April 20, 2009

Contrasting Situation
By Beth W. Orenstein
Radiology Today
Vol. 10 No. 8 P. 12

Except for cardiac imaging, contrast-enhanced ultrasound use in the United States lags behind its use in other countries. Some physicians are working to change that.

Contrast-enhanced ultrasound is widely used in Canada, as well as countries in Asia, Europe, and Latin America. Contrast is used not only to image the heart but also to diagnose abnormalities of the liver, carotid arteries, and gastrointestinal system.

However, in the United States, the use of contrast is more limited. The FDA has approved only two contrast agents for echocardiography—DEFINITY from Lantheus Medical Imaging and Optison from GE Healthcare—and not any other contrast ultrasound uses. Many U.S. physicians, including radiologists and cardiologists, are hopeful that the situation will soon change because a number of trends are converging that could result in FDA approval of contrast-enhanced ultrasound for diagnosing and treating more medical conditions. Those trends include the following:

• cooperation among specialties and researchers worldwide, with new data showing the safety-benefit ratio of the contrast agents;

• the need to reduce healthcare costs and a growing concern about the overuse of ionizing radiation from CT; and

• toxic side effects of gadolinium contrast used in MRI exams.

Changing Rapidly
Rafel Rieves, MD, director of the division of medical imaging and hematology products at the FDA’s Center for Drug Evaluation and Research, says the field of imaging, including contrast-enhanced ultrasound, is so dynamic that “it’s hard to stay ahead of it.” Still, he says, “We’re open for business if companies care to proceed with it.” (The FDA does not comment on any product currently under review.)

Ultrasound contrast agents are gas-filled microspheres or microbubbles that, when injected into patients, flow through their circulatory system, enhancing the reflectivity of the sonographic images. The concept of enhancing agents dates back to 1968, and the first paper was written by the late radiologist Raymond Gramiak, MD, who injected agitated saline to improve refraction, says Barry Goldberg, MD, a professor of radiology and the director of the Jefferson Ultrasound Research and Education Institute at Thomas Jefferson University Hospital in Philadelphia. The concept took off in the 1980s and 1990s when researchers wrote about tiny, coated bubbles that were smaller than red blood cells and thus could easily pass through the capillaries, Goldberg says.

“Before then, that wasn’t the case. As a result, you started to get companies that were manufacturing them and researchers who were getting grants to study them, and that’s how it really took off around the world,” he explains.

In 1997, the FDA approved two agents for use in ultrasound to visualize the chambers of the heart. “Those still are in use today,” Goldberg says. “But when the manufacturers, Amersham, which is now GE, and Lantheus, which had been part of Bristol-Myers Squibb, tried to get them approved for noncardiac use, the FDA gave them a hard time.”

FDA Issues
The problem, Goldberg explains, is that the FDA compared contrast-enhanced ultrasound of the liver with contrast-enhanced CT studies of the liver. Because the agency had already approved CT for characterizing liver lesions, it wanted researchers to prove that contrast-enhanced ultrasound was as good, if not better, for the same purpose.

“In Europe, they have shown that the two modalities are pretty equal,” Goldberg says. “But the FDA has said that if the ultrasound with contrast saw a liver mass and the CT did not detect it, the ultrasound was wrong. If masses were seen on both scans, and if they weren’t within 2 centimeters of each other, it was assumed the CT was right and the ultrasound was wrong. That was where the problem was.”

In the late 1990s, the FDA also became alarmed when about 200 adverse reactions, including cardiac arrest and heart rhythm problems, were reported among patients who had been given perflutren lipid microspheres (marketed under the trade names DEFINITY and Optison) during echocardiography. Seven patients subsequently died. Although the cases were self-reported and not adjudicated, in October 2007, the FDA issued black box warnings for DEFINITY and Optison, especially in cases where cardiac patients were severely ill. Researchers then provided the FDA with evidence that it was likely the patients’ grave condition and not the contrast agents that caused the adverse reactions, and severely ill patients were precisely the ones who could most benefit from contrast-enhanced echocardiography.

In May 2008, the FDA backed off its warnings and revised them, stating that “the benefits from the diagnostic information that could be obtained through the use of Optison and DEFINITY may outweigh the risk for serious cardiopulmonary reactions, even among some patients at particularly high risk for reactions.” Still, many continue to be scared off, and the use of contrast-enhanced ultrasound in the United States has been declining. A recent report by Arlington Medical Resources, which provides market analysis for the drug and diagnostic imaging industries, found that in 2008, the use of contrast for echocardiography was roughly 22% less than it had been in 2006.

New Effort
However, much has happened in recent years to brighten the picture for contrast-enhanced ultrasound. In 2005, the American Institute of Ultrasound in Medicine formed a committee led by then-president Lennard Greenbaum, MD, codirector of the Hughes Center for Fetal Diagnostics at the Winnie Palmer Hospital for Women & Babies in Orlando, Fla., to work toward FDA approval of contrast media for clinical ultrasound applications outside of cardiology. The committee published a white paper in the June 2007 issue of the Journal of Ultrasound in Medicine in which it outlined protocols for clinical trials using ultrasound contrast agents for the liver.

“We started an interaction with the FDA because the whole issue of ultrasound contrast agents had come to a standstill,” Greenbaum says. “The companies manufacturing the agents and the FDA were no longer talking to one another.”

The effort, including the white paper and a follow-up meeting with the FDA, convinced the FDA that it needed to compare sonograms with and without contrast agents and not contrast-enhanced ultrasound with CT or MR. As a result, Greenbaum says, Bracco Imaging, which manufactures the ultrasound contrast agent SonoVue, has started to set up a clinical trial of contrast-enhanced ultrasound of the liver.

Sonovue is stabilized sulphur hexafluoride microbubbles surrounded by phospholipids. Maurizio Denaro, MD, group vice president of research and development for Bracco Imaging SpA, which is part of the Bracco Group, who is responsible for contrast-enhanced ultrasound development and commercial operations globally, says the company is pursuing clinical trials for the use of SonoVue in both cardiac and noncardiac areas, and the FDA has shown “a very honest interest in understanding the technology and how it can be used to better patient care and in expanding the noncardiac market.”

Greenbaum and Denaro say approval is still a few years away, as the liver trial will take some time to complete. Lantheus and GE also have expressed interest in expanding the noncardiac market for their contrast ultrasound agents, Goldberg notes.

Broadening Contrast Use
Another effort underway to expand the safe and appropriate use of contrast ultrasound imaging is the International Contrast Ultrasound Society (ICUS). The group was founded in September 2008 by physicians around the world representing the fields of cardiology, radiology, gastrointestinal medicine, vascular medicine, internal medicine, hepatology, and other specialties and basic science disciplines. The copresidents of the group are Goldberg and Steven Feinstein, MD, director of echocardiography at Rush University Medical Center in Chicago. Other board members include contrast ultrasound experts from North America, Europe, Asia, and Latin America. Goldberg says the organization was structured to make sure that its leadership reflects the diverse medical specialties and geographic backgrounds that it encompasses.

Feinstein is excited about the ICUS promoting greater use of ultrasound contrast agents, which, he says, enable physicians to obtain optimal images of heart function. The spectacular images obtained with contrast ultrasound can change disease management, he says. Feinstein believes that the FDA’s placing on black box warnings was an overreaction to self-reported incidents that had not been adjudicated. The scientific evidence that contrast-enhanced ultrasound is safe and efficacious has since been gathered, he says.

“We’ve collected and published the prospective data. Having done that, we have met the criteria for safe usage. The use of the agents, as with anything, has to be driven first by just good science and good medicine, and we’re doing that, but most of us in the field have felt that was the case right along. And that’s why ICUS was created,” he says.

Among the goals of the ICUS are examining the accreditation of echocardiography labs in the United States and worldwide and publishing guidelines for the percentage of contrast needed to guarantee quality in these labs. A study by Melda Dolan, MD, of Saint Louis University School of Medicine, found that as many as one out of five patients could benefit from the use of contrast-enhanced studies.

The ICUS also hopes to collaborate with industry and other groups to help monitor and adjudicate any adverse effects. Feinstein says that because the ICUS represents multiple disciplines, it should be able to better promote the safe and appropriate use of ultrasound contrast among those who need it to obtain optimal images. The ICUS also will now run the annual Bubble Conference and expand the focus from primarily cardiology to a broader and more inclusive range of body imaging applications, Feinstein says.

Potential Cost Savings
Radiologists and cardiologists also believe that a number of other recent developments will result in increased use of contrast-enhanced ultrasound for diagnostic imaging and treatment. One is the push to control medical costs and imaging procedures. A sonogram costs considerably less than a CT scan or an MR scan. “What’s happening now with the potential for socialized medicine and where they want to reduce the cost and where they say there is overutilization of imaging procedures, I think all those will be factors in the long run and in a positive way [for the use of contrast-enhanced ultrasound],” Goldberg says.

Greenbaum agrees: “Contrast-enhanced ultrasound is a very cost-effective way of getting comparable information and, given the economic situation the country is in now, that could be a factor.” However, he adds, “I don’t think the FDA will approve contrast agents for use outside of cardiology just on the basis of cost-effectiveness.”

Ultrasound also has the advantage of being portable, as it can be brought to the patient’s bedside, unlike CT or MR where the patient has to be taken to the equipment to be scanned. “In places where the patient can’t be moved, in the ER [emergency room] or the OR [operating room], you can see contrast being used throughout the world,” Goldberg says.

Ultrasound is also safer because it doesn’t use ionizing radiation like CT or gadolinium like MR. “There is concern in patients with renal insufficiency about the use of gadolinium,” Goldberg says. “I could see potentially using contrast-enhanced ultrasound in some studies if it could provide the same diagnostic information and it can do it in real time.”

While many physicians are optimistic that more FDA approvals for noncardiology contrast-enhanced ultrasound studies are near, more studies and more technological advances could change the arguments.

Maybe Not
Rieves believes additional advances could even eliminate the need for contrast agents altogether. “Ultrasound devices are becoming so much more sophisticated,” he says, “that there are some who have the opinion that the use of the contrast agents may not be necessary. The technology has improved so much that the added benefit of a contrast agent may be minimal. It’s not solely the drug, but it’s the image and, if you can get an acceptable image without the drug, then one has to question the need for the drug. Of course, that’s not unique to ultrasound. That’s true for CT and MRI as well.”

— Beth W. Orenstein is a freelance medical writer and a regular contributor to Radiology Today. She writes from her home in Northampton, Pa.