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-β. In cardiomyocytes afterload
stress models, deletion of the PDGFR-β gene resulted in ventricular
hypertrophy, ventricular dilation and heart failure[37, 38]. PDGFR-β
was reported to be one of the targets of anti-angiogenic TKIs[39].
Inhibition of PDGFR-β would disrupt the cardiac adaptation mechanism to
afterload stress, thus lead to heart failure ultimately. In addition to
PDGFR-β 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.