Arterial aneurysm and dissection with systemic vascular endothelial growth factor inhibitors: A review of cases reported to the FDA Adverse Event Reporting System and published in the literature

Abstract

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.

A case of splenic artery aneurysm and rupture in a patient on a vascular endothelial growth factor inhibitor for renal cell carcinoma

“… 5 A similar study by Cheng et al reviewed the U.S. Food and Drug Administration Adverse Event Reporting System to identify 240 post‐market reports of arterial aneurysm or dissection associated with VEGF inhibitor with a median onset of 94 days and a fatality rate of 22%. 6 …”

“…Cheng et al have also identified 20 published case reports of patients developing an arterial aneurysm or dissection while on VEGF inhibitors but to our knowledge there are no reports on such adverse events for patients solely treated with pazopanib. 6 …”

“…5 A similar study by Cheng et al reviewed the U.S. Food and Drug Administration Adverse Event Reporting System to identify 240 post-market reports of arterial aneurysm or dissection associated with VEGF inhibitor with a median onset of 94 days and a fatality rate of 22%. 6 Cheng et al have also identified 20 published case reports of patients developing an arterial aneurysm or dissection while on VEGF inhibitors but to our knowledge there are no reports on such adverse events for patients solely treated with pazopanib. 6 It is important to note instances of these arterial events so clinicians can monitor their patients with appropriate vigilance while on treatment.…”

“…6 Cheng et al have also identified 20 published case reports of patients developing an arterial aneurysm or dissection while on VEGF inhibitors but to our knowledge there are no reports on such adverse events for patients solely treated with pazopanib. 6 It is important to note instances of these arterial events so clinicians can monitor their patients with appropriate vigilance while on treatment. Here we report an interesting case of a patient who was treated with pazopanib for over 5 years for metastatic renal cell carcinoma before developing a splenic artery aneurysm and subsequent rupture.…”

“…A review of the Japanese Adverse Drug Event Database by Oshima et al found that out of 16 441 patient treated with VEGF inhibitors, 49 of these patients experienced aortic dissection directly related to VEGF inhibitor use 5 . A similar study by Cheng et al reviewed the U.S. Food and Drug Administration Adverse Event Reporting System to identify 240 post‐market reports of arterial aneurysm or dissection associated with VEGF inhibitor with a median onset of 94 days and a fatality rate of 22% 6 …”