Angiogenesis inhibitors and the risk of peripheral artery aneurysm and dissection: a cross-database study

Anti-angiogenic inhibitors (AI) have transformed cancer treatment but are associated with vascular toxicities. The specific association with peripheral artery aneurysm and dissection (PAAD) remains uncharacterized. This study aimed to evaluate the association between AI exposure and PAAD risk and to delineate the temporal patterns of these adverse events across different exposure windows.

This analysis was conducted using the U.S. FDA Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases. Disproportionality analysis using the Reporting Odds Ratio was applied to identify safety signals. Univariate and multivariate logistic regression models were fitted to detect associated factors and quantify the effects of distinct exposure duration windows. Kaplan-Meier analysis and the Weibull distribution were utilized to characterize time-to-onset patterns.

In total, 757,900 FAERS and 136,170 JADER reports were included. Disproportionality analyses identified significantly higher RORs for PAAD (ROR = 3.276 in FAERS; ROR = 8.465 in JADER) and peripheral artery dissection (PAD) (ROR = 6.275 in FAERS; ROR = 9.372 in JADER). The peripheral arterial aneurysm (PAA) signal was marginally non-significant in FAERS but significant in JADER (ROR = 8.113). Subtype-specific analyses showed small-molecule VEGFR-targeted tyrosine kinase inhibitors (SMV-TKIs) were linked to higher reporting of PAAD and PAD, whereas anti-VEGF monoclonal antibodies (anti-VMAs) were associated with elevated reporting across all outcomes. Time-to-onset analyses uncovered temporal heterogeneity: PAAD and PAA occurred early in FAERS (median 29.5 days and 25.0 days, respectively), whereas PAD followed an early- and late-onset pattern. Within JADER, PAA events presented early, while PAD showed delayed onset (median 853.0 days). Multivariable regression supported significant independent associations between AI exposure and both PAAD and PAD, with adjusted Odds Ratios of 4.078 and 7.275 in FAERS and greater effect sizes in JADER. Time-window stratification confirmed dual reporting peaks in the early (0-29-day) and long-term (≥360-day) windows.

In conclusion, subclass-specific and time-dependent disproportional reporting signals of AI-associated PAAD were identified. Anti-VMAs were associated with elevated signals for PAAD, PAA, and PAD, whereas SMV-TKIs were mainly linked to PAAD and PAD. PAAD and PAA occurred predominantly early after drug initiation, whereas PAD showed prominent delayed onset.