Increased Risk Of Aneurysms And Artery Dissections With VEGF Inhibitors

August 26 2020 –  Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF)  is a signal protein produced by cells that stimulates the formation of blood vessels. VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).

VEGF is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions. Serum concentration of VEGF is high in bronchial asthma and diabetes mellitus. The normal function of VEGF is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. However, VEGF can contribute to development of diseases. For example and most prominently, solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can also cause vascular disease in the retina of the eye and other parts of the body.

Thus, VEGF-inhibitors are medications used in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as Bevacizumab (Avastin), antibody derivatives such as Ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF, such as Pazopanib (Votrient), Sorafenib (Nexavar), and Sunitinib (Sutent), among many others.

While they are therapeutically successful in many patients, VEGF-inhibitors also come with a variety of drug-induced undesired adverse effects, some of them rather serious and sometimes life threathening. This may not be too surprising when taking into account the many pathways (signalling and others) throughout the body might be affected by the targeting of these medicines of VEGF or VEGF-receptors. In any case, very recently, it became evident that treatment of patients with VEGF Inhibitors is associated with an increased risk of aneurysm and artery dissections. Thus, on July 31, 2020 the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update  entitled “Systemically administered VEGF pathway inhibitors: risk of aneurysm and artery dissection“, stating that before initiating systemic vascular endothelial growth factor (VEGF) pathway inhibitors, carefully  the risk of aneurysm and artery dissection in patients with risk factors should carefully be considered. In patients who receive a systemic VEGF pathway inhibitor, any modifiable risk factors such as hypertension need to be reduced as far as possible This drug safety update addresses two points in the “Update for healthcare professionals” section, namely that first the use of systemically administered VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms or artery dissections, and secondly that artery dissections are thought to occur  (although infrequently) in patients taking systemic VEGF pathway inhibitors. Some some fatal cases in such patients had been reported, mainly in relation to aortic aneurysm rupture and aortic dissection. Moreover, from within the same safety update, one could learn that a recent European review concluded that all systemically administered VEGF pathway inhibitors may promote the formation of aneurysm and artery dissection. The product information for all systemically administered VEGF pathway inhibitors was updated to include a warning about the risk of aneurysm and artery dissection and to recommend carefully considering these risks before initiating in patients with risk factors, such as hypertension.

Similarly, in the US  also, 16 brand name VEGF inhibitors appeared on the “January – March 2020 | Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS)“, which is sometimes called the FDA Watch List. These are the VEGF inhibitors identified in this most recent FDA Watch List: Axitinib (Inlyta), Bevacizumab (Avastin), Cabozantinib (Cabometyx), Vandetanib (Caprelsa), Cabozantinib (Cometriq), Ramucirumab (Cyramza), Ponatinib (Iclusig), Lenvatinib (Lenvima), Bevacizumab-awwb (Mvasi), Sorafenib (Nexavar), Nintedanib (Ofev), Regorafenib (Stivarga), Sunitinib (Sutent), Pazopanib (Votrient), Ziv-aflibercept (Zaltrap), and Bevacizumab-bvzr (Zirabev). The FDA Watch List document states a i) Potential Signal of a Serious Risk / New Safety Information -Aneurysm and artery dissection, and ii) additional information (as of June 12, 2020) – FDA is evaluating the need for regulatory action.

That said indicates, that with all these medications, a serious vascular adverse effect has been detected. Patients and other parties concerned about drug safety may also consult resources such as VigiBase which is the unique WHO global database of individual case safety reports (ICSRs). It is the largest database of its kind in the world, with over 20 million reports on virtually any drug on the marked worldwide. For legal aspects of unwanted drug effect, individuals may consult, an invaluable resource made available by Tom Lamb, who monitors the safety profiles for these VEGF inhibitors as well as for any other marketed drug including whether the FDA mandates any label changes which add warnings about an increased risks.

See here a short sequence on arterial dissection:

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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