Risk of Artery Dissection or Aneurysm With Use of Antiangiogenic Drugs

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In a pharmacovigilance study reported as a research letter in JAMA Oncology, Guyon et al found evidence that use of antiangiogenic drugs in cancer treatment is associated with increased risk of artery dissection and aneurysm.

Study Details

All artery dissection or aneurysm cases from July 2005 to January 2019 that were potentially associated with the receipt of 14 antiangiogenic drugs by patients with cancer were identified from VigiBase, the World Health Organization’s centralized database of adverse drug reaction cases spontaneously reported to national pharmacovigilance systems by patients and clinicians. Disproportionate reporting of artery dissection or aneurysm with use of antiangiogenic drugs was analyzed using both the proportional reporting ratio (PRR) and Bayesian information component (IC), with all other anticancer drugs being used as the reference group. Signals of disproportionate reporting were defined as either a PRR with a 95% confidence interval lower limit that exceeded 1, or an IC with a 95% credibility interval (CrI) lower limit that exceeded 0.

Key Findings

A total of 217,664 patients reported adverse drug reactions potentially associated with use of antiangiogenic drugs. Of these, 494 patients reported artery dissections or aneurysms. Among these 494 cases, 436 (88.3%) were serious, 120 (24.3%) were fatal, and 88 (17.8%) were life-threatening.

Drug reactions were most frequently associated with receipt of bevacizumab (222 cases, 44.9%), sunitinib (71 cases, 14.4%), and everolimus (55 cases, 11.1%). Hypertension was reported in 51 adverse reaction cases (10.3%) overall, but in only 2 (3.5%) of 57 cases involving mTOR inhibitor use. Overall, 138 patients (27.9%) were receiving drugs in addition to antiangiogenic agents that may have been associated with artery dissection or aneurysm.

Signals of disproportionate reporting of artery dissection or aneurysm were found for all antiangiogenic drugs combined (PRR = 2.76, 95% confidence interval [CI] = 2.48–3.07; IC = 1.14, 95% CrI = 0.99–1.25).

Signals of disproportionate reporting of artery dissection or aneurysm were found for nine specific drugs, consisting of:

  • Bevacizumab (PRR = 4.08, 95% CI = 3.54–4.70; IC = 1.86, 95% CrI = 1.63–2.02)
  • Ramucirumab (PRR = 3.34, 95% CI = 1.89–5.90; IC = 1.60, 95% CrI = 0.63–2.27)
  • Sunitinib (PRR = 2.38, 95% CI = 1.87–3.01; IC = 1.20, 95% CrI = 0.80–1.48)
  • Pazopanib (PRR = 1.57, 95% CI = 1.11–2.23; IC = 0.63, 95% CrI = 0.04–1.05)
  • Axitinib (PRR = 2.52, 95% CI = 1.51–4.19; IC = 1.26, 95% CrI = 0.39–1.86)
  • Nintedanib (PRR = 2.08, 95% CI = 1.27–3.40; IC = 1.00, 95% CrI = 0.16–1.58)
  • Lenvatinib (PRR = 4.17, 95% CI = 2.30–7.56; IC = 1.87, 95% CrI = 0.84–2.56)
  • Everolimus (PRR = 1.61, 95% CI = 1.23–2.11; IC = 0.66, 95% CrI = 0.21–0.98)
  • Cabozantinib (PRR = 2.25, 95% CI = 1.24–4.07; IC = 1.09, 95% CrI = 0.06–1.78).

In analysis limited to localized aortic and cerebral dissections or aneurysms, signals of disproportionate reporting of both aortic and cerebral events were found for VEGF inhibitors overall and tyrosine kinase inhibitors overall, as well as for three specific drugs: bevacizumab, sunitinib, and axitinib. For other VEGF inhibitors and tyrosine kinase inhibitors, signals of disproportionate reporting were found only for either aortic events or cerebral events.

The investigators concluded, “The results of this pharmacovigilance study provide additional information through the detection of new signals for arterial wall injuries associated with the receipt of antiangiogenic drugs. Population-based studies are needed to confirm and quantify the potential risk of artery dissections or aneurysms associated with the receipt of antiangiogenic drugs. 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.”

Pernelle Noize, PharmD, PhD, of the Department of Clinical Pharmacology, University Hospital of Bordeaux, University of Bordeaux, is the corresponding author for the JAMA Oncology article.

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