Cardiovascular Toxicities of Antiangiogenic Tyrosine Kinase Inhibitors: A Retrospective, Pharmacovigilance Study

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 (IC > 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), IC = 2.48] and hemorrhages [n = 3710 (7.2%), ROR = 1.28 (1.24-1.32), IC = 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 IC > 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), IC = 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.