PROSPECT Published: Combined IVUS Identifies Risky Nonculprit ACS Lesions

In patients with acute coronary syndromes (ACS) who undergo percutaneous coronary intervention (PCI), both culprit and nonculprit lesions are equally likely to spur subsequent adverse events over 3 years, according to a paper published in the January 20, 2011, issue of the New England Journal of Medicine. While nonculprit lesions responsible for such unanticipated events were generally mild on angiography, they often possessed distinctive characteristics on intravascular ultrasound (IVUS) indicative of vulnerable plaque.

Results from the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial, which sought to prospectively assess the natural history of coronary atherosclerosis, were previously presented in September 2009 at the annual Transcatheter Cardiovascular Therapeutics symposium in San Francisco, CA.

For the study, researchers led by Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), looked at 697 ACS patients who had undergone successful and uncomplicated PCI at 37 sites in the United States and Europe. All subjects were assessed after PCI with angiography as well as both gray-scale and radiofrequency IVUS in the left main coronary artery and the proximal 6 to 8 cm of each of the major epicardial coronary arteries. The median follow-up was 3.4 years. Subsequent MACE events (death from cardiac causes, cardiac arrest, MI, or rehospitalization due to unstable or progressive angina) were categorized according to whether they arose from culprit or nonculprit lesions.

Nonculprit Lesions Not Scot-Free

Kaplan-Meier estimates at 3 years found a cumulative MACE rate of 20.4% overall. Yet the distribution was nearly equal between events attributed to culprit and nonculprit lesions, with some being of indeterminate origin. Rehospitalizations for unstable or progressive angina were the most common complications, whereas cardiovascular events were relatively rare during follow-up (table 1).

Table 1. Kaplan-Meier Estimates of 3-Year Event Rates

At baseline, 30.2% of the 106 nonculprit lesions subsequently responsible for MACE were angiographically inconspicuous, with less than 30% stenosis on visual assessment. Quantitative angiography found that 28.3% of these lesions were between 50% and 70% stenotic, while only 4.7% were at least 70% stenotic. IVUS, meanwhile, found a baseline plaque burden of at least 40% in all of the 55 nonculprit lesions that were imaged with the technology.

On multivariate analysis, several characteristics were independently associated with higher risk of nonculprit lesion-related MACE. On a patient level, diabetes status was most influential. In terms of individual lesion characteristics, the main predictors were large plaque burden, thin-cap fibroatheroma, and small minimal luminal area (MLA), all of which were derived from IVUS assessment (table 2).

Table 2. Predictors of MACE Arising from Nonculprit Lesions

Among the 10.1% of subjects with lesions that both were thin-cap fibroatheromas and exhibited high plaque burden, the 3.4-year MACE rate was 16.4%. Patients with these 2 high-risk traits plus small MLA made up only 4.2% of the cohort and experienced a long-term MACE rate of 18.2%. In contrast, patients whose lesions lacked these factors showed MACE rates of 1.7% and 1.9%, respectively (P < 0.001 for both comparisons).

The investigators caution that “[a]lthough the in vivo detection of potentially vulnerable plaque is of considerable mechanistic interest, there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention.”

For one, the multimodal imaging procedure itself was not risk-free. Eleven patients (1.6%) experienced complications—10 dissections and 1 perforation—that resulted in 3 nonfatal MIs (0.4%). Other limitations include lack of ability to predict events with a high level of specificity and the fact that the IVUS catheters used in the study cannot evaluate the distal portions of coronary arteries. “Finally, it is unclear what therapeutic approaches might be effective in mitigating the risk associated with specific lesion features,” they write.

Clinical Use Limited

In a telephone interview with TCTMD, Dr. Stone stressed, “The main purpose of PROSPECT was not really to find a clinical application but instead to find out more about atherosclerosis. And that I think we’ve done.”

The study demonstrates that ACS patients with successful PCI have “an overall very good prognosis,” with low death and MI rates but a fair number of rehospitalizations for unstable and progressive angina, he added. Culprit and nonculprit lesions each carry about half the blame. Moreover, “PROSPECT is the first study to have shown how we can predict which of those nonculprit lesions, areas of so-called mild atherosclerosis, cause future events. They’re not really mild lesions but are actually pretty advanced,” he said. “We just can’t tell that from the angiogram.”

“Now, we just have to figure out what to do about it,” Dr. Stone said, acknowledging the many reasons why the imaging protocol was unlikely to debut in clinical practice anytime soon. “Most importantly, we don’t have any randomized data right now to say that if we find one of these blockages that we should go ahead and treat it with either stents or any other sort of focal or regional therapy. We’re thinking of planning such trials, but we’re not there yet.”

Dr. Stone proposed considering a dual strategy for treating atherosclerosis. “We’ve learned unrelated to PROSPECT that in the short term, the regions that produce ischemia are the ones that need to be treated,” he said. “PROSPECT is taking a longer-term picture. It suggests that bulky plaques that are fibroatheromas, especially thin-capped fibroatheromas, are the ones that are going to cause events from 1 to 3 years out. So it may be that treating the combination of those 2 types of lesions is going to get better results than just treating either of them alone.”

Taking the First Step

John A. Ambrose, MD, of the University of California, Fresno (Fresno, CA), agreed that the imaging approach in and of itself is “not ready for prime time” in everyday practice. But based on the disparity between angiographic and IVUS results in this study, PROSPECT could inspire more use of fractional flow reserve to guide treatment of nonculprit lesions that are angiographically moderate, he predicted.

Dr. Ambrose told TCTMD in a telephone interview the trial offers valuable lessons. “Doing a careful natural history study is very important,” he noted, as is the observation of “very low event rates” in the context of modern medical therapy. “The fact that a lot of the events are probably related to plaques that were actually significant and were left behind also is interesting. And from a very personal standpoint, [I’m pleased to see] it verifies the work we did 25 years ago showing that acute lesions [can] come from mild angiographic plaques. . . . It’s just that the angiogram underestimates disease.”

Another twist, said Renu Virmani, MD, of CVPath Institute (Gaithersburg, MD), is that only a minority of thin-cap fibroatheromas lead to adverse events.

There is no doubt that minimally narrowed segments of lesions with these characteristics can have sequelae, she told TCTMD in an e-mail communication, but these events occur at a rate below 5% within 3 years. “But this is not surprising when our understanding of all the factors that contribute to plaque rupture are at a nascent stage,” she said, explaining that current understanding of thin-cap fibroatheromas only takes into account morphologic characteristics that match those of rupture, and not the extent of narrowing across nearby sites. “The PROSPECT study now makes it clear that morphologic characteristics of [thin-cap fibroatheromas] alone are not sensitive enough to predict acute coronary syndromes. Instead, we need to add plaque burden, minimal lumen area, and extent of narrowing to the equation in order to increase the predictive capability.

“I am sure, with more precise invasive and non-invasive tools for the identification of non-ruptured vulnerable plaques, we will be able to with greater accuracy predict the ones likely to rupture within a reasonably short time,” she continued. “However, more such clinical trials are needed with more accurate tools.”

Dr. Ambrose also predicted that PROSPECT will inspire additional studies. He reported that some researchers are looking into the possibility of a dedicated self-expanding stent for vulnerable plaque. “To me, PROSPECT was stage one, because you had to identify the natural history,” he said. “Then the second stage is trying to figure out whether or not an interventional therapy is better than just treating with aggressive medical therapy.

“A lot of people who are conservative are going to look at this and say well, the interventionalists missed the lesions initially and the medical therapy did very well. That’s one way of looking at it,” Dr. Ambrose continued. “It depends on what your emphasis is.”

Note: Dr. Stone is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

---

Source:
Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2010;364:226-235.

 

 

Related Stories:

• PROSPECT Assesses Impact of Non-Culprit Lesions
• FFR Evaluation of Nonculprit Lesions Can Help Guide AMI Management
• Non-culprit Artery Intervention Sharply Raises Mortality Risk in STEMI Patients