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For other articles and previous issues click here. March 21, 2005 First
Step An approved contrast agent is a key step in exploring the potential of magnetic resonance angiography. It’s no secret that a contrast agent can help radiologists see things more clearly. But in the case of magnetic resonance angiography (MRA), an FDA-approved contrast agent is needed to visualize whether MRA will evolve into a widely used noninvasive way to image vascular disease. That’s more or less the story behind MS-325 (gadofosveset trisodium). According to E. Kent Yucel, MD, MS-325 is the first compound specifically developed for approval as an MRA contrast agent. Yucel, director of radiology at the VA Boston Healthcare System, has been involved in all phases of the clinical trials of MS-325. He is also a consultant to the companies developing MS-325. Less Invasive, Less Dose A joint venture between Schering AG and Epix Medical, MS-325 received an “approvable” letter from the FDA this past January. The agency’s version of the we-have-good-news-and-bad-news letter requested additional data about the noncontrast MRA scans used as a baseline comparison. Various published reports—including Schering releases—indicated that the FDA expressed concerns that there was insufficient standardization in how the noncontrast scans were obtained for the study, which in turn makes it difficult to compare their results to the contrast-enhanced MRA results. A Schering release also noted that a second FDA issue was the high number of uninterpretable scans in the noncontrast arm of the study. Because those uninterpretable results could not be read and were excluded from the study, the FDA questioned whether that action might inflate the benefit of MS-325. Radiologists have been investigating MRA over the years, but Yucel noted that the absence of an FDA-approved contrast slows research to explore MRA possibilities. MRA without contrast has been used in a range of protocols and provided inconsistent results—perhaps a reason why it’s been difficult to establish a noncontrast baseline. In an interview at RSNA 2004 in Chicago, Yucel described the common conundrum of the approval process. Researchers and companies spend years designing and testing a specific drug or device under a specific protocol for a specific approval—in this case, MS-325. Meanwhile, time and technology march forward. Only upon approval can the agent be widely used, allowing researchers to investigate its possibilities in light of developments during the product’s investigational phase. “You design these trials in 1997 and then come up with a trial plan,” Yucel explained. “Then you’re more or less committed to following that plan even though technology you submit to the FDA is evolving. It’s always a challenge figuring out how to use the actual knowledge gained from the trial as the technology evolves. The longer that window is, the more problematic that becomes. That’s why we’re hoping to get approval quickly so that we’ll be able to get it out there. Then the postapproval studies will begin and doctors will fine-tune how to use it.” Longer Imaging Window “Some radiologists are using agents for off-label uses,” Yucel said of the reasonably common practice throughout medicine. “There are a lot of people doing things. The difference is that this agent is the first to have a trial designed for approval. When you have an approved agent, a lot more people will accept and use it.” In addition to previously stated advantages of developing a noninvasive procedure without the radiation exposure of x-ray techniques, increasing the time in which images can be obtained may prove another strength of contrast-enhanced MRA. Yucel explained that MS-325 binds to albumin in the blood and thus stays in the bloodstream longer instead of diffusing quickly. So instead of injecting a bolus of contrast into an artery and catching the image before it diffuses, technologists would have a longer time window to acquire images—perhaps up to an hour. “You can obtain images from some regions of the body—such as the iliac and the feet—for much longer periods of time than currently available agents would allow you to scan,” Yucel said. “You may have minutes as opposed to seconds when chasing the bolus. With MR and the ability to scan for minutes, you can translate that extra time to better image quality, better image resolution, or both.” Yucel noted that this longer image window poses a potential problem: Images picked up from contrast in arteries may be obscured by images from contrast in the veins. One solution, he noted, is developing workstation imaging tools to separate arteries from veins digitally. “What’s really exciting about this whole area is how much progress has been made in tools to make the arteries stand out from the veins so that you can get a picture of just the arteries or just the veins, even in the blood pool phase,” Yucel said. “That’s really the next exciting area in equipment development where the agent [MS-325] really has a chance to change the way things are done. That trial program still needs to be developed. They need to develop equipment to suppress the information you don’t need so the information you do need stands out.” Of course, approval also expands reimbursement, which increases use among physicians. Beating the Standard Yucel quickly added that even catheter angiography is not an especially impressive standard. “As it turns out, one thing we learned in phase 2 is that x-ray angiography is a problematic standard,” Yucel said. “We learned that by looking at x-ray angio and having different readers look at the same film, we found how often they agreed…” Or didn’t agree, as too often happens. “…If you have a standard where reader A and reader B agree only 85% of the time and you have a test that’s as good as x-ray, those readers are only going to agree 85% of the time,” he added. “The real gold standard of these tests is interreader agreement. That’s the target. Using that standard, the results were the same with the agent as with x-ray.” Improving angiography accuracy is another area where contrast-enhanced MRA might someday improve on current techniques. Drawbacks, Too CT angiography (CTA) is another angiography option that in some ways falls between catheter angiography and MRA. The newly approved 64-slice CT units (as well as 32- and 40-slice models) are being widely investigated as alternatives to cardiac catheterization. Because no catheter is used, CTA offers a less invasive and more patient-friendly procedure. In CTA, contrast is injected into a vein—considered a technically less difficult procedure with a lower risk of complications than arterial injections. Patients typically leave the facility and resume normal activities immediately following a CTA procedure. And CT exams clearly show calcium deposits. On the downside, CT contrast agents are iodine-based (like x-ray angiography agents) and the patient is also exposed to ionizing radiation during CTA. While an approved contrast agent won’t automatically push MRA to the forefront, Yucel and other radiologists hope it will expand the opportunities to find out whether MRA merits pushing to the front line of angiography techniques. On their own, contrast agents won’t answer the questions about MRA’s future, but they might be the tool that makes learning those answers possible. — Jim Knaub is editor of Radiology Today. |
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