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About 1 in 7 stented patients with acute coronary syndromes (ACS) develop at least 1 silent plaque rupture in a nonculprit vessel, according to a subanalysis of the PROSPECT study published online March 12, 2014, ahead of print in JACC: Cardiovascular Imaging. While such ruptures are associated with a risky plaque phenotype, they do not increase long-term adverse events if patients receive optimal medical therapy.

In the main study, published in the New England Journal of Medicine in January 2011, after successful stenting, 697 ACS patients underwent grayscale and IVUS-virtual histology in the left main artery and the 3 main epicardial arteries. During a median follow-up of 3.4 years, major adverse events (cardiac death, cardiac arrest, MI, or rehospitalization due to unstable or progressive angina) were equally attributable to recurrence at the site of culprit and nonculprit lesions. Although nonculprit lesions were frequently mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics.

For the current analysis, investigators led by Akiko Maehara, MD, of Columbia University Medical Center (New York, NY), looked at 660 PROSPECT patients with complete IVUS data. IVUS identified 3,229 nonculprit lesions with a plaque burden of at least 40%; of these, 128 plaque ruptures were seen in 105 nonculprit lesions (4%) in 100 arteries from 93 patients (14.1%). Overall, 38% of nonculprit lesions with a plaque rupture were located in the culprit vessel and 62% in nonculprit vessels. There was no difference in lesion morphology between the locations.

Lesion Length, Plaque Burden Implicated in Rupture

Angiographically, patients with at least 1 plaque rupture showed a trend toward longer nonculprit lesions (20.9 mm vs 19.8 mm; P = 0.08). On IVUS, the percent total plaque volume was greater in patients with at least 1 nonculprit rupture than in those without a rupture (51.1% vs 48.9%; P < 0.0001). In addition, patients with at least 1 secondary plaque rupture were more likely to have at least 1 nonculprit lesion with a plaque burden ≥ 70% (50.5% vs 30.5%; P = 0.0001).

Grayscale IVUS analysis likewise showed that nonculprit lesions with a plaque rupture were almost twice as long as those without a rupture. Ruptured lesions also had a greater percent plaque volume, plaque burden at the minimal lumen area (MLA) site, and area stenosis (table 1).

Table 1. IVUS Grayscale Findings for Nonculprit Lesions^a

^a P < 0.0001 for all.

IVUS-VH revealed that nonculprit lesions with a plaque rupture were more often classified as fibroatheromas than were nonculprit lesions without plaque rupture (77.1% vs 51.4%; P < 0.0001). When subdivided by type, nonculprit lesions were more often classified as thin-cap fibroatheroma (38.1% vs 21.7%; P < 0.0001). Moreover, nonculprit fibroatheromas were more likely to contain multiple necrotic cores regardless of whether they were classified as a VH thin-cap or thick-cap fibroatheroma (32.4% vs 15.3%; P < 0.0001 and 36.2% vs 24.6%; P = 0.005, respectively). However, pathological intimal thickening was more common in lesions without a plaque rupture (36.8% vs 19.0%; P = 0.0004).

Independent predictors of plaque rupture were:

• Lesion length, per 10 mm (OR 1.30; P < 0.0001)
• Plaque burden at the MLA site, per 10% (OR 2.56; P < 0.0001)
• Vessel area at the MLA site, per 1 mm² (OR 1.13; P < 0.0001)
• VH thin-cap fibroatheroma (OR 1.80; P = 0.016)

No Difference in MACE

There were no differences in cardiac medications, including statins and dual antiplatelet therapy, between patients with or without a subclinical secondary plaque rupture either at discharge or during 3-year follow-up. Overall, 6 patients developed an MI and 68 were rehospitalized due to unstable or progressive angina. The incidence of MACE was similar between groups, although there was a trend toward more nonculprit MACE in lesions with a plaque rupture than in those without rupture (4.0% vs 1.8%; P = 0.09), driven by a trend toward more rehospitalizations (4.0% vs 1.7%; P = 0.07).

The authors acknowledge a number of limitations, including the likelihood that not all plaque ruptures were detected by IVUS because the thickness of the thin fibrous cap is below the resolution of grayscale IVUS. Therefore, some ruptures may have been obscured by thrombus, they explain.

Nonetheless, Dr. Maehara and colleagues say, “the current study extends the findings of other studies to indicate that patients with ACS who have secondary plaque ruptures have additional lesions with high-risk morphologies, albeit without frank plaque rupture, supporting the hypothesis that this may represent a multifocal phenomenon.”

According to the authors, in other studies plaque ruptures caused symptoms mainly in the setting of thrombus and lumen compromise. In contrast, in statin-treated patients with nonstenotic lesions, ruptures tended to heal, they add.

Systemic Disease Deserves Aggressive Treatment

The study “helps us understand the natural history of atherosclerosis. In particular that other lesions do rupture, and that they do not always result in clinical events,” Stephen J. Nicholls, MD, PhD, of the University of Adelaide (Adelaide, Australia), commented in an email with TCTMD. Moreover, the finding that both plaque burden and compositional features are important confirms prior research, he said, adding, “How much disease you have remains a very consistent and important predictor of clinical events.”

The bottom line is that “atherosclerosis is a systemic disease, and the study results reinforce the need for aggressive systemic treatment of these patients,” Dr. Nicholls concluded, even though “ultimately we don’t know which of these plaques that rupture will actually lead to clinical events.” 

Study Details 

Compared with patients without a plaque rupture, those with a rupture were more likely to be male, have a history of cardiac intervention, a higher BMI, and a worse lipid profile. Other risk factors and clinical presentation did not differ between groups.

Note: Dr. Maehara and several coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

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