Angiogenesis Inhibitors and Arterial Dissection or Aneurysm in Patients With Metastatic Colorectal Cancer.

Importance: Although pharmacovigilance signals and a strong pathophysiological rationale have suggested a potential risk of arterial dissections or aneurysms associated with angiogenesis inhibitors, this association deserves to be further investigated through clinical practice evidence studies. Objective: To evaluate the association between exposure to angiogenesis inhibitors and the occurrence of arterial dissections or aneurysms in patients treated for metastatic colorectal cancer (mCRC). Design, Setting, and Participants: A nested case-control study was conducted within a cohort of adults initiating targeted therapy (angiogenesis or epidermal growth factor receptor inhibitors) for mCRC between January 1, 2012, and December 31, 2017. Data were analyzed from April 2021 through August 2023. Data were drawn from the French nationwide Système National des Données de Santé database, which combines health insurance and hospital discharge records. Cases of arterial dissection or aneurysm were identified through 2019 and matched with up to 10 controls by age, sex, and time since cohort entry. Exposures: The angiogenesis inhibitors indicated for mCRC in France (ie, bevacizumab, aflibercept, ramucirumab, and regorafenib) were considered. Exposure was defined using 3 criteria: exposure at any point (exposed vs unexposed), recency (current, past, or unexposed), and cumulative duration of exposure (quartiles). Exposure periods were estimated using recommended administration schedules or drug elimination times. Main Outcomes and Measures: The primary outcome was incident hospitalization for arterial dissection or aneurysm, identified through hospital discharge diagnoses. Conditional logistic regression models were applied to estimate the association between exposure to angiogenesis inhibitors and the occurrence of arterial dissections or aneurysms, expressed as odds ratios (ORs) with 95% CIs. Results: Of the 34 733 patients included in the cohort, 195 incident cases (0.6%) were matched with 1950 controls. The study population (2145 patients) included 1562 male patients (72.8%); the median (IQR) age was 69 (63-73) years for cases and 68 (62-73) years for controls. Considering exposure at any point, 141 cases (72.3%) and 1381 controls (70.8%) were exposed to angiogenesis inhibitors; after adjustment for cardiovascular risk level, no association was observed between exposure and the occurrence of arterial events (OR, 1.07; 95% CI, 0.75-1.52). No associations were found with either recency or cumulative duration of exposure, regardless of the exposure estimation method. Conclusions and Relevance: In this case-control study of arterial dissections or aneurysms in patients receiving targeted therapy for mCRC, the lack of association with angiogenesis inhibitor exposure was reassuring, given the established benefits of these drugs, particularly bevacizumab, for this indication.