Comparative evaluation of cardiovascular risks among nine FDA-approved VEGFR-TKIs in patients with solid tumors: a Bayesian network analysis of randomized controlled trials

Abstract

Purpose The present meta-analysis study was performed to identify the potential cardiotoxicity risks when using Vascular Endothelial Growth Factor Receptor Tyrosine kinase inhibitors (VEGFR-TKIs) as anticancer drugs in patients with solid tumors. Methods Pubmed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for the randomized controlled trials. We have included 45 randomized controlled trials (RCTs) associated with nine VEGFR-TKIs Food and Drug Administration (FDA)-approved drugs used to treat patients with solid tumors. To evaluate the trials’ risk of bias, Cochrane Risk of Bias Tool was assessed. A direct comparison was assessed by RevMan5.3 software, calculating the odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was tested by the I2 statistic and Chi-square test for P value. Bayesian network meta-analysis was performed using Stata 15.0 and GeMTC 0.14.3 software, calculated OR along with corresponding 95% credible interval (CrI). The model’s convergence was evaluated by the potential scale reduced factor (PSRF). Consistency between direct and indirect comparisons was assessed by the “node-splitting” method. Results In this network meta-analysis, a total of 20,027 patients from 45 randomized controlled trials and associated with nine FDA-approved VEGFR-TKIs (axitinib, cabozantinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib), were enrolled. Findings indicated that lenvatinib had the most significant probability of provoking all grades cardiovascular incident and hypertension, followed by vandetanib, cabozantinib, axitinib, pazopanib, sorafenib, sunitinib, regorafenib and nintedanib. The nine agent’s severe cardiovascular and severe hypertension risk was probably similar. The ranking probability of cardiac toxicity shows that vandetanib ranked most likely to have the highest risk for cardiotoxicity among all the VEGFR-TKIs reviewed, followed by pazopanib, axitinib, sorafenib, sunitinib. In contrast, regorafenib and nintedanib did not exhibit an increased risk of cardiac damage. Conclusions The association between the nine VEGFR-TKIs with potential cardiotoxicity occurrence was reviewed. Both the regorafenib and nintedanib did not display detectable signs of cardiotoxic damage. In contrast, lenvatinib and vandetanib are ranked to have the most severe cardiotoxicity side impacts. These results may provide information for clinical practice guidelines, implementing strategies in selecting the adequate VEGFR-TKIs, and understanding the cardiovascular toxicity inflicted by the VEGFR-TKIs. PROSPERO identifier CRD 42,020,167,307.

Lenvatinib induces cardiac developmental toxicity in zebrafish embryos through regulation of Notch mediated‐oxidative stress generation

“…Lenvatinib is a small molecule tyrosine kinase inhibitor and clinically used for the treatment of radio‐iodide refractory differentiated thyroid cancer and other cancers. Related clinical reports suggested that lenvatinib had a serious risk of hypertension and cardiotoxicity, with mitochondrial toxicity in H9c2 cardiomyoblastic cell line exposed to lenvatinib 18–21 . With the increasing clinical use of lenvatinib, the effects of the parent and its metabolites discharged into the water on non‐target organisms should be taken into account.…”

“…Related clinical reports suggested that lenvatinib had a serious risk of hypertension and cardiotoxicity, with mitochondrial toxicity in H9c2 cardiomyoblastic cell line exposed to lenvatinib. [18][19][20][21] With the increasing clinical use of lenvatinib, the effects of the parent and its metabolites discharged into the water on non-target organisms should be taken into account. Here, we used zebrafish embryos to evaluate its cardiovascular effects.…”

Antiangiogenic Drugs in NASH: Evidence of a Possible New Therapeutic Approach

“…However, severe adverse events due to high plasma concentrations of TKIs may be also addressed by the application of TDM-guided dosing, ensuring levels within the therapeutic window [ 112 ]. Particularly relevant on this issue is the very recent meta-analysis by Hou et al performed to identify the potential cardiotoxicity risks of VEGFR–TKIs in patients with solid tumors [ 113 ]. These authors concluded that among the VEGFR–TKIs, lenvatinib and vandetanib revealed the highest possibility to provoke cardiovascular events and hypertension, followed by cabozantinib, axitinib, pazopanib, sorafenib, sunitinib, regorafenib, and nintedanib.…”

Natural Compounds Targeting VEGFRs in Kidney Cancer: An In silico Prediction

“…FDA approved VEGFR-TKIs for Kidney Cancers (Jeong et al, 2013;Roskoski, 2022) RCC: Renal Cell Carcinoma VEGFR-TKIs block VEGFR activation (mediated by VEGFs) and thus they inhibit angiogenesis and tumor cell growth. Although good results have been obtained in the treatment of RCC and other tumors with VEGFR-TKIs, adverse effects caused by them such as hypertension and cardiovascular damage and the development of drug resistance remain serious clinical problems (Pandey et al, 2018;Erman et al, 2021;Hou et al, 2021;Sharma et al, 2021). Hou et al (2021) reported that the degree of cardiotoxic risk differed between VEGFR-TKIs, and Lenvatinib has been associated with the highest probability of producing all degrees of cardiovascular injury and hypertension.…”

“…Although good results have been obtained in the treatment of RCC and other tumors with VEGFR-TKIs, adverse effects caused by them such as hypertension and cardiovascular damage and the development of drug resistance remain serious clinical problems (Pandey et al, 2018;Erman et al, 2021;Hou et al, 2021;Sharma et al, 2021). Hou et al (2021) reported that the degree of cardiotoxic risk differed between VEGFR-TKIs, and Lenvatinib has been associated with the highest probability of producing all degrees of cardiovascular injury and hypertension. Natural non-toxic compounds targeting VEGFRs might be an alternative to VEGFR-TKIs to reduce such adverse effects.…”