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.