Contrast echo demonstrates nuclear perfusion-level accuracy
Contrast-enhanced echocardiography (echo) imaging was well-tolerated and has similar diagnostic performance compared to nuclear perfusion in chest pain patients being evaluated for inducible ischemia. The results of a multi-center Phase III trial utilizing perflubutane polymer microspheres (PPM), developed by Accusphere and marketed as Imagify, were presented by Roxy Senior, MD, from the department of cardiovascular medicine at Northwick Park Hospital in Middlesex, U.K., at the American Heart Association’s Scientific Sessions held this week in Orlando, Fla. 

The Real-time Assessment of Myocardial Perfusion Imaging (RAMP)-1 and RAMP-2 were Phase 3 trials conducted to determine if Imagify, a synthetic biodegradable ultrasound contrast agent, can assess myocardial perfusion and detect coronary disease in patients being evaluated for inducible ischemia. The trials took place in 28 international sites.

As Senior explained to Cardiovascular Business News, Imagify is a microparticle, as opposed to other contrast agents, which are microbubbles. During his presentation, Senior said that one of the aims of the trial was to assess the safety and efficacy of using the contrast agent.

For the RAMP-1 and RAMP-2 trials, 662 angina patients with a median age of 62 underwent PPM echo imaging as well as 99mTc quantitative myocardial perfusion imaging at rest and dipyridamole stress testing at rest. Images were interpreted for presence of defects in wall motion and/or perfusion by independent blinded readers. Disease was defined by quantitative coronary angiography with more than 70 percent stenosis rate, or a 90-day outcome with clinical history and nuclear assessment. The primary efficacy endpoints—accuracy followed by sensitivity and specificity—were evaluated using non-inferiority and superiority analysis comparing the echo results to nuclear imaging results.

RAMP-1 consisted of 285 patients, 44 percent that were disease positive, and RAMP-2 consisted of 377 patients, 58 percent of which were disease positive. Compared to nuclear, 6, 4 and 3 of 6 echo readers were non-inferior for accuracy, sensitivity and specificity, respectively. Moreover, 2 and 3 echo readers also demonstrated superiority for specificity and sensitivity, respectively. The majority of side effects, such as headache, chest pain or discomfort, nausea and flushing, occurred following dipyridamole dosing, and were mild and transient. Senior said that only one patient experienced hypersensivity to Imagify and the effect was minor.

Senior and his colleagues concluded that results from the nuclear testing and the contrast echo were similar, and produced very few side effects. In addition, the patients were not subjected to radiation.

After his presentation, told Cardiovascular Business News that cardiologists want to use echo contrast perfusion imaging testing and yet regulatory issues prohibit them. If they were to use this form of testing, it is considered by the FDA to be an off-label usage, and therefore the cardiologists would not receive reimbursements. Yet, during his presentation, Senior encouraged his audience to use it, because the equipment is available to most cardiologists and the results are promising.

Senior also said that he doesn’t expect Imagify to receive the same FDA black-box warning as current contrast agents on the market because it is not an iodine or heavy-metal based compound. Senior said the FDA would have to look at Imagify as a completely different category. 

According to an Accusphere spokeswoman, the firm is currently preparing a New Drug Application (NDA) for the FDA, and intends to submit the NDA by early 2008. Initially, the Watertown, Mass.-based company had planned to submit by the conclusion of this year, but the spokeswoman said the developer wanted to ensure the application is completed properly.

Accusphere was the sole sponsor of the RAMP-1 and RAMP-2 trial.

Bristol Myers-Squibb and Astellas Healthcare funded the study.

Images were taken of the two patient groups prior to and after they underwent treatment for coronary artery disease. One group received optimal medical therapy (OMT) along with angioplasty, and the other group received OMT alone.

“Our outcomes in this sub-study don’t change the main COURAGE trial results,” according to Leslee Shaw, PhD, principal investigator of the nuclear sub-study and a professor of medicine at Emory University in Atlanta.

The researchers found no differences in rates of death, heart attack, stroke or hospitalization for acute coronary disease between the patients who underwent PCI and those who only received OMT.

Shaw said the study clarifies “care for a certain subset of stable chest pain patients who have stress-induced ischemia prior to treatment. This group of patients benefited from PCI and had a greater reduction in ischemia by one year. The main effect this could have on clinical practice is that patients with ischemia may be more referred to PCI for ischemia resolution.”

Overall, the groups were similar, including the anginal class, level of ischemia and the number of patients who had multiple diseased vessels.

In follow-up imaging, treatment reduced ischemia by 2.7 percent in patients who received PCI with OMT; OMT-only patients only had a 0.5 percent reduction. The SPECT images showed that patients had a significant heart muscle recovery (more than 5 percent); 33 percent of patients with PCI and OMT showed a reduction in ischemia of 5 percent or more, compared with 19 percent of OMT-only patients. With patients who had reduced ischemia, nearly 80 patients of both groups were angina free. However, in patients who began the study with high-risk ischemia (those with more than 10 percent of their heart muscle compromised), treatment with PCI and OMT were more commonly effective in reducing ischemia than OMT alone.

Shaw said that “statin therapy was similar therapy between the two groups.”

The researchers concluded that “PCI added to OMT resulted in greater reduction in ischemia when compared to OMT alone.” In fact, Shaw noted a 5 percent reduction in ischemic assessment, confirming the value of using MPS.

In response to a question about the current political trend against reimbursements, Shaw said that “approximately half of the sites in the study use imaging as part of their treatment. Some form of ischemic assessment was performed in each of the centers and that is hard to reverse.”