November 16, 2009

Gadolinium Contrast — An Update on Imaging’s Understanding
and Prevention of NSF

By Dan Harvey
Radiology Today
Vol. 10 No. 18 P. 16

Researchers are still investigating the suspected connection between gadolinium-based MRI contrast agents and nephrogenic systemic fibrosis (NSF) that made headlines a few years back. But as those studies (and numerous lawsuits) surrounding the suspected link play out, the imaging community has enacted screening protocols that have seemingly eliminated new NSF cases.

Gadolinium-based contrast agents have been used in more than 100 million people over the past two decades. While safe and effective in the vast majority of patients, evidence suggests that patients with compromised kidney function receiving gadolinium agents are at an elevated risk of NSF. While studies have not defined a causal link between gadolinium contrast and NSF, there is some evidence of an association.

“Almost all, if not all,” of the NSF cases were reported in patients who had received gadolinium contrast, says Emanuel Kanal, MD, a professor of radiology and neuroradiology and the director of MR services at the University of Pittsburgh Medical Center.

A small percentage of patients—estimated at less than one half of 1%—is at an elevated risk, says Eric Cantor, MD, head of medical and professional affairs for GE Healthcare’s diagnostic products. (GE Healthcare manufactures Omniscan, one of the gadolinium-based contrasts approved for use in the United States.) That elevated risk is estimated to impact 2% to 3% of patients with significantly compromised kidney function, according to Cantor. But that very small percentage has led to approximately 500 NSF cases, and it has also spawned more than 400 NSF-related lawsuits, according to a BusinessWeek article published in October.

No Smoking Gun
“Right now, there are no smoking guns,” says Alberto Spinazzi, MD, senior vice president of group medical and regulatory affairs for Bracco Diagnostics Inc, manufacturer of the gadolinium-based contrast agents MultiHance and ProHance. “But while there’s no hard evidence that gadolinium is involved in NSF development, companies still have a responsibility to warn physicians about the possible link. It’s always better to be cautious and highly conservative.”

After news of the gadolinium concerns became widely known in 2006, the FDA required manufacturers to include a boxed warning on their products.

Both the FDA and the ACR quickly advocated identifying at-risk patients through screening. Patient screening for renal disease level appears to have clamped down on new NSF cases.

“We are not aware of any new cases of NSF since 2007,” says Cantor, whose company has been heavily involved with researching the issue and educating the medical community on the questions surrounding gadolinium-based contrast agents.

“Throughout the country, radiologists have begun screening patients for their renal disease level before they make a decision about whether to deliver contrast,” Kanal says. “Further, if a certain disease level is present, they reassess contrast administration decisions. In some cases, they won’t even give a patient a gadolinium-based agent. In other cases, they’ll give an agent but in significantly decreased levels. Further, they may alter which agent to administer to one that is perceived today to be less associated with subsequent NSF development.”

All the Same?
One question surrounding the contrast issue is whether all five gadolinium products present the same risk to patients with compromised kidney function (see sidebar). The FDA is also involving the manufacturers in a prospective study to investigate the risk and incidence of NSF in those thought to be at moderate or high risk, according to Cantor.

Screening patients about their kidney function and, if appropriate, performing blood tests to assess kidney function has helped imaging facilities prevent potentially at-risk patients from receiving gadolinium-based contrast. In some cases, patients receive a lower contrast dose, which many believe also decreases the NSF risk.

 “Radiologists, to their credit, have learned about this disease in a short period of time [and] have begun proactively to look to identify people and avoided the use of gadolinium agents with those patients at high risk,” Cantor says. “Upon doing so, they have, in a short period of time, changed the course of a disease.”

No reliable cure has been developed for NSF, and progression can be rapid in some patients. Most symptoms manifest within a few weeks or months of administered doses. Immediately apparent symptoms frequently include a thickening of the skin, particularly in the extremities. That tightening can result in severely restricted joint flexibility and extension. Affected individuals may not be able to fully extend their elbows, hands, legs, and/or feet, and some afflicted individuals lose their ability to walk. NSF can also prove fatal if it affects internal organs such as the heart.

Investigating the Cause
The disease’s cause remains as elusive as its cure. “It isn’t yet understood why the contrast agents cause these adverse reactions,” says Christopher Hunt, MD, of the radiology department at the Mayo Clinic in Rochester, Minn., who was recently involved in a large-scale study that assessed adverse reactions to contrast agents.

According to Kanal, current theories suggest that the trigger may involve transmetallation and the subsequent release of free gadolinium. The gadolinium ion is a potent toxin bonded (or chelated) with a ligand molecule to make it safe for humans. After administration, kidneys normally eliminate the chelated gadolinium. But in patients with impaired renal function, the gadolinium chelate remains in their bodies for a longer time. Some researchers think that the longer the gadolinium chelate stays in the body, the more likely that gadolinium separates from the ligand molecule (the transmetallation process) and toxic gadolinium distributes to the skin and other tissues, where over time it activates cells that start the fibrotic process.

“The vast majority of cases—more than 85%—occurred in patients with chronic kidney disease, stage 4 or stage 5,” says Spinazzi. He adds that most cases occur at stage 5, where there is a glomerular filtration rate below 15 mL/min.

Two points need to be recognized, he adds. First, described ranges are broad and not sharply defined. Second, a significant number of patients diagnosed with NSF were in acute (not chronic) renal failure at the time of agent administration.

“That’s about one in eight NSF patients, and that’s important and relatively new information,” Kanal says. He also points out that it has been known since 2006 that higher doses of these agents in patients with significant renal disease are more likely to result in an NSF diagnosis than are lower doses.

In the past few years, articles have documented an increased association of NSF in patients who receive a higher total cumulative dose over months or even years. “This has significant potential ramifications for anyone who will be exposed to continued and/or long-term follow-up for their disease,” says Kanal.

Meanwhile, as some researchers search for the cause, others study the nature and frequency of adverse reactions. For instance, Hunt’s recent study, reported in the October issue of the American Journal of Roentgenology (“Frequency and Severity of Adverse Effects of Iodinated and Gadolinium Contrast Materials: Retrospective Review of 456,930 Doses”), indicated that iodinated and gadolinium-based contrast agents used in CT and MRI scans result in a very low rate of adverse effects.

Rare Complications
Hunt and Mayo Clinic colleagues Robert P. Hartman, MD, and Gina K. Hesley, MD, sought to determine the frequency and characteristics of adverse effects of low-osmolar iodinated and gadolinium contrast agents used in a large number of exams at the Mayo Clinic in Rochester. They conducted a retrospective review of all intravascular doses administered from 2002 through 2006.

“The four-year time period and large number of cases made this study unique in terms of scope, and it was also significant in terms of reportage,” says Hunt, the study’s lead author. “We attempted to update information, not only for clinicians’ knowledge, but also to provide better informed consent to patients.”

Hunt and colleagues identified only 522 instances of adverse effects, and a large majority of these instances involved mild reactions not NSF (eg, nausea, vomiting, minor rashes); 16 cases required transfer for observation and treatment.

Specifically, the researchers examined 298,491 low-osmolar iodinated and 158,439 gadolinium administrations. The 522 cases of adverse effects represented 0.11% of the total, including 458 low-osmolar iodinated and 64 gadolinium administrations. According to the researchers, the most common adverse effects were hives (274, or 52.5%) and nausea (92, or 17.6%). Of all adverse effects, 79 of low-osmolar iodinated and 15 of gadolinium contrast material necessitated treatment, with most treatments performed in the radiology department. In the 16 reaction cases, epinephrine was used to manage an adverse effect in nine instances. Only two of the premedicated reactions necessitated transfer to the emergency department.

In the study period, the researchers reported one death, which occurred after the administration of low-osmolar iodinated contrast material. The patient, a 79-year-old man, had no symptoms during the contrast administration or imaging. He died about a half-hour after receiving the contrast dose. Cause of death was described as sudden cardiovascular collapse.

Based on their results, the researchers concluded that both iodinated and gadolinium contrast agents are associated with a very low rate of adverse effects. Further, “[M]ost adverse effects are mild and can be managed in the radiology department. Transfer for additional treatment or observation is rarely needed.”

Changing Procedures
While acknowledging the agents’ general safety, Hunt underscores the need for careful review: “You need to take into consideration previous history of contrast agent reaction. If a patient has a history, medication can reduce risk of another reaction. Further, you need to ask an important question: Is a contrast agent really needed for another study? Many times, it’s not. Clinicians can find ways to get around it.”

Another recent study, conducted by researchers from the University of North Carolina and the Emory University Hospital in Atlanta and reported in the October issue of Radiology, set out to determine NSF incidence in both universities’ tertiary care centers following a switch from using gadodiamide to gadobenate dimeglumine and gadopentetate dimeglumine, as well as the adoption of restrictive gadolinium-based contrast agent policies. Researchers reported no NSF cases following that switch and the policy adoption.

“This study was especially important as it provided significant advances in knowledge,” says Spinazzi, who stressed the following points:

• Following the switch and adoption of restrictive gadolinium-based contrast policies, the benchmark incidence of NSF in patients who underwent gadolinium-enhanced MR showed no NSF diagnoses in 10,477 and 14,690 patients at the two institutions between June 2007 and June 2008.

• As far as patient care implications, the switch in gadolinium-based contrast agents and the implementation of a restrictive contrast administration policy at the two institutions revealed promising results in reducing NSF incidence, significantly in patients at risk of NSF or undergoing dialysis who underwent gadolinium-enhanced MR.

Cantor notes that Emory researchers concurrently changed both the screening protocol and contrast agent used in their study, making it impossible to determine which factor was responsible for the change in NSF incidence. He adds that facilities have changed their protocol and kept using gadodiamide and seen no new NSF cases.

Attitude Changes
With the apparent rarity of serious occurrences, what are prevailing attitudes about these risks?

“Attitudes vary,” says Kanal. “But in my travels as a consultant, I perceive a general consensus: We seem to know as much about NSF and its relation to contrast agents as we need to know, and whether it is direct causation or mere association, a cautious approach regarding the administration of these agents is warranted. In my opinion, that ‘cautious approach’ is a most reasonable one. Assess each case individually to determine the true need for contrast, the dose required, and the contrast brand to be administered.”

Hunt also sees a trending toward a case-by-case approach. “Such an approach enables clinicians to better determine whether a patient’s exam really needs to be enhanced by a contrast-based agent,” he says. More and more, clinicians embrace this risk management approach, which wasn’t the case four or five years ago. “The level of concern has certainly been heightened,” Hunt says, reiterating that reactions are extremely rare and easily preventable.

Further research will address the “why” question, Hunt says. “Studies will focus on why patients suffer adverse reaction and, in turn, potential preventive measures,” he says. “This research direction will focus on how we can better identify those at increased risk. Such knowledge will help us determine if and when premedication will help reduce reactions and severity. Or maybe we just don’t prescribe the agents at all. That’s one way that new screening tool development will prove invaluable. Such tools will significantly reduce or even eliminate any risk.”

Beyond meetings and safety issues, there are emerging legal ramifications, as evidenced by the growing number of lawsuits. “A new problem is emerging, and it has to do with responsibility,” Kanal says. “People don’t realize how tricky this area can be. Right now, they’re not focused on this direction; but they better get focused on it soon.”

— Dan Harvey is a freelance writer based in Wilmington, Del., and a frequent contributor to Radiology Today. (Radiology Today editor Jim Knaub contributed reporting to this article.)


Do All Gadolinium Agents Pose the Same Risk?

By Jim Knaub

Screening patients for kidney problems before any contrast-enhanced MRI appears effective in avoiding nephrogenic systemic fibrosis (NSF), but there remains a debate about whether all gadolinium-based agents are essentially equal or whether some come with greater NSF risks in patients with chronic or acute kidney disease.

Months after widespread news of the gadolinium concerns broke in 2006, the FDA required all five gadolinium-based contrast manufacturers to include a boxed warning on their products. The products and their manufacturers are Magnevist (Bayer Schering Pharma), MultiHance and ProHance, (Bracco Diagnostics), Omniscan (GE Healthcare), and OptiMARK (Mallinckrodt).

The FDA has not made any distinction between the five contrast agents, but a joint meeting of the Cardiovascular and Renal Drugs and the Drug Safety and Risk Management advisory committees is scheduled for December (as of press time for this issue) to further consider safety and labeling issues, as well as whether the current boxed warning should be changed.

The theory that different gadolinium compounds represent different NSF risks is based on evidence that some contrast formulations break down more easily than others, releasing toxic gadolinium ions into the body and potentially causing NSF. The breaking down process is called transmetalation. Healthy kidneys presumably eliminate the contrast before it breaks down; the potential problem arises when a patient’s poor kidney function fails to eliminate the contrast before it breaks down.

In their paper, “Gadolinium-based Contrast Media and the Development of Nephrogenic Systemic Fibrosis in Patients with Renal Insufficiency” published in 2007 in the Journal of Vascular and Interventional Radiology, Kieran J. Murphy, MD, and Rush H. Chewning, BA, report that Omniscan, Magnevist, and OptiMARK—which have been associated with NSF incidence—are open-chain compound agents. ProHance is a cyclic compound agent, and MultiHance is a linear compound agent. “Open-chain compounds have been demonstrated to be less stable and more susceptible to transmetalation than cyclic compounds,” the authors wrote. “Gadodiamide [Omniscan], the agent involved in most cases of NSF to date, is the least stable open-chain gadolinium compound and the one most susceptible to transmetalation.”

Recommendations from the ACR and the European Medicines Agency have pointed to Omniscan, suggesting it may have a higher incidence of NSF. Of the approximately 400 lawsuits related to NSF, about 300 involve Omniscan and 100 Magnevist, according to an October 15 article in BusinessWeek.

Eric Cantor, MD, head of medical and professional affairs for GE Healthcare’s diagnostic products, notes that the FDA has asked all manufacturers of gadolinium agents to participate in the first-of-its-kind prospective study to look directly at the risk and incidence of NSF in patients with glomerular filtration rates of 30 mL/min or below and those with glomerular filtration rates between 30 mL/min and 60 mL/min. The research will also consider whether there is any risk difference among the products.

— Jim Knaub is editor of Radiology Today.