Authors: Adam Goldman, David Bomze, Rachel Dankner, Dana Fourey, Ben Boursi, Michael Arad & Elad Maor
Abstract
Background
Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in the management of various solid tumors, particularly renal cell carcinoma (RCC). However, post-marketing data regarding their potential cardiovascular toxicities are scant.
Objective
To identify and characterize cardiovascular adverse events (CVAEs) of VEGFR-TKIs indicated for RCC.
Patients and Methods
Disproportionality analysis of the US Food and Drug Administration adverse event reporting system (July 2014–December 2019) using the reporting odds ratio (ROR) and the lower bound of the Information component (IC) 95% credibility interval (IC025 > 0 is significant).
Results
We identified 51,836 adverse event reports of sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib in the full database [36% women; median age 65 years (range 57–73)]. CVAEs accounted for 11,784 (23%) of the reports, with hypertension [n = 5548 (11%), ROR = 6.55 (95% CI 6.37–6.74), IC025 = 2.48] and hemorrhages [n = 3710 (7.2%), ROR = 1.28 (1.24–1.32), IC025 = 0.28] being the most frequent types. Additional CVAEs were over-reported with VEGFR-TKIs treatment, including aortic dissection [n = 61 (0.1%), ROR = 3.50 (2.71–4.51)], pericardial diseases [n = 173 (0.3%), ROR = 1.98 (1.70–2.30)], cardiomyopathy [n = 61 (0.1%), ROR = 1.89 (1.47–2.43)], heart failure [n = 868 (1.7%), ROR = 1.35 (1.26–1.44)], and venous thromboembolism [n = 604 (1.2%), ROR = 1.33 (1.23–1.45), all IC025 > 0]. The major pericardial disorder was non-malignant pericardial effusion [n = 134 (77%)]. Aortic dissections were also over-reported in patients without concomitant elevated blood pressure [ROR = 2.68 (1.97–3.63), IC025 = 0.91]. Finally, CVAEs were reported more often following lenvatinib and sunitinib treatment compared to other VEGFR-TKIs.
Conclusions
In post-marketing surveillance data, VEGFR-TKIs are associated with increased reporting of various CVAEs, including pericardial diseases, particularly non-malignant pericardial effusion, and aortic dissections. Moreover, VEGFR-TKIs differ in their CVAE reporting patterns. Clinicians should be conscious of these findings in the care of VEGFR-TKIs recipients.
Graphic Abstract
Cardiovascular toxicities of VEGFR-TKIs in the FDA adverse events reporting system (FAERS) database. Post-marketing data of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-associated cardiovascular toxicities are scant. We identified 51,836 safety reports of VEGFR-TKIs (sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib) in the FAERS database, including 11,784 (23%) cardiovascular adverse events (CVAEs). Hypertension, aortic dissections, and pericardial diseases had the highest reporting odds ratios. While the association of VEGFR-TKIs with hypertension is well established, pericardial diseases were not observed to date, and aortic dissection was reported in a small case series.
Key Summary Points |
While vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in various solid tumors, post-marketing data regarding their potential cardiovascular toxicities are scant. |
By analyzing a global repository of post-marketing safety reports, we provide an extensive characterization of VEGFR-TKI-associated cardiovascular adverse events. |
This study identifies pericardial diseases as a novel potential complication of VEGFR-TKIs, and provides evidence supporting their association with aortic dissections. Moreover, our results suggest potential differences in the cardiovascular adverse events reporting of VEGFR-TKI agents, which should be evaluated prospectively. |