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October 11, 2010

Contrasting Approach
By Beth W. Orenstein
For The Record
Vol. 22 No. 18 P. 24

The first FDA-approved blood-pool MR agent offers additional time for imaging and possibly some new applications.

Though an estimated 8 million to 12 million people in the United States have been diagnosed with peripheral vascular disease (PVD), the number of people affected by this condition that causes narrowing of the blood vessels outside the heart and brain is expected to increase as the population ages and grows heavier. PVD can cause pain, infection, strokes, and embolisms and result in the loss of limbs.

The gold standard for diagnosing PVD is angiography, most commonly x-ray angiography. More recently CT angiography (CTA) and MRI are being used. The issue with using x-ray angiography to diagnose PVD is that it is a time-consuming, expensive, and uncomfortable procedure in which a catheter must be inserted into a patient’s arteries through the groin area or arm. “That’s why in the clinical community, x-ray angiography has been largely replaced with CT or MRI as a diagnostic tool,” explains Mark G. Hibberd, MD, PhD, senior medical director of global medical affairs for Lantheus Medical Imaging, Inc.

But there are also issues with CTA, according to Hibberd. One problem is that it requires substantial doses of ionizing radiation, and the medical community’s and the public’s concerns about the safety of CT doses and associated cancer risks have been intensifying. Secondly, when calcium deposits cause the narrowing in the arteries, the CT images, especially in diabetic patients, can be ambiguous, making a diagnosis more difficult.
MR angiography (MRA) offers an alternative without the ionizing radiation. And now, Hibberd says, with Lantheus’ injectable blood-pool contrast agent called ABLAVAR (gadofosveset trisodium), radiologists can obtain enhanced images without inserting a catheter into a patient’s arteries.

Because of its unique profile, Hibberd believes MRA using a blood-pool contrast agent could become the gold standard for evaluating patients with aortoiliac occlusive disease, an upstream cause of PVD that occurs when the aorta and iliac arteries become narrowed or blocked. In December 2008, the FDA approved using ABLAVAR for the evaluation of aortoiliac occlusive disease in adults with suspected or known PVD, making it the first MRA contrast agent approved in the United States.

New Possibilities
Radiologists who have seen the compound used in trials and who have used ABLAVAR since it became available recognize its potential to provide high-resolution first-pass and blood-pool images. “I see ABLAVAR potentially opening up whole new applications that are not addressed with existing compounds,” says Martin Prince, MD, PhD, a radiology professor at Weill Medical College of Cornell University and Columbia College of Physicians and Surgeons.

ABLAVAR is different in several ways from all the gadolinium-based contrast agents that have been around for many years. Most importantly, ABLAVAR binds to protein in the blood so it remains in the blood much longer than existing angiography contrast agents. With the other agents, radiologists and technologists have as little as 30 to 90 seconds to obtain images. “Previous agents leak out of the bloodstream rapidly and you can’t image the arteries any longer unless you give a second dose,” Hibberd says. “ABLAVAR stays in the arteries and allows you to image for much longer, up to an hour after a dose.”

Epix developed the product because the other gadolinium agents weren’t really designed for MRA, Hibberd says. “Epix was interested in finding something that would stick within the blood and developed it because of its protein-binding characteristics,” he says. Because the contrast agent doesn’t wash out quickly, more time can be spent acquiring high-quality images. “The high resolution translates into sharper or better-defined images, and that detail can be very useful to physicians,” Hibberd says.

The additional time can also help when dealing with claustrophobic or fidgety patients, allowing imaging staff to take nervous patients out of the magnet, calm them, and then put them back inside and continue without using additional contrast.

Only a small dose of ABLAVAR must be administered because the albumin (blood protein) binding improves the signal, Hibberd says. To date, ABLAVAR has not been associated with nephrogenic systemic fibrosis (NSF), as has been seen in some other gadolinium-based contrast agents. Several years ago, some strong associations were made between the administration of gadolinium-based MR contrast agents and the subsequent development of NSF, which causes fibrosis of the skin and connective tissues throughout the body in patients with end-stage renal disease or acute kidney injury. Since 2007, the FDA has required all manufacturers to include a boxed warning on the label of gadolinium-based MR contrast agents, including ABLAVAR. When marketed as Vasovist, more than 90,000 gadofosveset doses were distributed and no NSF cases have been reported to date, Hibberd says. He notes the company does note promote ABLAVAR for patients with a glomerular filtration rate below 30 mL/min. (ABLAVAR is eliminated mainly by the kidneys and partly by the liver.)

ABLAVAR’s per-use cost is roughly equivalent to that of other gadolinium-based contrast agents, says Rick Williamson, senior director of marketing brand management for Lantheus. He says the same volume of ABLAVAR costs more than other gadolinium agents, but it requires a smaller dose per exam. That difference makes the cost per study more comparable. “The cost per 10 mL of other agents compared with 10 mL of ours, it may appear as though you’re paying a premium,” he explains. “But if you compare the amount you use per patient, it is relatively comparable. When based on patient weight and performing studies to evaluate adults for disease in the aortoiliac region, the cost is comparable.”

Workflow Changes
ABLAVAR is administered in a manner similar to other contrast agents. “There are some minor changes to the way the MR scanners are set, but they’re very easy for the technologist or physician to do. … The true value of ABLAVAR is providing both dynamic and blood-pool–phase images and the ability to reformat high-resolution images, which can delineate the presence or absence of arterial pathology,” Williamson says.

Hibberd notes that using the contrast agent requires a modest change in workflow because the technologist spends a few extra minutes acquiring the blood-pool images.

Jeffrey Maki, MD, PhD, an associate professor of radiology and director of body MRI at the University of Washington School of Medicine and the VA Puget Sound Health Care System in Seattle, has experience with the novel contrast agent dating back to when it was in clinical trials. He has found it to be “viable as a first-pass agent for MRA.” He particularly likes that “it gives you the opportunity to go back and look at the same vascular territory using high-resolution, blood-pool-phase imaging.”

However, Maki says it’s too soon to tell how widely ABLAVAR will be used. “It’s only been in our hands a couple of months, and we need to have interested researchers looking into how we might best use this agent, what niches we can find where it excels,” he says.

It has potential, Maki says, and could become the new paradigm in MRA if two things happen: “First, people have to believe it is at least as good as conventional agents for first-pass angiography and, second, they have to see an added value to having steady-state, blood-pool imaging. Once radiologists see there is added value to their ability to diagnose disease, then I think the agent will be very successful.”

“We used ABLAVAR in many patients with aortoiliac disease and were able to see detailed features of plaques and thrombus,” says Prince, who also believes it may prove useful for other purposes and should be investigated accordingly.

Prince is also excited about the potential for additional approved indications. For example, he says ABLAVAR could prove valuable in MRA of the skin for planning plastic surgery. Plastic surgeons must see detailed features of the arteries underneath the skin to optimally plan how they will harvest it to reconstruct other parts of the body, such as during breast reconstruction after a mastectomy. “It saves them time if they know exactly where the best blood vessel is,” Prince says. “ABLAVAR gives fantastic artery- and vein-to-background-tissue contrast so it [could be] ideal for doing this blood vessel mapping.”

Venous Imaging
It also could prove significant in cases in which physicians need to see a patient’s veins, says Prince, adding that with traditional angiography, it’s hard to image veins because there are so many of them. “With traditional angiography you’re only going to image the vein that the catheter is in. The great thing about ABLAVAR is that it goes to all the veins and not just the one you inject. I think we’re going to have a renaissance in venous imaging because of the ability of this blood-pool contrast agent,” he says.

Some new research suggests that multiple sclerosis is the result of elevated venous pressure in the brain and along the spinal cord. “Our neurologists have been requesting venous imaging,” Prince says. ABLAVAR could prove to be advantageous for detailed venous mapping in the head and neck.

Two other areas where ABLAVAR may prove useful are in imaging the cervix and bowel mucous, Prince says. Gadolinium has not been effective in imaging the perineal area, which has lots of blood vessels. “But ABLAVAR may be useful for cervical carcinoma because the cervix, perineum, and vaginal area have a lot of enhancement so you can get very-high-resolution images and a lot of anatomical detail,” he explains.

Also, Prince says, “We don’t use MR and gadolinium for imaging the bowel very much, but it’s starting to be used. With ABLAVAR, it might be useful in diagnosing and treating patients with Crohn’s disease and other inflammatory bowel conditions. We don’t have data to support it, but it’s a thought.”

— Beth W. Orenstein of Northampton, Pa., is a freelance medical writer.