PROSPECT: Vulnerable Lesions Lead to Unstable Angina Rather Than MI or Death

September 25, 2009

September 25, 2009 (San Francisco, California) — A natural-history study using multimodality imaging of the entire coronary tree has shown that approximately 20% of patients with acute coronary syndromes treated with stents and optimal medical therapy develop major adverse cardiac events (MACE) within three years, but 12% of these patients develop events from nonculprit lesions.

Importantly, those patients who do develop events from nonculprit lesions typically present with unstable angina or progressive angina, rather than with more serious clinical events, such as cardiac death, cardiac arrest, or MI.

Presenting the results of the study, known as the PROSPECT trial, during the late-breaking clinical-trials session here at the TCT 2009 meeting, lead investigator Dr Gregg Stone (Columbia University, New York) said the results are good news for patients with effective revascularization and optimal medical care. Importantly, they also validate the vulnerable-plaque hypothesis, as the study also showed that nonculprit lesions with high plaque burden and a thin-cap fibroatheroma are more likely to cause future events.

"As you know, we're pretty good in the cath lab in treating lesions in patients who present with symptomatic coronary disease," said Stone. "What we're not good at is predicting who is going to have sudden death, who is going to have myocardial infarction, or who is going to have unexpected adverse cardiovascular events."


In the PROSPECT study, investigators enrolled 700 patients with acute coronary syndromes who underwent successful PCI of one or two major coronary arteries. Once enrolled, patients underwent three-vessel imaging of the culprit artery, as well as nonculprit arteries, with angiography, intravascular ultrasound (IVUS), and virtual histology, as well as palpography in approximately 350 patients. All patients were treated with optimal medical therapy, including aspirin, clopidogrel for one year, and statin therapy, and underwent follow-up at one month, six months, one year, and out to three to five years.

Reporting the three-year results, Stone said the overall MACE rate, a composite end point that included cardiac death, cardiac arrest, MI, unstable angina requiring hospitalization, and progressive angina, occurred in 20.4% of all patients who were successfully stented. Of these patients, an adverse event occurred in 12.9% of the culprit lesions and 11.6% of nonculprit lesions. As noted, patients with clinical events in the nonculprit lesions typically presented with less severe cardiac events. Stone added that half of the lesions progressed rapidly to a clinical event, whereas half represented severe disease that was left behind and that wasn't clear on the angiogram.

PROSPECT: Three-Year Follow-Up

End point All lesions (%) Culprit lesions (%) Nonculprit lesions (%) Indeterminate (%)
Composite MACE 20.4 12.9 11.6 2.7
Cardiac death 1.9 0.2 0 1.8
Cardiac arrest 0.5 0.3 0 0.2
MI, STEMI or NSTEMI 3.3 2.0 1.0 0.3
Unstable angina 8.0 4.5 3.3 0.5
Increasing angina 14.5 9.2 8.5 0.3

In examining the imaging data from nonculprit lesions, Stone said they identified three characteristics that were associated with future events: thin-cap fibroatheroma, plaque burden >70%, and a minimum lumen area <4mm2. Individually, all three markers in nonculprit lesions were associated with significantly increased risks of cardiovascular events, and this risk was increased when the markers were combined.

"If you have a thin-cap fibroatheroma and a lot of plaque burden, then over a three-year period, 15% of those lesions would cause a problem for that lesion site," said Stone during a press conference announcing the results. "Now, those types of lesions are only present in about 11% of patients, so they're not very common, but if you see them, they are a high-risk lesion, and not something you would suspect angiographically."

Speaking with heartwire , Dr David Kong (Duke University, Durham, NC), who was not part of the PROSPECT trial, said the lack of mortality with the nonculprit lesions is reassuring, at least in the short term, and suggests that not every patient needs to be imaged, he said.

"As much as we like to think of treating vulnerable plaques as preventing future myocardial infarction or future events, it looks like whatever events they are, they are nonfatal events," said Kong. "This might help us determine what the patient's eventual treatment strategy is going to be. One of the frustrating things about the vulnerable-plaque hypothesis has been: If we find it, what do we do about it? Now, we're probably thinking about stratifying them on optimal medical therapy, and we might be able to identify them based on clinical characteristics, rather than imaging characteristics."

Asked about the implications of the findings, especially the larger question about whether or not clinicians should be invasively imaging these arteries to identify vulnerable plaques that lead to clinical events, Stone said the researchers are still digesting the data and what they mean for clinical practice.

"It's a complex question, and we're still considering the implications of it," said Stone. "The event rates are low enough and not severe enough that I don't personally believe it justifies routine three-vessel invasive screening. That could have been one of the conclusions if the event rates were higher, but it isn't. The real question arises is, what happens when you're in there and you happen to see a lesion that has a 15% event rate over the next three years?"

Commenting on the results of the study, Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) said the findings validate the vulnerable-plaque hypothesis, although clinicians and researchers still need to sort out ways to identify these lesions noninvasively. Dr Ron Waksman (Washington Hospital Center, Washington, DC) agreed that it is simply not practical to go looking for vulnerable plaque, but like Stone, wondered what physicians should do if they happen to see markers like thin-cap fibroatheroma, increased plaque, and a smaller lumen area on the IVUS.

Stone is on the advisory boards of Abbott and Boston Scientific. Cannon reports consulting for Intekrin Therapeutics, Novartis, Takeda, Accumetrics, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough. Waksman and Kong report no conflicts of interest.


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