhibition of PDGFR-\selectlanguage{greek}β
\selectlanguage{english}would disrupt the cardiac adaptation mechanism to afterload stress, thus
lead to heart failure ultimately. In addition to PDGFR-\selectlanguage{greek}β \selectlanguage{english}signaling
inhibition, there was another mechanism may also contribute to cardiac
failure. The interaction between endothelial cells(ECs) and
cardiomyocytes was essential for maintaining cardiac homeostasis and
angiogenesis{[}40{]}. VEGFR-2 on cardiac ECs inhibited by TKIs initiated
downstream signaling changes, leading to cardiomyocyte apoptosis,
hypertrophy, and finally resulted in cardiac failure{[}41{]}.

Besides, acute myocardial infarction(AMI) was also a fatal side effects
that may induced by TKIs in HCC patients according to our results.The
observed associations of TKIs with acute myocardial infarction(AMI) and
acute coronary syndrome(ACS) have been demonstrated in some cases and
studies {[}42, 43{]}.We found a significant positive correlation between
sorafenib or lenvatinib usage with AMI or ACS incidence. Besides,
according to our results, lenvatinib seems to be more prone to induce
AMI as well as ACS in the long-term use HCC patients. According to Prof.
Jason et al's study, sorafenib induced myocyte kind of programed form of
necrosis. In addition, sorafenib also potently induced stem cell
apoptosis and inhibited stem cell proliferation both in vitro and in
vivo experiments, which may ultimately result in suppression of the
generating new cardiac myocytes after AMI{[}44{]}.

Another fatal AE signal induce by TKIs was atrial fibrillation. Reports
of TKI-induced atrial fibrillation was most commonly with patients
taking sorafenib. In a phase II trial of 39 patients with advanced HCC,
the incidence of atrial fibrillation was 5.1\% when used in combination
with 5-fluorouracil{[}45{]}. Besides sorafenib, our study also
identified the association between regorafenib treatment and atrial
fibrillation, the pathogenetic mechanism of which may be due to the
inhibition of the PI3K/Akt pathway. Inhibition of PI3K-Akt signaling has
been implicated in the development of atrial fibrillation, while
increasing PI3K activity led to reduction of atrial fibrosis and
improved conduction in a mouse model. Atrial appendage PI3k activity is
lower in patients with atrial fibrillation than it is in those with
sinus rhythm{[}46{]}.

According to the reports collected in the current study, most of the
hypertension, cardiac failure and atrial fibrillation cases happened
within the first 30 days since the initiation of TKI treatment. However,
the proportion of patients who developed ACS increased after 180 days
use of lenvatinib or sorafenib. When it comes to lenvatinib, the
incidence of AMI also increased after 180 days use of lenvatinib.
Consequently, recognition of the difference in the onset time of varied
cardiac AEs may be worthful to guide distinct monitoring and management
strategies in TKIs recipient HCC patients. Indicating that cardiac AEs
management are necessary while patients are under anti-tumor therapy.

The FAERS database is one of the largest global repository of
post-marketing drug reporting systems, which could help to make
identifcation of pharmacovigilence signals of TKIs in a real-world
setting. However, there were also several limitations, first, the
reports in the FAERS database was spontaneous submited by drug users or
medical stuff, thus, false reporting, incomplete reporting, or
inaccuracy reporting are inevitable. Second, In addition to basic
information such as age, gender, weight, and medication, other
information such as lifestyle habits and family history is also very
helpful for the judgment and analysis of AEs, but this part of
information is not recorded in the system. Thus, the FAERS database is
only used in qualitative research and it is insufficient to prove a
causal relationship between certain AEs and drugs. Despite its
limitations, pharmacovigilance study based on FAERS database is an
important supplement to drug safety research, and could provide rational
evidence for drug safety research after marketing.

\textbf{6 Conclusion}

Our analysis of the FAERS database identified cardiac AEs for TKIs in a
real-world setting. Our study found similar cardiovascular adverse
effects with TKIs, Patients over 65 whose taking sorafenib, lenvatinib
and regorafenib were at increased risk for developing cardiac AEs. These
four TKIs were associated with increased risk of developing hypertension
and cardiac failure. Furthermore, aortic dissection was a new
complication with regorafenib. Use of lenvatinib may increase the risk
of developing acute coronary syndrome and myocardial infarction.
Clinicians should be aware of the various cardiac AEs associated with
TKIs and the assessment of cardiovascular risk should be done before
starting TKI treatments.

\textbf{ACKNOWLEDGEMENTS}

The authors are very grateful to all staffs of the institute of clinical
pharmacology at the First Affiliated Hospital of Nanchang University

\textbf{Conflict of interest}

The authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a
potential conflict of interest.

\textbf{Funding}

This study was funded by the National Natural Sciences Foundation
Committee (NSFC) (NO:81860035), Jiangxi Provincial Key Research and
Development Plan (NO:20203BBGL73210) and Clinical Pharmaceutical
Research Fund of the China International Medical Exchange
Foundation(Z-2021-46-2101)

\textbf{Author contributions}

Concept and design the work: HW-P, JF-H. Acquisition, analysis, or
interpretation of data: XL, QW. Management and checking of all data:
SF-J and XC-S. Drafting the article: XL and QW. All authors critically
reviewed the manuscript and interpreted the results. The final
manuscript was read, checked, and approved by all authors.

\textbf{Data availabilty statement}

Publicly available datasets were analysed in this study. This data can
be found at

\emph{https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.}

\textbf{References:}

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A,
et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence
and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J
Clin. 2021 2021-05-01;71(3):209-49.

2. Koulouris A, Tsagkaris C, Spyrou V, Pappa E, Troullinou A, Nikolaou
M. Hepatocellular Carcinoma: An Overview of the Changing Landscape of
Treatment Options. J Hepatocell Carcinoma. 2021 2021-01-20;8:387-401.

3. Rumgay H, Ferlay J, de Martel C, Georges D, Ibrahim AS, Zheng R, et
al. Global, regional and national burden of primary liver cancer by
subtype. EUR J CANCER. 2022 2022-01-01;161:108-18.

4. Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular
Carcinoma. GASTROENTEROLOGY. 2019 2019-01-01;156(2):477-91.

5. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A
global view of hepatocellular carcinoma: trends, risk, prevention and
management. Nat Rev Gastroenterol Hepatol. 2019
2019-10-01;16(10):589-604.

6. Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma:
Current Updates and Outlook. J Hepatocell Carcinoma. 2022
2022-01-20;9:233-63.

7. Falette PM, Pellat A, Assaf A, Ginestet C, Brezault C, Dhooge M, et
al. Therapeutic Management of Advanced Hepatocellular Carcinoma: An
Updated Review. Cancers (Basel). 2022 2022-05-10;14(10).

8. Qin S, Li A, Yi M, Yu S, Zhang M, Wu K. Recent advances on
anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy.
J HEMATOL ONCOL. 2019 2019-03-12;12(1):27.

9. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.
Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008
2008-07-24;359(4):378-90.

10. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy
and safety of sorafenib in patients in the Asia-Pacific region with
advanced hepatocellular carcinoma: a phase III randomised, double-blind,
placebo-controlled trial. LANCET ONCOL. 2009 2009-01-01;10(1):25-34.

11. Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, et
al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor
that targets multiple receptor tyrosine kinases in preclinical human
thyroid cancer models. J Thyroid Res. 2014 2014-01-20;2014:638747.

12. Matsuki M, Hoshi T, Yamamoto Y, Ikemori-Kawada M, Minoshima Y,
Funahashi Y, et al. Lenvatinib inhibits angiogenesis and tumor
fibroblast growth factor signaling pathways in human hepatocellular
carcinoma models. Cancer Med. 2018 2018-06-01;7(6):2641-53.

13. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al.
Lenvatinib versus sorafenib in first-line treatment of patients with
unresectable hepatocellular carcinoma: a randomised phase 3
non-inferiority trial. LANCET. 2018 2018-03-24;391(10126):1163-73.

14. Sherman M. Regorafenib for treatment of hepatocellular carcinoma.
HEPATOLOGY. 2018 2018-03-01;67(3):1162-5.

15. Galle PR, Dufour JF, Peck-Radosavljevic M, Trojan J, Vogel A.
Systemic therapy of advanced hepatocellular carcinoma. FUTURE ONCOL.
2021 2021-04-01;17(10):1237-51.

16. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al.
Regorafenib for patients with hepatocellular carcinoma who progressed on
sorafenib treatment (RESORCE): a randomised, double-blind,
placebo-controlled, phase 3 trial. LANCET. 2017
2017-01-07;389(10064):56-66.

17. Tumen D, Heumann P, Gulow K, Demirci CN, Cosma LS, Muller M, et al.
Pathogenesis and Current Treatment Strategies of Hepatocellular
Carcinoma. Biomedicines. 2022 2022-12-09;10(12).

18. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY,
et al. Cabozantinib in Patients with Advanced and Progressing
Hepatocellular Carcinoma. N Engl J Med. 2018 2018-07-05;379(1):54-63.

19. Justice CN, Derbala MH, Baich TM, Kempton AN, Guo AS, Ho TH, et al.
The Impact of Pazopanib on the Cardiovascular System. J Cardiovasc
Pharmacol Ther. 2018 2018-09-01;23(5):387-98.

20. Dobbin S, Petrie MC, Myles RC, Touyz RM, Lang NN. Cardiotoxic
effects of angiogenesis inhibitors. Clin Sci (Lond). 2021
2021-01-15;135(1):71-100.

21. Pinkhas D, Ho T, Smith S. Assessment of pazopanib-related
hypertension, cardiac dysfunction and identification of clinical risk
factors for their development. Cardiooncology. 2017 2017-01-20;3.

22. Fan Q, Hu Y, Yang C, Zhao B. Myocarditis following the use of
different immune checkpoint inhibitor regimens: A real-world analysis of
post-marketing surveillance data. INT IMMUNOPHARMACOL. 2019
2019-11-01;76:105866.

23. Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public
version of the FDA Adverse Event Reporting System. INT J MED SCI. 2013
2013-01-20;10(7):796-803.

24. Moslehi JJ. Cardiovascular Toxic Effects of Targeted Cancer
Therapies. N Engl J Med. 2016 2016-10-13;375(15):1457-67.

25. Li W, Croce K, Steensma DP, McDermott DF, Ben-Yehuda O, Moslehi J.
Vascular and Metabolic Implications of Novel Targeted Cancer Therapies:
Focus on Kinase Inhibitors. J AM COLL CARDIOL. 2015
2015-09-08;66(10):1160-78.

26. Rimassa L, Danesi R, Pressiani T, Merle P. Management of adverse
events associated with tyrosine kinase inhibitors: Improving outcomes
for patients with hepatocellular carcinoma. CANCER TREAT REV. 2019
2019-07-01;77:20-8.

27. Wirth LJ, Tahara M, Robinson B, Francis S, Brose MS, Habra MA, et
al. Treatment-emergent hypertension and efficacy in the phase 3 Study of
(E7080) lenvatinib in differentiated cancer of the thyroid (SELECT).
CANCER-AM CANCER SOC. 2018 2018-06-01;124(11):2365-72.

28. Yuan X, Mitsis A, Nienaber CA. Current Understanding of Aortic
Dissection. Life (Basel). 2022 2022-10-14;12(10).

29. Tsuchiya A, Ogawa M, Watanabe Y, Kimura N, Hayashi K, Suda T, et al.
Successful treatment of aortic dissection during sorafenib therapy for
hepatocellular carcinoma. Clin Case Rep. 2018 2018-08-01;6(8):1643-4.

30. Takada M, Yasui T, Oka T, Shioyama W, Kuroda T, Nakai Y, et al.
Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During
the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic
Renal Cell Carcinoma. INT HEART J. 2018 2018-09-26;59(5):1174-9.

31. Oshima Y, Tanimoto T, Yuji K, Tojo A. Association Between Aortic
Dissection and Systemic Exposure of Vascular Endothelial Growth Factor
Pathway Inhibitors in the Japanese Adverse Drug Event Report Database.
CIRCULATION. 2017 2017-02-21;135(8):815-7.

32. Zhou Z, Cecchi AC, Prakash SK, Milewicz DM. Risk Factors for
Thoracic Aortic Dissection. Genes (Basel). 2022 2022-10-07;13(10).

33. Dorks M, Jobski K, Herget-Rosenthal S, Hoffmann F, Douros A.
Tyrosine kinase inhibitors targeting vascular endothelial growth factor
and the risk of aortic dissection-A pharmacovigilance analysis.
Pharmacol Res Perspect. 2021 2021-02-01;9(1):e707.

34. Hatem R, Bebawi E, Schampaert E. Potential Sunitinib-Induced
Coronary Artery and Aortic Dissections. CAN J CARDIOL. 2017
2017-06-01;33(6):817-30.

35. Niwa N, Nishiyama T, Ozu C, Yagi Y, Saito S. Acute aortic dissection
in a patient with metastatic renal cell carcinoma treated with axitinib.
ACTA ONCOL. 2015 2015-04-01;54(4):561-2.

36. Bonnet C, Sibon I. Potential role of anti-VEGF targeted therapies in
cervical artery dissection: A case report. Rev Neurol (Paris). 2015
2015-09-01;171(8-9):677-9.

37. Bronte G, Bronte E, Novo G, Pernice G, Lo VF, Musso E, et al.
Conquests and perspectives of cardio-oncology in the field of tumor
angiogenesis-targeting tyrosine kinase inhibitor-based therapy. EXPERT
OPIN DRUG SAF. 2015 2015-02-01;14(2):253-67.

38. Chintalgattu V, Ai D, Langley RR, Zhang J, Bankson JA, Shih TL, et
al. Cardiomyocyte PDGFR-beta signaling is an essential component of the
mouse cardiac response to load-induced stress. J CLIN INVEST. 2010
2010-02-01;120(2):472-84.

39. Touyz RM, Herrmann J. Cardiotoxicity with vascular endothelial
growth factor inhibitor therapy. NPJ Precis Oncol. 2018 2018-01-20;2:13.

40. Scott SS, Greenlee AN, Matzko A, Stein M, Naughton MT, Zaramo TZ, et
al. Intracellular Signaling Pathways Mediating Tyrosine Kinase Inhibitor
Cardiotoxicity. HEART FAIL CLIN. 2022 2022-07-01;18(3):425-42.

41. Kivela R, Hemanthakumar KA, Vaparanta K, Robciuc M, Izumiya Y,
Kidoya H, et al. Endothelial Cells Regulate Physiological Cardiomyocyte
Growth via VEGFR2-Mediated Paracrine Signaling. CIRCULATION. 2019
2019-05-28;139(22):2570-84.

42. Takagi K, Takai M, Kawata K, Horie K, Kikuchi M, Kato T, et al.
{[}Three Patients with Acute Myocardial Infarction Associated with
Targeted Therapy of Sorafenib for Metastatic Renal Cell Carcinoma : Case
Report{]}. Hinyokika Kiyo. 2015 2015-09-01;61(9):347-51.

43. Paschke L, Lincke T, Muhlberg K, Lindner TH, Paschke R. Myocardial
Infarction after Long-Term Treatment with a Tyrosine Kinase Inhibitor
(TKI) with Anti-VEGF Receptor Activity. Case Rep Endocrinol. 2019
2019-01-20;2019:7927450.

44. Duran JM, Makarewich CA, Trappanese D, Gross P, Husain S, Dunn J, et
al. Sorafenib cardiotoxicity increases mortality after myocardial
infarction. CIRC RES. 2014 2014-05-23;114(11):1700-12.

45. Petrini I, Lencioni M, Ricasoli M, Iannopollo M, Orlandini C,
Oliveri F, et al. Phase II trial of sorafenib in combination with
5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer
Chemother Pharmacol. 2012 2012-03-01;69(3):773-80.

46. Lu Z, Wu CY, Jiang YP, Ballou LM, Clausen C, Cohen IS, et al.
Suppression of phosphoinositide 3-kinase signaling and alteration of
multiple ion currents in drug-induced long QT syndrome. SCI TRANSL MED.
2012 2012-04-25;4(131):131r-150r.

\textbf{Figure legends}

Figure 1 Post-marketing data of tyrosine kinase inhibitor
(TKI)-associated cardiac toxicities in the FAERS database

FAERS, Food and Drug Administration's Adverse Event Reporting System;
TKI, tyrosine kinase inhibitor.

Figure 2 Reporting odds ratios (RORs) of TKI-induced cardiac AEs. The
graph presents the RORs of each cardiac adverse events(AEs) compared to
reports in the full database. A lower limit of the ROR 95\% CI above 1
is considered signifcant. (a):Sorafenib;(b): Lenvatinib;
(c):Regorafenib;(d):Cabozantinib

*CI values exceeded graph limits.

\&:only the top 20 repored PT were listed.

\#:some of the RORs were too big to be presented

AE,adverse events; TKI, tyrosine kinase inhibitor.

Figure 3 Time to event onset of TKI-induced cardiac AEs.
(a):Hypertension; (b):Cardiac failure; (c):Atrial fibrillation;
(d):Acute myocardial infarction; (e):Acute coronary syndrome;

AE,adverse events; TKI, tyrosine kinase inhibitor.

Table 1. Summary of FDA-approved TKIs for HCC\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Initial US FDA approval year & Generic name & Brand name &
Target\tabularnewline
2005 & Sorafenib & Nexavar & Ttyrosine kinases\tabularnewline
2012 & Regorafenib & Stivarga & Ttyrosine kinases\tabularnewline
2012 & Cabozantinib & Cabometys & Ttyrosine kinases\tabularnewline
2015 & Lenvatinib & Lenvima & Ttyrosine kinases\tabularnewline
FDA,US Food and Drug Administration; Hepatocellular cancer; TKIs,
Ttyrosine kinases inhibitors. & FDA,US Food and Drug Administration;
Hepatocellular cancer; TKIs, Ttyrosine kinases inhibitors. & FDA,US Food
and Drug Administration; Hepatocellular cancer; TKIs, Ttyrosine kinases
inhibitors. & FDA,US Food and Drug Administration; Hepatocellular
cancer; TKIs, Ttyrosine kinases inhibitors.\tabularnewline
\bottomrule
\end{longtable}

Table 2.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Summary of major algorithms used for signal detection. & Summary of
major algorithms used for signal detection. & Summary of major
algorithms used for signal detection.\tabularnewline
Method & Calculation formulas & Judgement criteria\tabularnewline
ROR & ROR=ad/bc & 95\%CI\textgreater{}1,N[?]3\tabularnewline
& 95\%CI=eln(ROR)\selectlanguage{ngerman}±1.96(1/a+1/b+1/c+1/d)\^{}0.5 &\tabularnewline
PRR & PRR=a(c+d)/c(a+b) &
PRR[?]2,\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}[?]4,N[?]3\tabularnewline
&
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}=[(ad-bc)\^{}2](a+b+c+d)/[(a+b)(c+d)(a+c)(b+d)]
&\tabularnewline
BCPNN & IC = log\textsubscript{2}a(a + b + c + d)(a + c)(a + b) &
IC025\textgreater{} 0\tabularnewline
& 95\% CI = e\selectlanguage{ngerman}\textsuperscript{ln(IC) ± 1.96(1/a+1/b+1/c+1/d)\^{}0.5}
&\tabularnewline
MGPS & EBGM = a(a + b + c + d)/(a + c)/(a + b) & EBGM05\textgreater{}
2,\tabularnewline
& 95\% CI = e\selectlanguage{ngerman}\textsuperscript{ln(EBGM) ± 1.96(1/a+1/b+1/c+1/d)\^{}0.5} &
N\textgreater{}0\tabularnewline
a:the number of reports with suspect drug adverse event of the suspect
drug; b:the number of reports with the suspect AE of all other drugs,;
c:the number of reports with all other AEs of the suspect drug; d: the
number of reports with all other AEs of all other drugs; N:the number of
co-occurrences; BCPNN:Bayesian confidence propagation neural network;
CI:confidence interval; EBGM:empirical Bayesian geometric mean;
EBGM05:the lower 95\% one-sided CI of EBGMIC; IC: information component;
IC025: the lower limit of the 95\% two-sided CI of the IC;
MGPS:multi-item gamma Poisson shrinker; PRR Proportional Reporting
Ratio; ROR:Reporting Odds Ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. & a:the number of
reports with suspect drug adverse event of the suspect drug; b:the
number of reports with the suspect AE of all other drugs,; c:the number
of reports with all other AEs of the suspect drug; d: the number of
reports with all other AEs of all other drugs; N:the number of
co-occurrences; BCPNN:Bayesian confidence propagation neural network;
CI:confidence interval; EBGM:empirical Bayesian geometric mean;
EBGM05:the lower 95\% one-sided CI of EBGMIC; IC: information component;
IC025: the lower limit of the 95\% two-sided CI of the IC;
MGPS:multi-item gamma Poisson shrinker; PRR Proportional Reporting
Ratio; ROR:Reporting Odds Ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. & a:the number of
reports with suspect drug adverse event of the suspect drug; b:the
number of reports with the suspect AE of all other drugs,; c:the number
of reports with all other AEs of the suspect drug; d: the number of
reports with all other AEs of all other drugs; N:the number of
co-occurrences; BCPNN:Bayesian confidence propagation neural network;
CI:confidence interval; EBGM:empirical Bayesian geometric mean;
EBGM05:the lower 95\% one-sided CI of EBGMIC; IC: information component;
IC025: the lower limit of the 95\% two-sided CI of the IC;
MGPS:multi-item gamma Poisson shrinker; PRR Proportional Reporting
Ratio; ROR:Reporting Odds Ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared.\tabularnewline
\bottomrule
\end{longtable}

Table 3. Clinical characteristics of patients with cardiac AEs using
TKIs in the FAERS database (January 2004 to Dem 2021)\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Characteristics & Number of reports, no. (\%) & Number of reports, no.
(\%) & Number of reports, no. (\%) & Number of reports, no.
(\%)\tabularnewline
& Sorafenib & Lenvatinib & Regorafenib & Cabozantinib\tabularnewline
Country & & & &\tabularnewline
United States & 271(13.6) & 80(25.2) & 237(37.6) &
1211(68.6)\tabularnewline
Japan & 191(9.6) & 38(11.9) & 122(19.4) & 113(6.4)\tabularnewline
France & 46(2.3) & 14(4.4) & 47(7.5) & 79(4.5)\tabularnewline
others & 410(20.6) & 165(51.9) & 203(32.2) & 277(15.7)\tabularnewline
Unknown or missing & 1076(54.0) & 21(6.6) & 21(3.3) &
86(4.9)\tabularnewline
Reporter & & & &\tabularnewline
Medical staff & 1524(76.4) & 309(97.2) & 502(79.7) &
663(37.5)\tabularnewline
Non-medical staff & 314(15.7) & 6(1.9) & 128(20.3) &
1072(60.7)\tabularnewline
Unknown or missing & 156(7.8) & 3(0.9) & / & 31(1.8)\tabularnewline
Reporting time & & & &\tabularnewline
2006 & 136(6.8) & / & / & /\tabularnewline
2007 & 83(4.2) & / & / & /\tabularnewline
2008 & 105(5.3) & / & / & /\tabularnewline
2009 & 177(8.9) & / & / & /\tabularnewline
2010 & 221(11.1) & / & / & /\tabularnewline
2011 & 224(11.2) & / & / & /\tabularnewline
2012 & 145(7.3) & / & 4(0.6) & /\tabularnewline
2013 & 116(5.8) & / & 54(8.6) & 55(3.1)\tabularnewline
2014 & 124(6.2) & / & 92(14.6) & 46(2.6)\tabularnewline
2015 & 109(5.5) & 10(3.1) & 73(11.6) & 50(2.8)\tabularnewline
2016 & 109(5.5) & 12(3.8) & 66(10.5) & 45(2.5)\tabularnewline
2017 & 100(5.0) & 17(5.3) & 100(15.9) & 160(9.1)\tabularnewline
2018 & 134(6.7) & 18(5.7) & 87(13.8) & 264(14.9)\tabularnewline
2019 & 96(4.8) & 66(20.8) & 60(9.5) & 346(19.6)\tabularnewline
2020 & 61(3.1) & 85(26.7) & 75(11.9) & 345(19.5)\tabularnewline
2021 & 54(2.7) & 110(34.6) & 19(3.0) & 455(25.8)\tabularnewline
Gender & & & &\tabularnewline
Female & 520(26.1) & 163(51.3) & 254(40.3) & 508(28.8)\tabularnewline
Male & 1394(69.9) & 155(48.7) & 358(56.8) & 1208(68.4)\tabularnewline
Unknown or missing & 80(4.0) & / & 18(2.9) & 50(2.8)\tabularnewline
Age (year) & & & &\tabularnewline
\textless{} 18 & 21(1.1) & 8(2.5) & 2(0.3) & 7(0.4)\tabularnewline
18-64 & 727(36.5) & 127(39.9) & 249(39.5) & 478(27.1)\tabularnewline
[?]65 & 1049(52.6) & 177(55.7) & 288(45.7) & 597(33.8)\tabularnewline
Unknown or missing & 197(9.9) & 6(1.9) & 91(14.4) &
684(38.7)\tabularnewline
Cardiac AEs, Cardiac adverse events; FAERS, Food and Drug
Administration's Adverse Event Reporting System; TKI, Ttyrosine kinases
inhibitors. & Cardiac AEs, Cardiac adverse events; FAERS, Food and Drug
Administration's Adverse Event Reporting System; TKI, Ttyrosine kinases
inhibitors. & Cardiac AEs, Cardiac adverse events; FAERS, Food and Drug
Administration's Adverse Event Reporting System; TKI, Ttyrosine kinases
inhibitors. & Cardiac AEs, Cardiac adverse events; FAERS, Food and Drug
Administration's Adverse Event Reporting System; TKI, Ttyrosine kinases
inhibitors. & Cardiac AEs, Cardiac adverse events; FAERS, Food and Drug
Administration's Adverse Event Reporting System; TKI, Ttyrosine kinases
inhibitors.\tabularnewline
\bottomrule
\end{longtable}

Table 4. Disproportionality analysis of TKI-associated cardiac AEs\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllllll@{}}
\toprule
Drugs & PT & N & ROR (95\% two-sided CI) & PRR (\selectlanguage{greek}χ\selectlanguage{english}2) & IC (95\% two-sided
CI) & EBGM (95\% one-sided CI) & Drugs & PT & N & ROR (95\% two-sided
CI) & PRR (\selectlanguage{greek}χ\selectlanguage{english}2) & IC (95\% two-sided CI) & EBGM (95\% one-sided
CI)\tabularnewline
Cabozantinib\textsuperscript{a} & Blood pressure inadequately controlled
& 940 & 282.9 (262.45,304.94) & 267.52 (189269.04) & 59.66 (55.35,64.31)
& 60287401469.68 (60287401469.68) & Sorafenib\textsuperscript{a} &
Hypertension & 1008 & 7.33 (6.88,7.82) & 6.97 (5155.99) & 64.74
(60.73,69) & 2181489196.28 (2181489196.28)\tabularnewline
& Dry gangrene & 440 & 6883.12 (5198.37,9113.87) & 6707.38 (327829.76) &
55.59 (41.98,73.61) & 221538384975.11 (221538384975.11) & & Atrial
fibrillation & 150 & 1.82 (1.55,2.14) & 1.81 (54.61) & 61.17
(52.08,71.85) & 570144491.93 (570144491.93)\tabularnewline
& Superficial vein thrombosis & 143 & 46.28 (39.08,54.8) & 45.9
(5956.13) & 56.45 (47.67,66.84) & 12936474658.03 (12936474658.03) & &
Haemorrhage & 118 & 1.53 (1.28,1.83) & 1.53 (21.45) & 60.73
(50.66,72.79) & 480576781.18 (480576781.18)\tabularnewline
& Sinus tachycardia & 72 & 5.84 (4.63,7.36) & 5.82 (285.41) & 57.38
(45.49,72.38) & 1717187481.63 (1717187481.63) & & Deep vein thrombosis &
92 & 1.44 (1.18,1.77) & 1.44 (12.5) & 60.09 (48.95,73.77) & 454279143.52
(454279143.52)\tabularnewline
& Cardiac discomfort & 51 & 45.14 (34.04,59.85) & 45.01 (2082.97) & 53.5
(40.35,70.94) & 12698066771.18 (12698066771.18) & & Cardiac failure & 91
& 1.31 (1.06,1.61) & 1.31 (6.57) & 60.2 (48.99,73.98) & 411702241.09
(411702241.09)\tabularnewline
& Hypoperfusion & 43 & 50.97 (37.45,69.37) & 50.85 (1981.31) & 52.84
(38.83,71.91) & 14251222570.71 (14251222570.71) & & Acute myocardial
infarction & 65 & 2.22 (1.74,2.84) & 2.22 (43.52) & 58.47 (45.81,74.62)
& 698464980.44 (698464980.44)\tabularnewline
& Cardiac dysfunction & 43 & 22.89 (16.9,31) & 22.83 (873.97) & 53.95
(39.83,73.06) & 6607225260.89 (6607225260.89) & & Flushing & 61 & 1.81
(1.41,2.33) & 1.81 (22.07) & 58.58 (45.55,75.34) & 569596145.82
(569596145.82)\tabularnewline
& Cardiac failure acute & 30 & 5.92 (4.13,8.47) & 5.91 (121.47) & 54.83
(38.28,78.55) & 1743684816.44 (1743684816.44) & & Arrhythmia & 61 & 1.43
(1.11,1.84) & 1.43 (7.93) & 58.92 (45.81,75.77) & 450778645.54
(450778645.54)\tabularnewline
& Cardiac aneurysm & 22 & 24.82 (16.24,37.94) & 24.79 (487.91) & 51.9
(33.95,79.33) & 7158061394.43 (7158061394.43) & & Blood pressure
fluctuation & 39 & 2.42 (1.76,3.31) & 2.41 (32.18) & 56.87 (41.52,77.91)
& 758858171 (758858171)\tabularnewline
& Labile hypertension & 20 & 85.22 (53.78,135.02) & 85.12 (1509.4) &
49.94 (31.52,79.13) & 22970569870.69 (22970569870.69) & & Pericardial
effusion & 31 & 1.61 (1.13,2.3) & 1.61 (7.23) & 56.79 (39.91,80.81) &
508091449.33 (508091449.33)\tabularnewline
& Distributive shock & 20 & 26.52 (16.99,41.4) & 26.49 (475.56) & 51.53
(33.01,80.45) & 7633405301.59 (7633405301.59) & & Myocardial ischaemia &
29 & 2.41 (1.68,3.48) & 2.41 (23.91) & 56.02 (38.9,80.68) & 758735245.6
(758735245.6)\tabularnewline
& Supraventricular tachycardia & 20 & 2.38 (1.53,3.69) & 2.38 (15.89) &
54.97 (35.43,85.28) & 704140932.61 (704140932.61) & & Cardiomyopathy &
29 & 2.12 (1.47,3.05) & 2.12 (17.1) & 56.21 (39.03,80.94) & 666806456.55
(666806456.55)\tabularnewline
& Right ventricular hypertrophy & 18 & 21.74 (13.61,34.71) & 21.71
(346.73) & 51.51 (32.25,82.26) & 6291938703.71 (6291938703.71) & & Left
ventricular dysfunction & 27 & 4.66 (3.19,6.8) & 4.65 (77.02) & 54.87
(37.58,80.12) & 1459822016.31 (1459822016.31)\tabularnewline
& Orthostatic hypertension & 15 & 45.44 (27.02,76.42) & 45.4 (617.91) &
49.96 (29.71,84.01) & 12802946049.5 (12802946049.5) & & Circulatory
collapse & 26 & 1.57 (1.07,2.3) & 1.57 (5.33) & 56.33 (38.33,82.78) &
493489672.02 (493489672.02)\tabularnewline
& Hypovolaemic shock & 12 & 2.93 (1.66,5.16) & 2.93 (15.18) & 53.2
(30.17,93.78) & 867140677.64 (867140677.64) & & Cardiotoxicity & 24 &
3.95 (2.64,5.89) & 3.94 (52.45) & 54.77 (36.66,81.81) & 1237677312.35
(1237677312.35)\tabularnewline
& Hyperaemia & 9 & 5.9 (3.06,11.36) & 5.9 (36.33) & 51.36 (26.66,98.96)
& 1740167686.48 (1740167686.48) & & Internal haemorrhage & 24 & 2.3
(1.54,3.44) & 2.3 (17.63) & 55.54 (37.2,82.93) & 724135762.42
(724135762.42)\tabularnewline
& Phlebitis superficial & 8 & 21.51 (10.66,43.4) & 21.5 (152.45) & 49.18
(24.37,99.23) & 6230767077.43 (6230767077.43) & & Acute coronary
syndrome & 23 & 2.81 (1.87,4.24) & 2.81 (26.75) & 55.13 (36.6,83.04) &
883811563.27 (883811563.27)\tabularnewline
& Peripheral artery thrombosis & 8 & 7.27 (3.62,14.58) & 7.27 (42.87) &
50.72 (25.29,101.74) & 2141617040.58 (2141617040.58) & & Aortic
dissection & 21 & 5.08 (3.31,7.8) & 5.07 (68.28) & 54.02 (35.17,82.98) &
1591058105.9 (1591058105.9)\tabularnewline
& Cardiorenal syndrome & 6 & 13.42 (5.99,30.06) & 13.41 (67.85) & 49.02
(21.88,109.82) & 3924892647.2 (3924892647.2) & & Shock haemorrhagic & 21
& 3.1 (2.02,4.76) & 3.1 (29.7) & 54.73 (35.65,84.03) & 973126858.13
(973126858.13)\tabularnewline
& Thrombophlebitis migrans & 5 & 40.71 (16.59,99.9) & 40.7 (184.66) &
46.94 (19.13,115.18) & 11538457550.79 (11538457550.79) & &
Supraventricular tachycardia & 21 & 2.42 (1.58,3.72) & 2.42 (17.48) &
55.08 (35.88,84.56) & 761703054.23 (761703054.23)\tabularnewline
Drugs & PT & N & ROR (95\% two-sided CI) & PRR (\selectlanguage{greek}χ\selectlanguage{english}2) & IC (95\% two-sided
CI) & EBGM (95\% one-sided CI) & Drugs & PT & N & ROR (95\% two-sided
CI) & PRR (\selectlanguage{greek}χ\selectlanguage{english}2) & IC (95\% two-sided CI) & EBGM (95\% one-sided
CI)\tabularnewline
Lenvatinib & Hypertension & 163 & 7.98 (6.81,9.35) & 7.55 (932.22) &
59.36 (50.65,69.56) & 52381539.17 (52381539.17) & Regorafenib &
Hypertension & 471 & 8.06 (7.35,8.85) & 7.62 (2722.53) & 62.41
(56.84,68.52) & 433925901.61 (433925901.61)\tabularnewline
& Myocardial infarction & 39 & 1.46 (1.06,2) & 1.45 (5.53) & 57.61
(41.99,79.03) & 10084133.57 (10084133.57) & & Atrial fibrillation & 48 &
1.36 (1.03,1.81) & 1.36 (4.6) & 58.3 (43.89,77.44) & 77667091.94
(77667091.94)\tabularnewline
& Acute myocardial infarction & 34 & 7.91 (5.64,11.09) & 7.82 (202.18) &
54.78 (39.05,76.86) & 54251070.65 (54251070.65) & & Haemorrhage & 46 &
1.4 (1.05,1.87) & 1.4 (5.2) & 58.14 (43.5,77.69) & 79751845.5
(79751845.5)\tabularnewline
& Cardiac failure & 26 & 2.53 (1.72,3.72) & 2.51 (23.8) & 55.64
(37.81,81.89) & 17466798.23 (17466798.23) & & Cardiac failure & 42 &
1.42 (1.05,1.92) & 1.42 (5.16) & 57.85 (42.71,78.36) & 80889706.97
(80889706.97)\tabularnewline
& Hypertensive crisis & 16 & 10.73 (6.56,17.54) & 10.67 (139.98) & 52.16
(31.89,85.31) & 73988760.86 (73988760.86) & & Blood pressure fluctuation
& 29 & 4.23 (2.93,6.09) & 4.21 (70.98) & 55.22 (38.33,79.54) &
240212796.17 (240212796.17)\tabularnewline
& Acute coronary syndrome & 14 & 11.57 (6.84,19.58) & 11.52 (134.26) &
51.66 (30.54,87.4) & 79883667.56 (79883667.56) & & Hypertensive crisis &
19 & 4.43 (2.82,6.95) & 4.42 (50.17) & 53.93 (34.36,84.64) & 251885628.1
(251885628.1)\tabularnewline
& Embolism & 12 & 10.56 (5.99,18.63) & 10.51 (103.17) & 51.35
(29.11,90.59) & 72936075.24 (72936075.24) & & Embolism & 11 & 3.36
(1.86,6.08) & 3.36 (18.21) & 52.74 (29.18,95.33) & 191671633.99
(191671633.99)\tabularnewline
& Cardiac failure acute & 6 & 7.7 (3.46,17.17) & 7.69 (34.87) & 49.8
(22.34,111.02) & 53349813.43 (53349813.43) & & Blood pressure
inadequately controlled & 7 & 3.45 (1.65,7.25) & 3.45 (12.17) & 51.4
(24.48,107.93) & 196895455.02 (196895455.02)\tabularnewline
& Myocarditis & 6 & 5.39 (2.42,12.02) & 5.38 (21.41) & 50.31
(22.57,112.14) & 37385847.36 (37385847.36) & & Aortic dissection & 6 &
3.39 (1.52,7.56) & 3.39 (10.11) & 50.98 (22.88,113.6) & 193517448.44
(193517448.44)\tabularnewline
& Hypertensive urgency & 3 & 97.5 (31.11,305.54) & 97.39 (281.2) & 44.16
(14.09,138.39) & 665011627.88 (665011627.88) & & Left ventricular
dysfunction & 6 & 2.42 (1.09,5.39) & 2.42 (4.99) & 51.47 (23.1,114.66) &
138098680.3 (138098680.3)\tabularnewline
& Arterial haemorrhage & 3 & 20.42 (6.57,63.48) & 20.39 (55.13) & 46.4
(14.92,144.26) & 141212345.67 (141212345.67) & & Thrombophlebitis
migrans & 5 & 60.58 (24.86,147.6) & 60.54 (283.79) & 46.34
(19.02,112.91) & 3352917345.37 (3352917345.37)\tabularnewline
& Aortic thrombosis & 3 & 20.78 (6.68,64.6) & 20.75 (56.2) & 46.37
(14.91,144.18) & 143695979.89 (143695979.89) & & Hypovolaemic shock & 5
& 2.78 (1.16,6.68) & 2.78 (5.68) & 50.74 (21.1,122.03) & 158459126.5
(158459126.5)\tabularnewline
& Hypovolaemic shock & 3 & 4.78 (1.54,14.84) & 4.78 (8.95) & 48.49
(15.62,150.51) & 33163815.6 (33163815.6) & & Lymphoedema & 5 & 2.52
(1.05,6.05) & 2.52 (4.56) & 50.89 (21.16,122.36) & 143595777.01
(143595777.01)\tabularnewline
& Stress cardiomyopathy & 3 & 4.76 (1.53,14.77) & 4.75 (8.89) & 48.49
(15.62,150.53) & 33010678.21 (33010678.21) & & Systolic hypertension & 4
& 23.78 (8.87,63.75) & 23.76 (86.16) & 47.02 (17.54,126.07) &
1341166938.15 (1341166938.15)\tabularnewline
& Left ventricular dysfunction & 3 & 3.47 (1.12,10.77) & 3.47 (5.27) &
48.95 (15.77,151.92) & 24085491.68 (24085491.68) & & Ventricular
hypokinesia & 4 & 3.13 (1.17,8.35) & 3.13 (5.78) & 49.93 (18.72,133.17)
& 178457315.04 (178457315.04)\tabularnewline
& / & & / & / & / & / & & Hypertensive emergency & 3 & 7.47 (2.4,23.2) &
7.46 (16.73) & 47.85 (15.39,148.72) & 424760772.51
(424760772.51)\tabularnewline
& / & & / & / & / & / & & Cardiac discomfort & 3 & 5.75 (1.85,17.87) &
5.75 (11.74) & 48.22 (15.52,149.81) & 327587728.65
(327587728.65)\tabularnewline
a:only the top 20 repored PT were listed; N:the number of reports of
TKI-associated cardiac AEs; ROR:reporting odds ratio; CI:confidence
interval; PRR:proportional reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT,
preferred term; AEs, adverse events. & a:only the top 20 repored PT were
listed; N:the number of reports of TKI-associated cardiac AEs;
ROR:reporting odds ratio; CI:confidence interval; PRR:proportional
reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term; AEs, adverse
events. & a:only the top 20 repored PT were listed; N:the number of
reports of TKI-associated cardiac AEs; ROR:reporting odds ratio;
CI:confidence interval; PRR:proportional reporting ratio;
\selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term; AEs, adverse events. & a:only the
top 20 repored PT were listed; N:the number of reports of TKI-associated
cardiac AEs; ROR:reporting odds ratio; CI:confidence interval;
PRR:proportional reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term;
AEs, adverse events. & a:only the top 20 repored PT were listed; N:the
number of reports of TKI-associated cardiac AEs; ROR:reporting odds
ratio; CI:confidence interval; PRR:proportional reporting ratio;
\selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term; AEs, adverse events. & a:only the
top 20 repored PT were listed; N:the number of reports of TKI-associated
cardiac AEs; ROR:reporting odds ratio; CI:confidence interval;
PRR:proportional reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term;
AEs, adverse events. & a:only the top 20 repored PT were listed; N:the
number of reports of TKI-associated cardiac AEs; ROR:reporting odds
ratio; CI:confidence interval; PRR:proportional reporting ratio;
\selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term; AEs, adverse events. & a:only the
top 20 repored PT were listed; N:the number of reports of TKI-associated
cardiac AEs; ROR:reporting odds ratio; CI:confidence interval;
PRR:proportional reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term;
AEs, adverse events. & a:only the top 20 repored PT were listed; N:the
number of reports of TKI-associated cardiac AEs; ROR:reporting odds
ratio; CI:confidence interval; PRR:proportional reporting ratio;
\selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term; AEs, adverse events. & a:only the
top 20 repored PT were listed; N:the number of reports of TKI-associated
cardiac AEs; ROR:reporting odds ratio; CI:confidence interval;
PRR:proportional reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term;
AEs, adverse events. & a:only the top 20 repored PT were listed; N:the
number of reports of TKI-associated cardiac AEs; ROR:reporting odds
ratio; CI:confidence interval; PRR:proportional reporting ratio;
\selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term; AEs, adverse events. & a:only the
top 20 repored PT were listed; N:the number of reports of TKI-associated
cardiac AEs; ROR:reporting odds ratio; CI:confidence interval;
PRR:proportional reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term;
AEs, adverse events. & a:only the top 20 repored PT were listed; N:the
number of reports of TKI-associated cardiac AEs; ROR:reporting odds
ratio; CI:confidence interval; PRR:proportional reporting ratio;
\selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term; AEs, adverse events. & a:only the
top 20 repored PT were listed; N:the number of reports of TKI-associated
cardiac AEs; ROR:reporting odds ratio; CI:confidence interval;
PRR:proportional reporting ratio; \selectlanguage{greek}χ\selectlanguage{english}2:chi-squared. PT, preferred term;
AEs, adverse events.\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

