Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Division of Oncology, Office of Oncologic Diseases, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Vasc Med. 2021 Oct;26(5):526-534. doi: 10.1177/1358863X211006470. Epub 2021 Apr 12.
The US Food and Drug Administration (FDA) has approved multiple systemic vascular endothelial growth factor (VEGF) inhibitors since 2004 to treat various malignancies. Inhibition of the VEGF signaling pathway can result in impairment of vascular wall integrity through medial degeneration and endothelial dysfunction, potentially resulting in arterial (including aortic) aneurysm/dissection. We performed a postmarketing review to evaluate arterial aneurysm/dissection as a potential safety risk for patients with cancer treated with VEGF inhibitors. We searched the FDA Adverse Event Reporting System (FAERS) database and literature for reports of arterial (including aortic) aneurysm/dissection with VEGF inhibitors currently approved by the FDA for a cancer indication. We identified 240 cases of arterial aneurysm/dissection associated with VEGF inhibitors. The median time to onset of an arterial aneurysm/dissection event from the initiation of a VEGF inhibitor was 94 days (range 1-1955 days). Notably, 22% (53/240) of cases reported fatal outcomes related to arterial aneurysm/dissection. We determined the drug-event association as probable in 15 cases that lacked relevant confounding factors for arterial aneurysm/dissection, which is supported by unremarkable computed tomography (CT) findings prior to starting VEGF inhibitor therapy, despite nondrug-associated background arterial aneurysm/dissection generally demonstrating preexisting arterial abnormalities. FAERS and literature case-level evidence suggests that VEGF inhibitors may have contributed to arterial aneurysm/dissection, as a class effect, based on short onset relative to natural history of disease and biologic plausibility. Cardiovascular and oncology healthcare professionals should be aware of this rare, but life-threatening safety risk associated with VEGF inhibitors.
自 2004 年以来，美国食品和药物管理局（FDA）已批准多种全身血管内皮生长因子（VEGF）抑制剂用于治疗各种恶性肿瘤。抑制 VEGF 信号通路可导致血管壁完整性受损，表现为中膜退化和内皮功能障碍，可能导致动脉（包括主动脉）瘤/夹层。我们进行了上市后审查，以评估 VEGF 抑制剂治疗的癌症患者发生动脉瘤/夹层的潜在安全性风险。我们在 FDA 批准用于癌症适应证的 VEGF 抑制剂的不良事件报告系统（FAERS）数据库和文献中搜索了与 VEGF 抑制剂相关的动脉（包括主动脉）瘤/夹层的报告。我们确定了 240 例与 VEGF 抑制剂相关的动脉瘤/夹层病例。从开始使用 VEGF 抑制剂到发生动脉瘤/夹层事件的中位时间为 94 天（范围 1-1955 天）。值得注意的是，22%（53/240）的病例报告与动脉瘤/夹层相关的致命结局。我们在 15 例缺乏动脉瘤/夹层相关混杂因素的病例中确定了药物-事件相关性为可能，这与开始使用 VEGF 抑制剂治疗前 CT 检查结果无明显异常一致，尽管非药物相关的背景动脉瘤/夹层通常表现为先前存在的动脉异常。FAERS 和文献中的病例水平证据表明，VEGF 抑制剂可能导致了动脉瘤/夹层，这是一种类效应，其发生时间相对疾病的自然病程较短，且具有生物学合理性。心血管和肿瘤学医疗保健专业人员应意识到与 VEGF 抑制剂相关的这种罕见但危及生命的安全性风险。
