Over the last twelve months, several new contrast agents have been added to the radiologist’s toolbox. That means new ways to obtain clearer images in CT, MR, and ultrasound, as well as new questions and challenges in providing meaningful care safely. For ultrasound in particular, there has been a flurry of activity, like the introduction of Bracco’s Lumason contrast, which marks the company’s entrance into the ultrasound contrast market in the U.S., a segment previously dominated by Lantheus and GE exclusively.

There have also been a number of FDA approvals. With contrast, those approvals are not exclusively concerned with new fluid mediums, but often have to do with manufacturing certifications. Getting approved to manufacture a contrast agent in a given location can yield significant results in improving a company’s supply chain.

Dr. Paul Bhella is the director of cardiac imaging for the JPS Health Network in Texas. For him, any discussion of contrast agents must take into account the wide range of complexity and potential for complications uniquely associated with different agents and imaging modalities. “There are many different forms of contrast agents. Lumping them all together has some utility, but they all work very differently,” he says.

And it isn’t simply a question of CT contrast versus MR or ultrasound contrast. Even within the different imaging modalities there are competing brands offering similar — but not identical — contrast formulas. It might not make sense for an MR imaging facility to carry two different types of gadoliniumbased contrast agents, for example, so what is that decision based on?

Also, in these times of radiation dose initiatives, what kind of impact are those initiatives having on contrast dose volume and concentration? Physicians are taking pains to ensure patients are not getting more contrast than necessary, therefore reducing the likelihood of allergic reactions and other harmful side effects and offer more benefit than harm,” says Christiane Pering, head of innovation for medical care, at Bayer. She believes, and others in the industry seem to agree, finding ways to maximize those benefits is key.

FDA approvals
For Bayer, there were breakthrough FDA approvals in the indications for using their MR contrast, Gadavist. “The first was that we completed both of our studies to demonstrate safety for breast MRI,” says Pering. “That was an important milestone because we think contrast enhanced MRI breast imaging is still undervalued and has greater clinical potential.”

The other approval was for children below the age of two. Pering says, “One of the missing items in the U.S. was the approved use of contrast agents in these children, and Gadavist is now the first approved contrast for use with neonates going up to all age groups.”

“Those two major advances focused in the U.S. market where the regulatory landscape is slightly different, but in the U.S. that was big,” says Pering. For Bayer, CT contrast is a much bigger part of their international business than it is domestically. Bracco’s ultrasound agent, Lumason, was approved in October. For conducting ultrasound with contrast in the U.S., that means they’ve joined Lantheus, (with Definity) and GE Healthcare, (with Optison) as the primary players in that segment of the marketplace. Lantheus’ Definity is FDA approved for manufacturing by Jubilant HollisterStier, and now their SPECT/CT contrast agent, Neurolite, is also approved for manufacturing by that company. The timing for that approval will help the company ensure they have a steady supply of the contrast, which has recently been approved for use in Japan and Australia.

Lantheus reached a similar agreement with the Institute for Radioelements to manufacture Xenon 133, which is an inhaled contrast agent used for imaging the lungs and evaluating pulmonary function, and with SHINE Medical Technologies to supply Mo-99, which is for nuclear medicine.

Last November, Bracco announced FDA approval of a multi-dose compliant packaging of Isovue, an agent used with CT. There are certain benefits associated with packaging contrast agents differently.
Pharmacy bulk packages (PBPs) for multi-dose contrast agents were initially approved in the 1990s, but the Joint Commission began to crack down on the bulk packaging.

The approval of Bracco’s Isovue made it the only multi-dose compliant contrast medium in the U.S., which the company believes can allow for faster throughput, greater cost-effectiveness, and reduced contrast waste for CT imaging departments.

For Bayer, pre-filled syringes are a staple of their international product portfolio. “There is a trend towards pre-packaged syringes in some countries and markets,” says Pering, “That is not new to us; it has always been in our portfolio. In some markets there is a strong preference for various reasons — patient safety concerns, hygiene and sterility.”

Risk reduction challenges
In terms of radiation exposure, MR has certain patient advantages over CT, but the value of a good CT image often justifies the dose involved. For Pering, there is a somewhat analogous decision-making process when choosing whether or not to use a contrast agent, and which one to use.

“There is a general perception that all iodine contrasts (CT) are alike and all gadolinium-based (MR) contrasts are alike, but they do differ a bit,” says Pering. Over time, a body of evidence has formed that helps cardiologists make informed decisions about when to use contrast and when it could be a hazard. There are also recommended usage rules for cardiologists to consult on a patient-by-patient basis. Bhella at JPS Health Network says those considerations affect not only what contrast to use on a given patient, but which ones a facility will choose to keep in stock.

The first reason he started using Definity, the ultrasound from Lantheus, was simply because it was what his fellow cardiologists were already using — but that had not always been the case, “We had other agents in the hospital before my tenure, but the hospital chose Definity.” It’s a decision that Bhella says needs to be made with consideration to patient population and the safety profile of a given contrast agent.

Bayer’s Pering also stresses the importance of obtaining a thorough history of the patient. In particular, she says, finding out about any allergic predisposition or kidney or any organ failure is essential in doing an individual risk-benefit assessment. While some physicians may give medication before injection of contrast agents in order to limit the likelihood of adverse reactions, Pering says that practice requires further research before it can be responsibly recommended.

Bhella says, for ultrasound contrast, the American Society of Echocardiography provides appropriate use criteria which can inform proper usage. Those guidelines, coupled with asking the right questions of the patient, and knowing the product you are using, can take most of the risk and mystery out of contrast usage.

“Ask a patient if they have ever received a contrast agent before. Find out if they have known allergies, as certain allergies would preclude certain contrast agents,” says Bhella, who adds that individual contrasts are packaged with guidelines that help inform a patient’s candidacy.

Ultrasound
While contrast in ultrasound is nothing new, there are only a few companies competing in the domestic market. Bayer, for instance, stepped away from the ultrasound market over a decade ago and currently has no plans of getting back into it. For Bhella, there are a number of factors that go into selecting an ultrasound contrast, deciding when to use it, and upon whom.

One advantage of ultrasound, (versus CT and MR) is the mobility of the modality, says Bhella. It is portable and does not emit radiation. The use of contrast with ultrasound sometimes depends on circumstances that arise from that flexibility.

Using contrast improves the ability to see how the heart is functioning in patients where visibility is unsatisfactory. “If you try to do an echo on someone in the ICU who is on a ventilator and you can’t change body position to get the heart aligned with the ultrasound probe,” Bhella says you may require contrast to obtain an image that might have been satisfactory in an outpatient setting.

Meanwhile, there are some situations where a patient’s anatomy makes contrast useful. A larger person with a barrel chest, for instance, may have the lungs more in front of their heart, which Bhella says could compromise ultrasound images due to an inability to scan air structures, and therefore require the use of a contrast like Definity.

Just enough and not too much
Used correctly, contrast agents can add a valuable boost to advanced imaging procedures. Taking cases on a patient-by-patient basis, radiologists can figure out which contrast agents to use, and when. In a sense, it’s an approach that has been incorporated into health care in general; getting better outcomes with minimal risk to the patient, and lowering costs.

Bayer’s Pering points out that in some situations, using too little contrast can result in unnecessary repeat imaging of the patient. That kind of redundancy can be costly, and ultimately exposes the patient to more contrast, more radiation, and a prolonged imaging process. “You don’t want to give too much, but you have to give enough,” says Pering.