Tyrosine kinase inhibitors targeting vascular endothelial growth factor and the risk of aortic dissection-A pharmacovigilance analysis

There are concerns by the United States Food and Drug Administration (FDA) regarding a potential link between tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF-TKIs) and the risk of aortic dissection. Elevation of blood pressure induced by VEGF-TKIs has been discussed as part of the pathomechanism. To address this important safety issue, we conducted a large pharmacovigilance study assessing the risk of aortic dissection reporting associated with the use of VEGF-TKIs, thereby exploring the role of blood pressure. We queried the FDA Adverse Event Reporting System from 2004 to 2019 for reports including VEGF-TKIs and aortic dissection and estimated reporting odds ratios (RORs) and 95% confidence intervals (CIs) of aortic dissection associated with the use of VEGF-TKIs. Secondary analyses stratified by the strength of blood pressure elevation (>= 10 mmHg vs. <10 mmHg increased systolic or diastolic bloods pressure) and pre-existing arterial hypertension. There were 81 reports of aortic dissection related to VEGF-TKIs during the study period. VEGF-TKIs were associated with an increased risk of aortic dissection reporting (ROR, 4.31; 95% CI, 3.43 to 5.42). The risk was higher among compounds strongly increasing blood pressure (ROR, 5.33; 95% CI, 3.88 to 7.32) than among compounds moderately increasing blood pressure (ROR, 2.79; 95% CI, 1.83 to 4.27). Pre-existing arterial hypertension did not modify the association. Overall, our study showed an increased risk of aortic dissection reporting associated with the use of VEGF-TKIs. Blood pressure elevation seems to play a role in the pathophysiology of this adverse effect.