Applied Radiology

Val M. Runge, MD Rosenbaum Professor of Diagnostic Radiology, University of Kentucky, Lexington

By almost any measure, injectable gadolinium-based magnetic resonance (MR) imaging contrast agents are among the safest exogenously administered compounds. Administered at volumes well below those associated with iodinated contrast agents, and cleared by the kidneys with no demonstrated nephrotoxic effects at approved doses, these compounds are often considered innocuous. Several published reviews attest to the excellent safety profile of the gadolinium agents as a class. ^1,2 These studies show the gadolinium chelates to be safe and well tolerated. Minor adverse reactions do occur, and the articles point out that radiologists and technologists should expect to see nausea in a small percentage of patients and hives in a lower percentage of patients, regardless of the agent used. The published reviews also show that the agents cannot be differentiated on the basis of adverse reaction rates.

Published case reports in the literature also attest to that fact that idiosyncratic, anaphylactoid events can be associated with the administration of gadolinium contrast agents. ^3-8 In fact, at least one published report links the use of a gadolinium contrast agent (Magnevist) with the death of a patient. ⁹ Overall, the literature on the safety of MR contrast agents is sparse and occasionally misleading. This reflects radiologists' satisfaction with the performance of this class of agents as well as a general lack of safety studies sponsored by the contrast agent manufacturers and distributors. In some instances, inappropriate attempts have been made to differentiate various gadolinium agents on the basis of survey data or individual published adverse event reports. Therefore, a more comprehensive review of the available data on the safety of MR contrast media is warranted.

Molecular Structure

There are currently four agents approved for use in the United States (figure 1). The main chemical difference found in these agents is in the molecular structure, or chelate, which can be linear (Magnevist, Omniscan, OptiMARK) or macrocyclic (ProHance, Dotarem). The chelate (from the Greek root "chelos" or claw) holds the gadolinium ion tightly and securely and ensures rapid excretion via the kidney. Since gadolinium is known to be highly toxic in a noncomplexed state, the chelate is thus the basis for the acceptable safety of this group of contrast agents. The stronger bonds of the macrocyclic type agents show less tendency to release elemental gadolinium over time. ^10-12 While this structural difference appears to have little to no impact on the acute safety effects of these agents, chelate stability has potential safety implications in cases of delayed clearance (renal impairment) or repeated injections (patients receiving multiple follow-up examinations, such as patients with treated tumors or multiple sclerosis). Fritz and colleagues described the potential for dechelation of the gadolinium chelate complex in vivo using a model involving liposomal gadolinium agents. ¹³ However, the clinical consequences of free gadolinium require further research.

Molecular Charge

The other key difference in the physicochemical properties of these agents is related to the charge of the molecule (table 1). Agents such as Magnevist or Dotarem (Gd-DOTA, available only in Europe and South America, but not in the United States) with a net negative charge must be formulated with positively charged ions to assure a net zero charge in the final formulated product. Agents such as ProHance and Omniscan with neutral molecules need no additives to be electrically neutral. Thus, the osmolality (particles per unit of solution) is much lower for the non-ionic agents (e.g., 630 mOsmol/kg for ProHance vs. 1,960 mOsmol/kg for Magnevist). Clinically, this difference translates into increased viscosity of the higher osmolar agents, and a greater potential for local irritation upon injection and tissue damage in cases of accidental extravasation. ¹⁴

Adverse Reaction Rates

Determining the "true" rate of adverse events associated with gado-linium agents is challenging for several reasons. A certain number of adverse reactions are likely related to anxiety produced by the MR imaging examination itself. In their review of the literature on non-contrast MR imaging, Melendez and McCrank determined that up to 30% of patients experience "anxiety-related reactions" when studied by MR imaging. ¹⁵ These reactions range from annoyance to claustrophobia or panic. In addition, patients undergoing MR imaging exams are often severely ill and exhibit a host of symptoms usually associated with their disease processes. Thus, determining what reactions might be attributable to the contrast agent used can be problematic. The usual assumption is that a fraction of the adverse events recorded in clinical studies are actually related to the agent administered.

Package Inserts

The most comparable safety data sets for the available gadolinium chelates are found in the package inserts. The approved labeling for each gadolinium agent contains a description of the safety profile of the agent as evaluated under controlled conditions during the clinical trials conducted for FDA registration. A quick evaluation of the package inserts for the four gadolinium chelates currently marketed in the United States shows that the type and incidence of adverse reactions with these agents are similar (table 2). All of the gadolinium agents approved in the United States cause nausea at a rate of approximately 1% to 3%. The reported incidence of nausea with Magnevist is 2.7%; ProHance, 1.4%; Omniscan, <3.0%; and OptiMARK 3.2%. It is important to note that although the rate of adverse events is slightly higher with OptiMARK, this most likely represents a trend to increased adverse event reporting in clinical trials, as this agent was the most recently tested and approved. Overall, the evidence suggests that there is no clinically relevant difference in adverse events between the agents in use in the United States today.

In addition to nausea, hives is also a relatively common adverse reaction, and it is an event that we see more frequently the more we look. Typically, hives will begin to develop 5 to 10 minutes after injection. The presentation clinically is often that of four or five large hives (1 cm diameter) scattered over the torso. Generally, they resolve without treatment and disappear within 4 to 5 hours. Overall, only about 1 in 200 patients develops hives. Most physicians and technologists have never seen a hive caused by a gadolinium chelate. The reasons are multifactorial: symptoms are minimal, patients are often released prior to maximal development, and a physical exam is almost never done following contrast injection.

Safety Studies

The first gadolinium agent to be available clinically was Magnevist, which was approved in the US in 1988. Well over five million injections have been administered worldwide since the first approval of this agent. ¹⁶ The safety profile of this agent in clinical practice is generally considered to be excellent.

The first study using a gadolinium contrast agent in humans was published by Laniado in 1984. ¹⁷ In this study, Magnevist (Gd-DTPA) was well tolerated in 20 healthy volunteers. One of the earliest large-scale safety studies of a gadolinium contrast agent reported in the literature was published by Carollo and colleagues in 1990. ¹⁸ In this study of 225 consecutive patients receiving Magnevist, 17% of patients experienced an adverse event, with 5% reporting events that were considered to be related to contrast administration. The most commonly reported adverse events were injection site pain (5.7%), headache (5.3%), and nausea (1.7%). Also in 1990, Goldstein and colleagues published the safety profile of Magnevist as assessed in US clinical trials. ¹⁹ As expected, the most frequent adverse events in this series of 1,068 patients were headache (6.5%), injection site discomfort (3.6%), and nausea (1.9%).

In one of the largest sponsored post-marketing safety studies, Nelson et al reported on 15,496 patients given Magnevist. ²⁰ In this prospective study 2.4% of patients reported an adverse event; the most common being nausea and headache, each with a reported incidence of about 0.4%. Interestingly, slightly less than half the adverse events reported in this study were recorded at least 1 hour after drug administration (but within the first 24 hours after injection). Since in clinical practice most patients leave the MR suite soon after their exam is completed, this study suggests that the overall rate of adverse events may be higher than clinicians usually suspect.

A rigorous prospective study of the safety of one gadolinium agent (ProHance) at a single center was published by Hieronim and colleagues from the University of Pittsburgh in 1995. ²¹ In this study, the overall rate of adverse events after ProHance administration in 3,558 patients was 2.1%, a rate similar to that reported for Magnevist (2.4%) in the prospective study by Nelson et al. ²⁰ Hieromin also reports earlier data from a retrospective chart review to document the reported safety of Magnevist. The overall rate of recorded adverse events with Magnevist in the retrospective portion of the study was 1.3%. Since prospective data collection is known to provide more comprehensive and accurate data than retrospective data collection, the rates reported for ProHance (prospective, 2.1%) and Magnevist (retrospective, 1.3%) should be considered equivalent. For both agents the most frequently reported adverse event was nausea with and without emesis, occurring in less than 1% of patients dosed.

An important study (and one that is often quoted out of context) was published by Murphy et al of the University of Michigan in 1996. ²² This study was a single-site, retrospective study of adverse reactions to gadolinium contrast agents at the University of Michigan. This study was neither designed nor presented as a comparative study. The authors reported results from approximately 20,580 patients given Magnevist, approximately 372 patients given Omniscan and less than 50 patients given ProHance. The researchers found 36 recorded reactions (0.2%). A total of 15 patients had nausea or vomiting, 12 had hives or diffuse erythema, 7 experienced moderate respiratory symptoms, and 2 patients experienced cases of life-threatening respiratory distress. Both of the severe reactions were in patients who received Magnevist. Murphy reported 29 reactions after Magnevist (0.14%), 5 reactions after ProHance (10.42%), and no reactions after Omniscan. The authors conclude that although gadolinium is a safe contrast medium, anaphylactoid reactions do occur.

This study probably underestimates the true incidence of adverse events after Magnevist because data were collected retrospectively and because injection site reactions and delayed reactions were not included in the analysis. Nevertheless, due to the large number of patients involved, the study has considerable value for assessing routinely reported reactions to Magnevist (over 98% of all patients in this analysis received Magnevist). For Omniscan, and especially for ProHance, the number of patients involved is insufficient for making any judgment about the performance of these agents in routine clinical practice. For example, the reported reaction rate for ProHance in Murphy's small sample is about 30% to 50% higher than that found in well-controlled clinical trials with ProHance, and five times higher than the rate reported by Heironim and colleagues (2.1%) in their prospective trial with ProHance in over 3,500 patients. ²¹

A later study, published by Murphy in 1999, is also often quoted out of context when discussing adverse reactions. ²³ For this study, Murphy and colleagues conducted a survey of American Society of Neuroradiology (ASNR) Fellowship Directors to assess the reported prevalence of adverse reactions to gadolinium-based MR contrast agents. A questionnaire was mailed to 105 directors of ASNR fellowship programs, with a response rate of about 50%. Program directors were questioned on the number of procedures performed annually utilizing various MR contrast media. They were also asked to assess (from memory or a retrospective review of records) adverse events to gadolinium contrast agents and categorize them as allergic or non-allergic.

Respondents reported administering over 867,000 doses of Magnevist, and recalled 314 (0.046%) non-allergic reactions, 107 (0.016%) mild allergic reactions, 28 (0.004%) moderate reactions, and 5 (0.0007%) severe reactions. For Omniscan and ProHance the number of administered doses was significantly less. About 74,000 doses of Omniscan were administered with 11 (0.015%) reported non-allergic reactions, 12 (0.016%) mild reactions and no moderate or severe reactions. For ProHance, respondents reported administering about 64,000 doses, with 171 (0.27%) non-allergic reactions, 49 (0.077%) mild allergic reactions, 29 (0.045%) moderate reactions, and 11 (0.017%) severe reactions reported.

The most important take-home point from this survey is that, as a class, the MR contrast agents are thought to be among the safest intravenously administered drugs ever developed. The total reported reaction rate was well under 1%, indicating that these drugs are perceived to be extremely safe.

As a record of physician opinion this survey is very informative. As a scientific study, however, this publication suffers from severe limitations. First, it is a retrospective study in which participants were asked to recall the number of doses administered and the number of adverse reactions they experienced. Therefore, the survey is subject to reporting bias and under-reporting. In addition, there was no verification of the responses with the source data. Therefore, neither the denominator (administered doses) nor the numerator (reported reactions) can be assumed to be accurate. Naturally, this makes calculating adverse event rates highly suspect.

A second problem with the survey is that of unequal distribution of patients in the different study groups. Over 90% of the participants were injected with only one agent, Magnevist. In addition, the data for another agent (ProHance) is heavily skewed by a single center noted for "meticulous record keeping" which administered 26% of the reported ProHance doses but accounted for over 80% of all adverse events reported for ProHance (this center also reported a 7.5% reaction rate with Magnevist, well above the rate reported from other centers). This center reported 10 of the 11 severe reactions attributed to ProHance and 1 of the 5 severe reactions attributed to Magnevist. It is clear that the inclusion of this center biased the data provided for ProHance in a unfavorable way. The authors acknowledge this problem in their discussion of the results, but then compound it by attempting to perform statistics on the survey data to calculate an odds ratio for experiencing an adverse event to a given gadolinium agent. Given the unreliability of the source data and the skewing effect of the one center reporting high adverse event rates, attempting to perform statistics on the survey data is probably not appropriate.

As the authors state in the conclusion of the paper, due to the numerous limitations of the design and analysis of the study, "the results can therefore be interpreted as the opinions of only a small number of experts and do not necessarily represent a sample of practice patterns used throughout the world." Despite its obvious shortcomings, this survey has been occasionally quoted to suggest differing rates of adverse reactions with different agents. However, due to the problems reported above, performance comparisons between agents using this dataset are ill-advised. The balance of the literature suggests all available gadolinium chelates have a similar safety profile when used as directed.

In 1995, an overview of the safety of ProHance in the U.S. clinical trial experience was published by Olukotun. ²⁴ This study reported on over 1,700 patients and volunteers given ProHance at doses from 0.05 to 0.3 mmol/kg. As expected, the incidence of nausea was very low (1.4%). All other adverse reactions other than taste perversion were recorded in less than 1% of subjects dosed. ²⁴ This study also reported no statistically significant difference in adverse reaction rates between bolus and infusion of ProHance.

A larger study, published in Europe, compiled worldwide data and included over 2,000 injections of ProHance. ²⁵ Again the data fall within the expected range: nausea at about 1.5%, taste perversion slightly less than 1%, and other adverse reactions less than 1%. All of these studies documented in the literature combine to confirm the excellent safety profile of ProHance.

Recent Reviews

Now, 20 years after this group of agents was initially developed, it is appropriate to go back and look at the fundamental safety basis for this group of agents. Two recent review articles look at the overall safety for the approved gadolinium chelates. ^1,2 The researchers found that the safety profiles for Magnevist, Omniscan, and ProHance were comparable. They found a transient elevation in serum iron with both Magnevist and Omniscan, believed to be the result of some instability of the chelate and some red-blood hemolysis with injection. One review also noted the problem with higher osmolality contrast agents (specifically Magnevist), namely that contrast extravasation can lead to tissue necrosis. Table 3 presents a comparison of safety data from the U.S. clinical trials of the four agents currently on the market. The data confirm that these agents cannot be differentiated on the basis of adverse reactions. For example, the incidence of nausea in U.S. clinical trials was 1.9% for Magnevist; 1.6% for Omniscan; 3.2%, for OptiMARK; and 1.7% for ProHance.

Conclusion

In conclusion, it is clear from the literature that the safety profiles of all the currently approved gadolinium chelates are similar. Headache, nausea and hives remain the most commonly seen reactions and are generally self-limiting. The headache reported in clinical trials is thought to be due to the exam conditions rather than to the agent itself. Severe, potentially life-threatening reactions, although very rare, have been seen with all the gadolinium chelates, and practitioners should be prepared to treat them. Some differences do exist between the agents due to their physicochemical properties. For example, a higher osmolar agent such as Magnevist (1,960 mOsmol/kg) is more viscous (and therefore harder to inject by hand) and may cause more local irritation upon injection and more tissue damage in case of accidental extravasation as compared to a lower osmolar agent such as ProHance (630 mOsmol/kg). In most clinical settings, however, the safety profile of the available gadolinium chelates is virtually identical.