A half-dozen double doses of Bracco's gadolinium contrast agent ProHance, administered over two years to a patient with severely impaired renal function, have been linked to the development of nephrogenic systemic fibrosis. This is the first such incident associated with the Bracco agent.
Its significance goes well beyond the addition of another case to the ranks of NSF or the agent involved.
Discussion lately has focused on the molecular structure of MR contrast agents as the determining risk factor in their use. Most contrast agents have linear chelates that bind the gadolinium metal to the agent. ProHance and two others not on the U.S. market (Gadovist and Dotarem) have cyclical chelates, which are believed to provide greater chemical stability, affording more time for the body to excrete the agent.
But even the most stable MR agents have the potential to release gadolinium, if doses are very high and excretion of the agent is impaired, said Alberto Spinazzi, senior vice president of Bracco Diagnostics Group's Medical and Regulatory Affairs.
"If gadolinium chelates are involved in the genesis of NSF, and stability is related to that, then it is important to understand that it is not that no gadolinium is released by the most stable agent, it is that less gadolinium is released by the most stable agent," Spinazzi told DI SCAN. "The risk is not zero."
In the June 28 letter he sent to healthcare providers, Spinazzi described the case of a dialysis patient with stage 5 chronic kidney disease who received six injections of 32 mL ProHance within two years. It illustrates, he said, that dosage is a prime consideration in patient management, as important as molecular structure or even more so.
"The dose used is very important," he said. "Dose should be minimized and (should be kept) as low as possible."
Bracco first learned of the incident involving a patient, who was described as having end-stage renal disease and was undergoing dialysis, on June 18. Although unable to validate the information through the assessment of medical records, the company quickly reported the case to the regulatory officials, including the FDA, according to Spinazzi. Based on the information available, a causal role for ProHance could not be ruled out.
In the June 28 letter that followed, Bracco notes that other NSF cases involving the company's agents have occurred. But in each of the four previously reported instances, the patients had received a Bracco agent as well as another MR agent, according to the letter. Two involved sequential doses of MultiHance and Omniscan; the other two were sequential doses of ProHance and Omniscan.
"When you have mixed cases, then it could be either agent that causes the NSF," Spinazzi said. "You can be more comfortable at attributing a NSF case to an agent when you have just the sole administration of that agent."
In the interview with DI SCAN, Spinazzi said that Bracco is seeking reports of NSF that involve its agents and is forwarding them to the imaging community.
"We are actively looking for NSF cases," he said. "This is very important."
The most recent case - an extreme one in terms of dosage - is the first involving ProHance alone, he said. It came as a surprise, because the macrocyclic structure of ProHance is believed to be most resistant to transmetallation, the process by which gadolinium breaks free from the chemical complex and circulates in the body.
The exact mechanism by which gadolinium may contribute to NSF is obscured by the time that often passes between administration of the agent and detection of the disease. The ProHance case, for example, was diagnosed 2.5 years after the first administration of the agent and six months after the last. Adding to the mystery is the occurrence of NSF in the absence of any administration of gadolinium-based MR agents, as was recently described in two cases in a paper published electronically in the American Journal of Transplantation in August.
The link between NSF and gadolinium agents is strong enough, however, to have led the FDA in May to request that makers of these agents add a black-box warning to their products FDA requests boxed warning for contrast agents used to improve MRI images.
New practice guidelines written by the Blue Ribbon Panel on MR Safety of the American College of Radiology were published in the June issue of the American Journal of RoentgenologyACR guidance document for safe MR practices: 2007 and include concerns that radiologists should address.
Whether the heightened caution and awareness of the risks expressed by regulators will pose problems for the development of future gadolinium-based agents is debatable. Spinazzi believes it will not, because the FDA makes decisions on the basis of evidence, not hypotheses. More to the point, he said, is whether new gadolinium-based agents can provide significant added value compared with what is already on the market, a question Spinazzi did not try to answer.