Cardiovascular Toxicities of Antiangiogenic Tyrosine Kinase Inhibitors: A Retrospective Pharmacovigilance Study. - The 68th Annual Conference of the Israel Heart Society in association with the Israel Society of Cardiothoracic Surgery

Adam Goldman ¹ David Bomze ¹ Rachel Dankner ^2,3 Dana Fourey ¹ Ben Boursi ^1,4,5 Michael Arad ^1,6 Elad Maor ^1,6

¹School of Medicine, Sackler Faculty of Medicine, Israel
²Unit for Cardiovascular Epidemiology, The Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Tel HaShomer., Israel
³Department of Epidemiology and Preventive Medicine,,, School of Public Health, Sackler School of Medicine, Tel Aviv University., Israel
⁴Department of Oncology, Sheba Medical Center, Tel HaShomer., Israel
⁵Center for Clinical Epidemiology and Biostatistics,, University of Pennsylvania, USA
⁶Leviev Heart Center., Sheba Medical Center, Tel HaShomer., Israel

Background: vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in the management of various solid tumors. However, post-marketing data regarding their potential cardiovascular toxicities are scant.

Objective: To identify and characterize cardiovascular adverse events (CVAEs) that are associated with VEGFR-TKIs.

Patients and Methods: Disproportionality analysis of the FDA adverse event reporting system (07/2014-12/2019) 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[57-73]). CVAEs accounted for 11,784 (23%) of the reports, with hypertension (n=5,548[11%], ROR=6.55[95% CI: 6.37-6.74], IC₀₂₅=2.48) and hemorrhages (n=3,710[7.2%], ROR=1.28[1.24-1.32], IC₀₂₅=0.28) being the most frequent types. Additional CVAEs were associated 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 over-reported also in patients without concurrent report of 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 various CVAEs, including pericardial diseases, particularly non-malignant pericardial effusion, and aortic dissections. Moreover, VEGFR-TKIs differ in their CVAEs reporting patterns. Clinicians should be conscious of these findings in the care of VEGFR-TKIs recipients.