Angiogenesis Inhibitors Not Linked to Arterial Dissections, Aneurysms in Colorectal Cancer

Exposure to angiogenesis inhibitors was not associated with a higher risk of arterial dissections or aneurysms in patients with metastatic colorectal cancer (mCRC), a French study found.¹ Despite earlier pharmacovigilance concerns, adjusted analyses showed no association across exposure status, recency, or cumulative duration, offering reassurance about the cardiovascular safety of these widely used targeted therapies.

This nationwide case-control study is published in JAMA Network Open.

“This study provides reassuring evidence regarding the association between angiogenesis inhibitor exposure and arterial dissections or aneurysms in patients treated for mCRC,” wrote the researchers of the study. “To our knowledge, no comparable study has been published.”

Angiogenesis is the process by which new blood vessels form, driven by the growth and movement of endothelial cells that line vessel walls.² This process is normally balanced by chemical signals that either promote or inhibit blood vessel formation. Vascular endothelial growth factor and other stimulators encourage new vessel growth, while angiogenesis inhibitors block these signals to prevent excessive or abnormal blood vessel formation. Maintaining this balance is critical, as unregulated angiogenesis can contribute to diseases such as cancer and age-related wet macular degeneration.

To evaluate whether angiogenesis inhibitors are linked to arterial dissections or aneurysms in patients with mCRC, researchers conducted a nested case-control study within a larger group of adults who started targeted therapy between 2012 and 2017.¹ The study used data that included health insurance and hospital records. Patients who experienced an arterial dissection or aneurysm through 2019 were identified and matched with up to 10 similar patients by age, sex, and time since starting therapy.

Researchers assessed exposure to commonly used angiogenesis inhibitors in France—bevacizumab, aflibercept, ramucirumab, and regorafenib—looking at whether patients had ever used the drug, how recently they had used it, and cumulative duration of use. Hospitalizations for arterial events were analyzed using statistical models to determine whether there was an association with angiogenesis inhibitor use.

Among the 34,733 patients in the study, 195 experienced an arterial dissection or aneurysm (0.6%) and were matched with 1950 controls. The overall study population of 2145 patients was predominantly male (72.8%), with a median (IQR) age of 69 years (63-73) for cases and 68 years (62-73) for controls. When examining exposure to angiogenesis inhibitors, 72.3% of cases and 70.8% of controls had used these drugs at some point.

After accounting for cardiovascular risk factors, there was no significant association between angiogenesis inhibitor use and arterial events (OR, 1.07; 95% CI, 0.75-1.52). Similarly, no links were found when considering how recently patients had been treated or the cumulative duration of exposure, regardless of how exposure was measured.

The researchers acknowledged some limitations on their findings, including a small number of arterial events and a low proportion of patients who had never been exposed to angiogenesis inhibitors, which may have affected the estimates. However, the researchers noted the study period offered a pre–COVID-19 context, avoiding pandemic-related disruptions in cancer care, and predated regulatory warnings on angiogenesis inhibitors, minimizing potential bias.

Despite these constraints, the researchers believe the findings remain relevant, as angiogenesis inhibitors—particularly bevacizumab—are still widely used in first-line and subsequent treatments for mCRC.

“These findings are relevant to routine clinical practice, given the well-established survival benefits of angiogenesis inhibitors in mCRC, especially bevacizumab, including in older patients with cardiovascular comorbidities, as well as their increasing use beyond first-line treatment,” wrote the researchers. “However, these reassuring findings should not diminish the importance of individual patient monitoring, particularly for those with a high-risk profile for arterial events, such as smokers with peripheral arterial disease.”

References

1. Singier A, Munoz AJ, Maumus-Robert S, et al. Angiogenesis inhibitors and arterial dissection or aneurysm in patients with metastatic colorectal cancer. JAMA Netw Open. 2025;8(12):e2546960. doi:10.1001/jamanetworkopen.2025.46960

2. Angiogenesis inhibitors. Natinal Cancer Institute. Reviewed April 2, 2018. Accessed December 2, 2025. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet