Gadolinium-based contrast agents (GBCAs) have revolutionized MRI, enabling physicians to obtain crucial life-saving medical information that often cannot be obtained with other imaging modalities. Since initial approval by the FDA in 1988, more than 450 million intravenous GBCA doses have been administered worldwide, with an extremely favorable pharmacologic safety profile. However, recent information has raised new concerns about the safety of GBCAs.
On Feb. 15, 2018, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) convened an international meeting in Bethesda, Md., to identify and prioritize future research initiatives regarding the mechanisms, biological importance, and clinical implications of gadolinium retention. The research roadmap resulting from this workshop identifies knowledge gaps about gadolinium retention and prioritizes directions for needed research. The Bulletin recently spoke with Herbert Y. Kressel, MD, FACR, co-author of the roadmap, and Deborah Levine, MD, FACR, also a co-author of the report, to discuss their efforts to shed light on this tool in diagnostic imaging.
What was the result of the workshop?
HK: In December of 2017, the FDA issued a communication about GBCAs as part of its post-market monitoring of drug safety — requiring a class-wide warning about gadolinium retention in the labeling of these agents, and additional studies by manufacturers to assess their safety. In 2018, the NIBIB workshop, sponsored by the ACR, NIH, and RSNA, was held to review what is known about gadolinium retention and its potential clinical significance. Most importantly, a major goal was to identify key gaps in current knowledge to form the basis of a prioritized research roadmap.
Two reports based on the workshop have been published. In May of 2018, at the request of the FDA, the four manufacturers of GBCAs — Bayer, Bracco, GE Healthcare, and Guerbet — co-authored a letter sent to all providers, alerting them that GBCAs may remain in the body months to years after injection. The letter noted that retention is highest with the linear agents and lower with the macrocyclics. The letter also clarified that no adverse clinical or pathological consequences of this retention have as yet been identified. To help educate patients, the FDA — in collaboration with the GBCA manufacturers — has created a medication guide specific to each agent for distribution prior to a contrast-enhanced MRI examination.
What led to the development of the resources?
DL: Both Dr. Kressel and I had been working in the editorial office of Radiology, and we had accepted for publication early reports of gadolinium deposition in the brain; we knew that this was a very important topic. And because we’re talking about a very low incidence — if any — of patients having symptoms, we needed large studies; we needed researchers to collaborate to answer this really important question. But as more papers came out, it seemed like different research groups were working in their own silos and doing their own studies differently — using different types of contrast, different concentrations, different techniques — not all of which were optimized for detecting gadolinium — so you couldn’t really compare or combine results. So the idea of bringing this scientific community together was to figure out where the research gaps were and to make a roadmap — to really talk about best practices for studies going forward so that hopefully we could generate interest from the research community to collaboratively come up with answers.
The important thing to understand about the controversy with gadolinium is that, historically, the safety profile is still there; it’s still an exceptionally safe contrast medium. We don’t want to scare people and have them not use gadolinium with contrast because it’s so helpful for so many different medical conditions. So we always talk about a cost-benefit ratio; the benefit is getting the right diagnosis, or helping with treatment or tailoring treatment in cancer patients, and the risk — right now — is still a theoretic risk.
How can the radiology community use these presentations as a resource?
HK: The slides of the entire workshop have been posted on the NIBIB website. These include presentations on the chemical properties, stability, biodistribution, toxicology, and speciation of these agents — as well as on retention in central nervous system (CNS) and non-CNS tissues in animals and in humans.
DL: Having the slides available on the NIBIB website was something that we thought was very important because, again, there is only so much that you can put in print. By having the original agenda, the transcript of what was actually said at the meeting, and the slides available, we believe that anybody doing research in this area can use these resources. In addition, most of the general ACR community aren’t researchers, but if they do MR, they want to have a good understanding of contrast. This resource can help them understand the benefits and the risks of using GBCAs, as well as how to put those risks in context — because a lot of patients will come in and have questions, and rightly so.