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A disproportionate number of aneurysms and artery dissections were reported among cancer patients on antiangiogenic drugs in a pharmacovigilance study involving more than 1.5 million adverse reactions to cancer therapies.

The analysis of the WHO's VigiBase database found that artery dissections or aneurysms were nearly three times as likely to be reported with antiangiogenic agents as compared with other cancer drugs (proportional reporting ratio 2.76, 95% CI 2.48-3.07; Bayesian information component 1.14, 95% credibility interval 0.99-1.25), reported Pernelle Noize, PharmD, PhD, of Bordeaux University Hospital in France, and colleagues.

Among nearly 500 cases of artery dissections or aneurysms associated with these agents, 88.3% were serious, with 24.3% being fatal, 17.8% considered life-threatening, and 24.7% leading to or prolonging hospitalization, according to the findings in .

"Population-based studies are needed to confirm and quantify the potential risk," the group wrote. "However, this study's results warrant the cautious use of antiangiogenic drugs, whatever their mechanism, among individuals at risk of artery dissections or aneurysms, as already advised by Canadian and European agencies."

Noize and co-authors noted that "notoriety bias is unlikely" in this setting, since the association between antiangiogenic drugs and artery dissections or aneurysms is largely absent from the literature, with only a few reported cases to date.

"Vascular endothelial growth factor blockade can produce conditions favoring artery dissections or aneurysms, notably hypertension, through the inhibition of nitric oxide synthesis and the rarefaction of tissue capillaries," the group wrote.

Hypertension was reported in 10.3% of the cases, and in just 3.5% of patients on mammalian target of rapamycin (mTOR) inhibitors.

Other mechanisms, they posited, could include "arterial wall injuries through alteration of the extracellular matrix by (1) rarefaction of vasa vasorum that alter vessel wall blood supply and may initiate acute rupture and (2) overexpression of degradation enzymes (i.e., elastin and collagen) that may weaken the matrix structure," or the induction of vascular aging with vascular endothelial growth factor (VEGF) inhibitors.

The analysis from Noize's team captured 1,521,231 adverse events with cancer drugs reported in VigiBase from 2005 to 2019, which included 217,664 reports associated with antiangiogenic agents.

Median age among the 494 patients with artery dissections or aneurysms associated with antiangiogenic agents was 67 years. Just over half of the cases involved women, and a little more than a fourth of patients were also on other drugs that could have contributed to artery dissections or aneurysms. Most cases involved the aorta (42.1%) and cerebral arteries (35.2%), with the remaining involving other arteries or not otherwise indicated.

Fourteen individual agents in the class were associated with artery dissections or aneurysms, including the VEGF inhibitors bevacizumab (Avastin) and ramucirumab (Cyramza); the tyrosine kinase inhibitors (TKIs) sunitinib (Sutent), pazopanib (Votrient), axitinib (Inlyta), nintedanib (Ofev), and lenvatinib (Lenvima); the multikinase inhibitor cabozantinib (Cometriq, Cabometyx); and the mTOR inhibitor everolimus (Afinitor). A number of these agents were also associated with both aortic- and cerebral-specific events.

VEGF inhibitors were the most commonly involved antiangiogenic agent (51.4%), followed by TKIs (35.8%) and mTOR inhibitors (11.5%). For individual agents, bevacizumab (44.9%), sunitinib (14.4%), and everolimus (11.1%) were most frequently associated with these events. Median time to onset was 89 days (interquartile range 27-212) where data were available.

The study authors acknowledged that other patient risk factors not captured -- smoking or uncontrolled hypertension, for example -- could also have contributed to the events.

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