Use of a drug or contrast agent for a listed contraindication or excluded use cannot be considered to be off-label; they are against label however they might still be necessary and patient-specific appropriate if used with the proper diligence. A new situation arose when the FDA decided to put a black box warning label on all gadolinium-based contrast agents in 2007 as a response to the occurrence of cases with NSF (nephrogenic systemic fibrosis).⁶ Before we review the current status of this severe adverse reaction to gadolinium-containing MR contrast agents, let us finish with the labeling aspects. What is the intent of such a warning and what does it mean from a practical point of view? First, it is the strongest warning mechanism that the regulatory agencies have to ensure the user/health care professional is aware of a change in a label and product or class-associated warning, and second, gives regulatory guidance on the appropriate use. The FDA black box label means, for example, that any contrast dosage outside the contrast agent-specific label cannot be considered off-label anymore but will have to be considered against the label. In summary, the country-specific label of an MR contrast agent must be known and appropriately considered in the clinical practice of cardiovascular MR/MRA and will continue to change.

Safety of MR Contrast Agents

Although any contrast agent that received marketing approval needed to previously prove safety and identify use and warnings labels, cardiovascular MR imaging had its share of specific issues in the recent past that are highlighted to raise proper awareness and understanding in managing patients with cardiovascular disease.

The nonimaging community was warned in a 2003 letter to the editor of the New England Journal of Medicine that severe pseudohypocalcemia was observed after gadolinium-enhanced MRA.⁷ The authors noted lower calcium values in blood samples obtained in patients immediately after they had an MRA performed with gadodiamide (Omniscan, GE Healthcare Medical Diagnostics) as MR contrast agent. The interaction of excess chelate in the gadodiamide with colorimetric calcium tests was recognized by experts but was neither included in the product label nor commonly known and caused multiple issues, especially in patients who had undergone CE MRA.⁸^,⁹ A subsequent letter and editorial revealed that these drug laboratory test interactions are not specific to MRA, but to two contrast agent formulations, gadodiamide and gadoversetamide (Optimark, Mallinckrodt) that interact to lead to false lower calcium levels in colorimetric but not in ionic calcium tests.¹⁰ These observations and subsequent public discussion can be credited with increasing awareness about MR contrast agent safety, which was perceived as entirely safe with considerable complacency evolving.

One of the most essential safety aspects of a contrast agent is that it needs to be completely eliminated after injection into the patient. Although this sounds trivial, imaging agents did have some dark clouds in their history when thorium dioxide (Thorotrast, Heyden) was discovered and subsequently used as a capable x-ray contrast agent, however, its retention in the body and radioactivity (alpha-particle) was not readily recognized in the early part of the last century.¹¹ Most MR imaging agents including gadolinium chelates are eliminated via renal clearance; iron oxides, with the liver and reticuloendothelial system (RES). It is important to understand the specific characteristics and elimination pathway of an agent as well as what happens if elimination is impaired. Therefore, it should not be a surprise that a drug that depends on renal elimination has the potential to change its biologic behavior if the pathway is impaired, consequently making agents with multiple or other elimination pathways highly desirable for patient populations with renal impairment. Contrast agents should always be given at the lowest effective dose to enable diagnostic-appropriate visualization of the target organ system, here the cardiovascular system; however, at this juncture, is also the pitfall. For a time some in our community suggested that “more is better” which frequently did improve the image quality obtainable by still evolving MR methodologies, however, the safety profile does change with changing populations and dosages. Similar to the speed rating of a tire, safety of medications can and does vary when we use it beyond recommended usage. From a safety perspective, the rapid elimination from the body, no or limited drug to drug interactions and no or limited toxicity are the key desirable safety aspects of a contrast agent.

Pharmacovigilance of MR Contrast Agents

Pharmacovigilance is the analysis of observed adverse events of an available drug, in this case MR contrast agent, and is the methodology employed to monitor the safety when a drug is broadly available. It is still a growing science as we continue to learn more about how to assess, manage, and predict the safety of drugs in large, diverse patient populations and with considerable changes in the way we practice medicine. Aside from post-marketing, phase IV studies, the information source is solely based on adverse event reporting. A healthcare provider is encouraged and sometimes mandated by country-specific laws to report any adverse event observed during the clinical use of medications/drugs—either directly to the vendor or to a regulatory body sponsored website such as MedWatch by the FDA.¹² Although this spontaneous adverse event reporting has its shortcomings, it is the best and only broad-based mechanism currently available. Unfortunately, drug manufacturers and, as such, also the vendors of MR contrast agents do not commonly voluntarily release their adverse event reporting database which they are required to compile on a global basis. The manufacturer does know how many doses of a drug are sold and those sales data are then related to the adverse event reporting rates. In an adverse event report, the reporter documents the observations, some patient characteristics, severity of the adverse event, and assesses the relationship to the contrast agent. Depending on the severity and expectancy of the adverse event, the regulatory agency and/or manufacturer may further investigate such a report. As part of country-specific marketing approvals, a manufacturer may have to report the noted observations, however these are typically not publically available documents. The largest released reporting of pharmacovigilance data on an MR contrast agent is available on the use of Gd-DTPA (Magnevist, Bayer HealthCare Pharmaceutical) and has been voluntarily reported. These data indicate for specific event categories, such as cardiovascular reactions rates, of 4 to 8 events per 100,000 doses administered.¹³ Renal impairment was identified in adverse event reports from 0.1 to 0.8 events per 100,000 doses and was with angioedema, the only major category that showed an increasing trend in the recent years of adverse event reporting. Further analysis of those reports indicating renal impairment revealed that patients most commonly had preexisting renal conditions due to nephrotoxic medications and were receiving higher than labeled contrast agent doses. Unfortunately, these data are not publically available for the other commonly used MR contrast agents. The current annual global use of MR contrast agents is estimated to be around 12 million patient doses. Although no broad-based data are currently available on the cardiovascular MRA examinations being performed, estimates suggest an annual rate of about 2 to 3 million procedures. In order to further put adverse event reporting in perspective, it must be highlighted that those for the Gd-DTPA MR contrast agent are two to three times lower than those reported for nonionic monomeric iodinated contrast agents used in x-ray, and allergic reactions are reported about eight times more frequently for nonionic iodinated contrast media used in x-ray than for the Gd-DTPA, an MR contrast agent.¹⁴ Anaphylactoid reactions have been seen in Gd-DTPA at a reporting rate of 3 to 4 per million, whereas urticaria has been reported at a rate of 29 to 79 per million.