CHAPTER 18 Contrast Agents in Magnetic Resonance Imaging

INTRODUCTION

Intravenous contrast agents have become integral to the clinical practice of cardiovascular magnetic resonance (MR) imaging. Myocardial perfusion and myocardial delayed enhancement MR are important contrast-enhanced techniques for the clinical evaluation for myocardial disease. Contrast-enhanced magnetic resonance angiography (CE MRA) has become the preferred method for fast and accurate assessment of common arterial structures such as the thoracic aorta, abdominal aorta, carotid arteries, renal arteries, and peripheral arteries. These applications were facilitated by innovations in MRI instrumentation that improved acquisition speed and in optimization of cardiovascular imaging protocols.¹ This chapter will focus solely on those MR contrast agents that have, or promise to have, value for cardiovascular applications.

The value of a contrast agent depends on its ability to generate image contrast for a given imaging modality. Radiographic contrast agents lead to an attenuation of the transmitted x-rays; MR agents rely on a completely different biophysical principle. MR contrast agents generate image contrast by locally changing the relaxivity of the recipient tissue. For example, all contrast agents for x-ray computer tomography (CT) use iodine as their central ion, whereas MR contrast agents depend on the magnetic moment of the central atom. For cardiovascular MR imaging, we classify today’s available agents into paramagnetic (mostly gadolinium-based) and super-paramagnetic (mostly iron oxide-based).² We also experience a substantial variability in country specific availability of MR contrast agents for cardiovascular imaging as well as regulatory approvals, which is especially evident for cardiovascular imaging. Therefore, we will initially discuss the development and safety of MR contrast agents before we will review some of their type-specific characteristics for cardiovascular MR and MRA.

Development of MR Contrast Agents

Before a discussion of the different characteristics of contrast agents, it should be recognized that contrast agents are medications or drugs and as such they require a stringent safety evaluation as well as an assessment of suitable clinical indications for their use. MR contrast agents are, therefore, clinically developed similarly to any other therapeutic medication. After completion of preclinical evaluations and extensive toxicology, contrast agents undergo a typical phase I (feasibility), phase II (dose-ranging) and multiple phase (III) (efficacy and safety) assessments prior to submission for regulatory approval to market and distribute a contrast agent. Similar to therapeutic drugs, such a full clinical development program is more than a 10-year process that typically includes more than 500 patient examinations and costs in the range between tens to hundreds of millions of U.S. dollars.

Regulatory Label of MR Contrast Agents

The regulatory approval by an agency such as the Food and Drug Administration (FDA) in the United States defines the indicated use frequently—also referred to as the labeled use—as well as how to use it appropriately, any warnings and contraindications. For healthcare providers, the package insert and the prescribing information is the locally appropriate and always updated contrast agent specific information source. Although our scientific community is global and the contrast agents we use are virtually available worldwide, the regulatory environment remains a national responsibility with considerable differences among jurisdictions reflected in the availability and approved label. Reading information product labels (package inserts) is not only essential to the good practice of healthcare, it is mandatory! Having stressed this labeling and its importance, we must recognize that health care technologic and methodologic advances are frequently much faster than regulatory solutions.

Using a medication or drug, which requires a physician order or prescription, outside its regulatory defined approved, labeled use is considered to be at least off-label; however it could also be against-label if such a use is defined as a contraindication or a defined warning applies. The vast majority of contrast-enhanced MRI examinations of the cardiovascular system performed globally to date has been done “off-label”.³ In 2010, none of the marketed MR contrast agents in the United States has an FDA-approved indication for use in cardiac MRI despite a huge number of clinical trials and clinical experience; and only one, gadofosveset trisodium (Ablavor, Lantheus Medical Imaging, North Billerica, MA) has an FDA-approved MRA indication and only “to evaluate aortoiliac occlusive disease (AIOD) in adults with known or suspected peripheral vascular disease.”

Our imaging community is frequently perplexed with this situation and asks, “What is the difference if I use a contrast agent to do a brain MRI compared to the same dose injected in the same way for a cardiac MRI or vascular MRA?” The most important aspect here is that a regulatory approval requires proof of both efficacy and safety in an indication-specific population. Our community frequently does not appreciate that both are imperative. Furthermore, a population studied for evaluation of the brain does have a substantially different safety profile than one for a cardiovascular question. This is an important aspect and has led to issues that have changed how we appropriately use contrast agents today and in the future. Before we discuss the safety in more detail, let us complete the review on labeling. Labels of contrast agents (i.e., the official drug prescribing information that is contained on drug package inserts) are regulated, regularly updated, do change, and require that the health care provider has a process in place that ensures timely updates. Phase IV studies are also called postmarketing studies and are frequently requested from regulatory agencies to “review” the safety and efficacy in clinical practice populations, which can be different from the time of the original clinical trials or population studied. Magnetic resonance imaging has undergone a tremendous growth in the last two decades—not only in the number and performance of MR systems available, but also in the patient population being served. In particular, more frail patients are being studied more frequently and the overall outstanding safety of MR has led to some complacency that is not warranted and requires a review of appropriate training and standard operating procedures for the whole healthcare team involved in MRI. In this regard, the label or regulatory approved use becomes important because substantially more diligence must be expected for off-label use where safety considerations and contraindications might not yet have been fully established.

An off-label use has its foundation in the declaration of Helsinki and is basically founded in the physician’s prerogative to provide the most appropriate care to patients. Off-label use is a common and essential part of today’s practice of medicine, but it also requires appropriate diligence in its use. First of all, off-label use and clinical research are quite different. An investigational use (i.e., research use) requires a formal protocol approved by the Institutional Review Board (IRB) or an equivalent ethics board and typically informed consent; whereas off-label use requires only peer reviewed evidence. Why peer reviewed evidence? The regulatory agencies and legal interpretations expect objectivity without bias or conflict of interest. It is well recognized that regulatory agencies are appropriately very sensitive on the propagation of off-label use of drugs and therefore disallow drug vendors to advertise, market, or otherwise incentivize such off-label use as can be seen by a $2.3 billion ⁴ fine recently enforced for off-label propagation of a therapeutic drug and numerous warning letters being posted by FDA.⁵ A key distinction of off-label use versus an investigational use is that off-label use pertains only to applications for patient care (i.e., clinical practice) and not for a research aim or objective.

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.